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

• US 9,066,881 B2
• Filed: 03/12/2013
• Issued: 06/30/2015
• 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:
  US13/797,657
• Publication Number:
  US 20130189365A1
• Time in Patent Office: 840 Days
• Field of Search: 424/130.1, 424/491, 530/387.1, 530/387.3, 530/389.1, 530/389.2
• US Class Current: 1/1
• 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 of promoting binding of an active agent to a preformed crystalline diketopiperazine microparticle in suspension comprising:

modifying the chemical potential of the active agent in the suspension by modifying the structure, flexibility, rigidity, solubility or stability of the active agent to allow for an energetically favorable interaction between the active agent and the preformed crystalline diketopiperazine microparticle independent of removal of solvent;

wherein said modifying step causes adsorption of said active agent onto a surface of said preformed crystalline diketopiperazine microparticle to provide a coating of said active agent on said preformed crystalline diketopiperazine microparticle, said preformed crystalline diketopiperazine microparticle does not comprise an active agent, and said active agent comprises an antibody or fragment thereof.

2. The method of claim 1 wherein the antibody or fragment thereof is humanized or chimeric.

3. The method of claim 1 wherein the antibody or fragment thereof comprises F(ab), F(ab)2, or a single-chain antibody.

4. The method of claim 3 wherein the antibody or fragment thereof is fused to a polypeptide.

5. The method of claim 1 wherein the antibody or fragment thereof can recognize a disease-associated antigen.

6. The method of claim 5 wherein the disease-associated antigen is a tumor-associated antigen or an infectious pathogen-related antigen.

7. The method of claim 5 wherein the disease-associated antigen is one of cancer antigens, cytokines, infectious agents, inflammatory mediators, hormones, and cell surface antigens.

8. The method of claim 7 wherein the antibody or fragment thereof is one of anti-SSX-2_41-49 (synovial sarcoma, X breakpoint 2), anti-NY-ESO-1 (esophageal tumor associated antigen), anti-PRAME (preferentially expressed antigen of melanoma), anti-PSMA (prostate-specific membrane antigen), anti-Melan-A (melanoma tumor associated antigen), anti-tyrosinase (melanoma tumor associated antigen), and anti-MOPC-21 (myeloma plasma-cell protein).

9. The method of claim 1 wherein modifying the chemical potential of the active agent comprises altering solution conditions by adding an active agent modifier to the solution wherein said active agent modifier is selected from the group consisting of sodium chloride, hexylene-glycol (Hex-Gly), trehalose, glycine, polyethylene glycol, trimethylamine N-oxide, mannitol, proline, methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, NaSCN, (CH₃)₃N—

HCl, Na₂NO₃, NaClO₄, cesium chloride, sodium citrate, sodium sulfate, and water.

10. The method of claim 9 wherein said active agent modifier is sodium chloride.

11. The method of claim 1 wherein said modifying the chemical potential of the active agent step comprises dissolving the active agent in a fluid phase of the suspension of preformed crystalline diketopiperazine microparticles and changing the pH of the fluid phase.

12. The method of claim 9 wherein the active agent modifier improves the structural stability of the active agent.

13. The method of claim 1 wherein the diketopiperazine is fumaryl diketopiperazine.

14. The method of claim 1 further comprising a step for removing the solvent after the adsorption has occurred.