Method of Drug Formulation Based on Increasing the Affinity of Active Agents for Crystalline Microparticle Surfaces

• US 20110003004A1
• Filed: 09/16/2010
• Published: 01/06/2011
• Est. Priority Date: 09/14/2005
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Hokenson, Mark, Oberg, Keith A.
• Granted Patent: US 9,089,497 B2
• Time in Patent Office: Days
• US Class Current: 424/491
• 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 the steps in the sequence set forth of:

i) modifying the chemical potential of a protein, polypeptide or peptide active agent wherein said modifying allows for an energetically favorable interaction between the active agent and the preformed crystalline diketopiperazine microparticle independent of removal of solvent;

followed by

ii) allowing adsorption of the active agent onto the surface of the preformed crystalline diketopiperazine microparticle;

wherein said modifying step causes said adsorbing 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 and

wherein said preformed crystalline diketopiperazine microparticle does not comprise an active agent.

2. The method of claim 1 wherein modifying the chemical potential comprises modifying the structure, flexibility, rigidity, solubility or stability of the active agent.

3. The method of claim 2 wherein modifying the chemical potential of the active agent comprises altering solution conditions.

4. The method of claim 3 wherein said altering solution conditions comprise adding an active agent modifier to the solution and 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, and sodium sulfate.

5. The method of claim 4 wherein said active agent modifier is sodium chloride.

6. The method of claim 1 wherein said modifying 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.

7. The method of claim 6 wherein the pH is changed prior to the addition of active agent.

8. The method of claim 6 wherein the pH is changed subsequent to the addition of active agent.

9. The method of claim 4 wherein the active agent modifier improves the structural stability or pharmacodynamics of the active agent.

10. The method of claim 1 wherein the active agent is selected from the group consisting of insulin, ghrelin, growth hormone, and parathyroid hormone (PTH).

11. The method of claim 2 wherein modifying the chemical potential of the active agent comprises modulating one or more energetically favorable interactions with the crystalline diketopiperazine microparticle surface.

12. The method of claim 11 wherein the one or more energetically favorable interactions between the active agent and the crystalline diketopiperazine microparticle comprises an electrostatic interaction.

13. The method of claim 11 wherein the one or more energetically favorable interactions between the active agent and microparticle comprises a hydrophobic interaction.

14. The method of claim 11 wherein the one or more energetically favorable interactions between the active agent and microparticle comprises a hydrogen bonding interaction.

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

16. The method of claim 1 further comprising a step for removing the solvent after the allowing step.

17. A process for preparing a drug delivery composition comprising an active agent and a crystalline diketopiperazine microparticle comprising the steps in the sequence set forth of:

i) providing an active agent solution comprising a protein, polypeptide or peptide active agent molecule and providing a preformed crystalline diketopiperazine microparticle in a suspension or powder;

next

ii) combining said active agent solution with said preformed crystalline diketopiperazine microparticle suspension or powder to form a fluid phase; and

iii) then modifying the chemical potential of the active agent in the fluid phase;

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.

18. The process of claim 17 wherein the modifying step allows for interaction between the active agent and the preformed crystalline diketopiperazine microparticle.

19. The process of claim 17 wherein the modifying step comprises adding an active agent modifier to the fluid phase 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, and sodium sulfate.

20. The process of claim 17 wherein the modifying step comprises the addition of water and wherein said modification decreases the solubility of the active agent.

21. The process of claim 17 wherein the active agent modifier promotes association between the active agent and a preformed crystalline diketopiperazine microparticle.

22. The process of claim 17 wherein the active agent modifier improves the structural stability of the active agent molecule.

23. The process of claim 17 wherein the diketopiperazine is fumaryl diketopiperazine.

24. A process for preparing a drug delivery composition comprising an active agent and a crystalline diketopiperazine microparticle comprising the steps in the sequence set forth of:

i) providing an active agent solution comprising a protein, polypeptide or peptide active agent molecule and providing a preformed crystalline diketopiperazine microparticle in a suspension or powder;

next

ii) modifying the chemical potential of the active agent in the active agent solution; and

iii) then combining said active agent solution with said preformed crystalline diketopiperazine microparticle suspension or powder to form a fluid phase wherein said modifying step causes adsorption of said active agent onto a surface of said preformed crystalline microparticle to provide a coating of said active agent on said preformed crystalline diketopiperazine microparticle.