Inhalable pharmaceutical compositions

• US 10,022,303 B2
• Filed: 02/28/2013
• Issued: 07/17/2018
• Est. Priority Date: 02/28/2012
• Status: Active Grant

• Current Assignee: Iceutica Pty Limited (Assertio Holdings, Inc.)
• Original Assignee: Iceutica Pty Limited (Assertio Holdings, Inc.)
• Inventors: Bosch, H. William, Callahan, Matthew, Meiser, Felix, Norret, Marck, Russell, Adrian
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Tcherkasskaya, Olga V
• Application Number:
  US13/781,115
• Publication Number:
  US 20140065219A1
• Time in Patent Office: 1,965 Days
• CPC Class Codes: A61J 3/02 into the form of powders pulverising in general B02C
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles

Abstract

Methods for making inhalable composite particles comprising a pharmaceutically-active agent, the method comprising: a) providing composite particles comprising a millable grinding matrix and a solid pharmaceutically-active agent, wherein the pharmaceutically-active agent has an median particle size on a volume average basis between 50 nm and 3 μm; and b) milling the composite particles in a mill without milling bodies for a time period sufficient to produce inhalable composite particles having a mass median aerodynamic diameter between 1 μm and 20 μm are described.

Claims

1. A method for making inhalable composite particles comprising a pharmaceutically-active agent, the method comprising:

a) dry milling a composition comprising a solid pharmaceutically active agent and a millable grinding matrix in a mill comprising a plurality of milling bodies for a time period sufficient to produce composite particles comprising the millable grinding matrix and the solid pharmaceutically-active agent, wherein the pharmaceutically-active agent has median particle size on a volume basis between 50 nm and 1,000 nm subsequent to milling, as measured by laser diffraction; and

b) milling the composite particles in a mill without milling bodies for a time period sufficient to produce inhalable composite particles having a volume weighted mean diameter (D4,3) between 1,000 nm and 10,000 nm, as measured by laser diffraction, and wherein the step of milling in mill without milling bodies reduces the size of the composite particles without reducing the median particle size of the pharmaceutically active agent.

2. The method of claim 1, wherein 90% of the inhalable composite particles, determined on a particle volume basis, have a diameter less than or equal to 15,000 nm.

3. The method of claim 1, wherein 90% of the inhalable composite particles, determined on a particle volume basis, have a diameter greater than or equal to 2000 nm.

4. The method of claim 1, wherein the mill without milling bodies is selected from a jet mill and air jet mill.

5. The method of claim 1, wherein the millable grinding matrix comprises a carbohydrate or an amino acid.

6. The method of claim 5, wherein the carbohydrate is selected from the group consisting of:

mannitol, sorbitol, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, lactose, sucrose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, trehalose, a maltodextrin, a dextran, inulin, and 1-O-alpha-D -glucopyranosyl-D-mannitol.

7. The method of claim 5, wherein the amino acid is selected from the group consisting of:

aspartic acid, glutamic acid, leucine, L-leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, serine, phenylalanine, lysine, and N-acetyl-L-cysteine.

8. The method of claim 6, wherein the millable grinding matrix comprises lactose and at least one compound selected from the group consisting of:

sodium chloride, anhydrous lactose, mannitol, glucose, sucrose, trehalose, sorbitol, 1-O-alpha-D-glucopyranosyl-D-mannitol, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose, inulin, sodium citrate, sodium ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine, phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidylinositol, phospatidylcholines, hosphatidylethanolamine, phosphatidylglycerols, phosphatidylinositol, phosphatidylserine, sodium lauryl sulphate, magnesium lauryl sulphate;

leucine, L-leucine, isoleucine, lysine, valine, methionine, phenylalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine, alanine, and serine.