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

• US 9,283,193 B2
• Filed: 04/10/2014
• Issued: 03/15/2016
• Est. Priority Date: 09/14/2005
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Oberg, Keith A., Sulner, Joseph, Grant, Marshall L.
• Primary Examiner(s): Ha, Julie
• Application Number:
  US14/249,621
• Publication Number:
  US 20140308358A1
• Time in Patent Office: 705 Days
• Field of Search: 514/5.9, 514/11.8, 514/11.3, 514/11.9, 514/7.2, 514/9.7, 514/6.5, 424/491
• 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 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 fumaryl diketopiperazine (FDKP) core microparticle and an insulin coating, wherein the insulin coating is about 9% to about 12% of the total weight of the microparticle.

2. The microparticle of claim 1, wherein the insulin coating is a continuous or non-continuous monolayer.

3. The microparticle of claim 1, wherein at least about 9% insulin, based upon the total weight of the microparticle, is bound to the core microparticle.

4. The microparticle of claim 3, wherein at least 75% of the insulin coating is bound to the core microparticle.

5. The microparticle of claim 4, wherein the insulin coating is bound so that at least 75% of the insulin coating will remain on the core microparticle surface when the microparticle is dispersed in water.

6. The microparticle of claim 3, wherein at least about 9% insulin, based upon the total weight of the microparticle, is electrostatically bound to the core microparticle.

7. The microparticle of claim 1, wherein the insulin coating is about 11.4% of the total weight of microparticle.

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

9. The microparticle of claim 7, wherein the core microparticle further comprises polysorbate 80.

10. The microparticle of claim 9, wherein the polysorbate 80 is present in an amount of at least 0.007 mg/mg of microparticle.