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

• US 20070059373A1
• Filed: 09/14/2006
• Published: 03/15/2007
• Est. Priority Date: 09/14/2005
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Oberg, Keith
• Granted Patent: US 7,799,344 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• 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 method of coating a preformed crystalline microparticle in suspension with an active agent comprising;

i) adjusting the energetic interaction between the active agent and the crystalline microparticle independent of solvent removal; and

ii) adsorbing the active agent onto the surface of the microparticle.

2. The method of claim 1 further comprising the step of removing or exchanging the solvent.

3. The method of claim 2 wherein the step of removing or exchanging the solvent is without substantial effect on the interaction between active agent and microparticle.

4. The method of claim 1 wherein said adjusting step comprises modifying the surface properties of the microparticle.

5. The method of claim 4 wherein modification of the surface properties of the microparticle comprises altering solution conditions.

6. The method of claim 5 wherein altering solution conditions comprises changing the pH.

7. The method of claim 6 further comprising the step of dissolving the active agent in a fluid phase of the suspension of microparticles and subsequently changing the pH of the fluid phase.

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

9. The method of claim 5 wherein modification of the surface properties of the microparticle comprises altering the polarity of the solution.

10. The method of claim 5 wherein modification of the surface properties of the microparticle comprises addition of monovalent or multivalent ions.

11. The method of claim 5 wherein modification of the surface properties of the microparticle comprises chemical derivatization of the microparticle.

12. The method of claim 4 wherein the surface properties comprise electrostatic properties.

13. The method of claim 4 wherein the surface properties comprise hydrophobic properties.

14. The method of claim 4 wherein the surface properties comprise hydrogen bonding properties.

15. The method of claim 1 wherein the microparticle is porous and has interior surfaces accessible to the bulk fluid of the solution.

16. The method of claim 1 wherein the microparticle comprises a diketopiperazine.

17. The method of claim 16 wherein the diketopiperazine is fumaryl diketopiperazine.

18. The method of claim 1 wherein the method of coating produces a monolayer of active agent on the microparticle surface.

19. The method of claim 18 wherein the monolayer is continuous.

20. The method of claim 18 or 19 wherein the active agent in the monolayer has a preferred orientation.

21. The method of claim 1 wherein the active agent is insulin or an insulin analog.

22. A method of coating a pre-formed crystalline microparticle in suspension with insulin comprising:

i) adjusting the energetic interaction between the active agent and the crystalline microparticle independent of solvent removal; and

ii) absorbing the insulin onto the surface of the microparticles.