Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents

• US 9,717,689 B2
• Filed: 02/05/2016
• Issued: 08/01/2017
• Est. Priority Date: 09/14/2005
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Sulner, Joseph, Oberg, Keith A., Grant, Marshall L.
• Primary Examiner(s): Ha, Julie
• Application Number:
  US15/017,153
• Publication Number:
  US 20160151287A1
• Time in Patent Office: 543 Days
• Field of Search: 514 59, 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 coating crystalline microparticles with an active agent by altering the surface properties of the microparticles in order to facilitate favorable association on the microparticle by the active agent. Types of surface properties that are altered by the disclosed methods include electrostatic properties, hydrophobic properties, and hydrogen bonding properties.

Claims

1. A microparticle comprising a fumaryl diketopiperazine (FDKP) core and an active agent coating;

wherein at least a portion of the active agent is bound to a surface of the FDKP core, and wherein the surface of the FDKP core to which the active agent is bound contains a plurality of carboxylic acid groups, part of which are ionized;

wherein the plurality of carboxylic acid groups are ionized in an amount that is equivalent to the amount of ionized carboxylic acid groups that would be present on the surface if the FDKP core were dispersed in an aqueous solution having a pH of about 4 to about 5.

2. The microparticle of claim 1, wherein the plurality of carboxylic acid groups are ionized in an amount that is equivalent to the amount of ionized carboxylic acid groups that would be present on the surface if the FDKP core were dispersed in an aqueous solution having a pH of about 4.4 to about 5.

3. The microparticle of claim 1, comprising about 9% to about 12% active agent by weight.

4. The microparticle of claim 1, wherein the core microparticle further comprises polysorbate 80.

5. The microparticle of claim 1, comprising at least 0.7% polysorbate 80 by weight.

6. The microparticle of claim 5, comprising between 0.7% and 3.5% polysorbate 80 by weight.

7. The microparticle of claim 1, wherein the active agent coating is predominantly a monolayer.

8. The microparticle of claim 1, wherein at least a portion of the active agent is electrostatically bound to the FDKP core.

9. The microparticle of claim 8, wherein a majority of the active agent coating is bound to the FDKP core.

10. The microparticle of claim 9, wherein the active agent coating is bound so that a majority of the active agent coating will remain on the surface of the FDKP core when the microparticle is dispersed in water.

11. The microparticle of claim 1, wherein the active agent coating is about 11.4% of the total weight of microparticle.

12. The microparticle of claim 1,

wherein the pharmaceutical microparticle is prepared by a process comprising providing a dispersion of preformed FDKP microparticles in an aqueous solution comprising an active agent, the solution having a pH of about 4.2 to about 5 to adjust the surface charge density of the preformed FDKP microparticles.

13. The microparticle of claim 12, comprising about 10% to about 12% active agent by weight.

14. The microparticle of claim 12, wherein the FDKP core further comprises polysorbate 80.

15. The microparticle of claim 1, wherein the active agent comprises at least one of a peptide, polypeptide, or a protein.

16. The microparticle of claim 1, wherein the active agent comprises at least one of insulin, parathyroid hormone, growth hormone, ghrelin, GLP-1, anti-SSZ2_41-49 monoclonal antibody, or anti-MOPC-21 monoclonal antibody.

17. The microparticle of claim 1, wherein the active agent comprises at least one of insulin, an insulin analog, growth hormone, parathyroid hormone, ghrelin, granulocyte macrophage colony stimulating factor (GM-CSF), glucagon-like peptide 1 (GLP-1), Texas Red, alkynes, cyclosporins, clopiogrel and PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone), or antibodies and fragments thereof.

18. The microparticle of claim 17, wherein the antibodies or fragments thereof include humanized or chimeric antibodies.

19. The microparticle of claim 18, wherein the humanized or chimeric antibodies are selected from F(ab);

F(ab)₂;

single-chain antibody alone or fused to other polypeptides;

therapeutic or diagnostic monoclonal antibodies to cancer antigens, cytokines, infectious agents, inflammatory mediators, hormones, and cell surface antigens.

20. The microparticle of claim 19, wherein the antibodies to tumor antigens are selected from anti-SSX-2_41-49, anti-NY-ESO-1, anti-PRAME, anti-PSMA, anti-Melan-A, anti-tyrosinase, and anti-MOPC-21.