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

• US 8,729,019 B2
• Filed: 07/06/2010
• Issued: 05/20/2014
• Est. Priority Date: 09/14/2005
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Oberg, Keith A., Sulner, Joseph
• Primary Examiner(s): Ha, Julie
• Application Number:
  US12/830,557
• Publication Number:
  US 20100278924A1
• Time in Patent Office: 1,414 Days
• Field of Search: 514/11.3, 514/11.7, 514/11.8, 514/11.9, 514/5.9, 514/6.5, 514/7.2, 514/9.7, 424/400, 424/489, 424/491
• US Class Current: 514/11.8
• 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. Type of surface properties that are altered by the disclosed methods include by electrostatic properties, hydrophobic properties and hydrogen bonding properties.

Claims

1. A microparticle comprising a diketopiperazine and polysorbate 80.

2. The microparticle of claim 1 further comprising an active agent.

3. The microparticle of claim 1 wherein the diketopiperazine is crystalline.

4. The microparticle of claim 3 further comprising an active agent wherein the active agent is adsorbed to a crystalline surface of the diketopiperazine.

5. The microparticle of claim 4 wherein the active agent forms a monolayer on the crystalline surface.

6. The microparticle of claim 5 wherein the monolayer is continuous.

7. The microparticle of claim 4 wherein the adsorption of the active agent is mediated by an electrostatic, polar, ionic, hydrophobic, hydrogen bonding, or van der Waals interaction.

8. The microparticle of claim 1 wherein the diketopiperazine is selected from the group consisting of:

3,6-di(4-aminobutyl)-2,5-diketopiperazine;

3,6-di(succinyl-4-aminobutyl)-2,5-diketopiperazine;

3,6-di(maleyl-4-aminobutyl)-2,5-diketopiperazine;

3,6-di(citraconyl-4-aminobutyl)-2-5-diketopiperazine;

3,6-di(glutaryl-4-aminobutyl)-2,5-diketopiperazine;

3,6-di(malonyl-4-aminobutyl)-2,5-diketopiperazine;

3,6-di(oxalyl-4-aminobutyl)-2,5-diketopiperazine; and

3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine.

9. The microparticle of claim 1 comprising approximately 0.8% w/w polysorbate 80.

10. The microparticle of claim 2 wherein the active agent is selected from the group consisting of insulin or an analog thereof, growth hormone, parathyroid hormone (PTH), ghrelin, granulocyte macrophage colony stimulating factor (GM-CSF), glucagon-like peptide 1 (GLP-1), antibodies and fragments thereof, and cyclosporins.

11. The microparticle of claim 10 wherein the active agent comprises insulin or analog thereof.

12. The microparticle of claim 4 wherein the active agent is selected from the group consisting of insulin or an analog thereof, growth hormone, parathyroid hormone (PTH), ghrelin, granulocyte macrophage colony stimulating factor (GM-CSF), glucagon-like peptide 1 (GLP-1), antibodies and fragments thereof, and cyclosporins.

13. The microparticle of claim 12 wherein the active agent comprises insulin or analog thereof.

14. A method of preparing the diketopiperazine microparticles of claim 1 comprising:

a. obtaining a solution of a diketopiperazine with limited solubility at low pH, b. adding polysorbate 80 to the solution, and c. precipitating diketopiperazine particles comprising polysorbate 80 by a step comprising adding an acid to the solution thereby forming a suspension of microparticles.

15. The method of claim 14 wherein the diketopiperazine is selected from the group consisting of:

3,6-di(succinyl-4-aminobutyl)-2,5-diketopiperazine;

3,6-di(maleyl-4-aminobutyl)-2,5-diketopiperazine;

3,6-di(citraconyl-4-aminobutyl)-2-5-diketopiperazine;

3,6-di(glutaryl-4-aminobutyl)-2,5-diketopiperazine;

3,6-di(malonyl-4-aminobutyl)-2,5-diketopiperazine;

3,6-di(oxalyl-4-aminobutyl)-2,5-diketopiperazine; and

3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine.

16. The method of claim 15 wherein the diketopiperazine is 3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine.

17. The method of claim 14 wherein the precipitation comprises the addition of acetic acid to the solution.

18. The method of claim 14 wherein the method further comprises adding an active agent to the suspension.

19. The method of claim 18 wherein the active agent is selected from the group consisting of insulin or an analog thereof, growth hormone, parathyroid hormone (PTH), ghrelin, granulocyte macrophage colony stimulating factor (GM-CSF), glucagon-like peptide 1 (GLP-1), antibodies and fragments thereof, and cyclosporins.

20. The method of claim 19 wherein the active agent comprises insulin or an analog thereof.

21. The method of claim 18, further comprising altering suspension conditions in said suspension of microparticles to modify an energetic interaction between said active agent and said microparticles wherein said altering suspension conditions is selected from the group consisting of altering the pH of the solvent, adding monovalent or multivalent ions, altering the polarity, and adding hydrogen bond donors or acceptors to modify a surface property of said microparticle wherein said altering step does not include a step of removing said solvent from said suspension;

and

adsorbing said active agent onto a surface of said microparticles to provide a coating of said active agent on said microparticles without removing solvent from said suspension;

wherein said altering step causes said adsorbing of said active agent onto a surface of said microparticles.