Method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent

Patent metadata

Field	Value
Publication number	US-2016101049-A1
Application number	US-201514971785-A
Country	US
Kind code	A1
Filing date	Dec 16, 2015
Priority date	Feb 22, 2006
Publication date	Apr 14, 2016
Grant date	—

Abstract

Methods are provided for drying a particle. Specifically, there is provided a spray-dried diketopiperazine-insulin particle formulation having improved aerodynamic performance and in which the active agent is more stabile and efficiently delivered as compared to that of the lyophilized diketopiperazine-insulin formulation. The dry powders have utility as pharmaceutical formulations for pulmonary delivery.

First claim

What is claimed is:

1 . A method for forming a dry powder medicament with an improved pharmaceutic property, comprising
a) a step for forming microparticles comprising a diketopiperazine with acidic or basic side chains, resulting in a suspension of microparticles of the diketopiperazine with acidic or basic side chains in a solvent, and optionally a step for loading said microparticles with an active agent, then b) removing solvent by spray drying to obtain a dry powder, wherein the dry powder has an improved pharmaceutic property as compared to a dry powder obtained by removing solvent by lyophilization, and wherein the improved pharmaceutic property is increased density of the powder, increased aerodynamic performance of the powder, or improved stability of the active agent, if present.

2 . The method of claim 1 , wherein said diketopiperazine is a diketopiperazine having the formula 3,6-di(4-X-aminobutyl)-2,5-diketopiperazine, wherein X is succinyl, glutaryl, maleyl, or fumaryl.

3 . The method of claim 2 , wherein X is fumaryl diketopiperazine.

4 . The method of claim 1 , wherein the method comprises a step for loading the microparticle with an active agent prior to the solvent removal step.

5 . The method of claim 4 , wherein said loading step comprises: providing a solution or a suspension of the active agent; and adding said solution or suspension of active agent to the suspension of microparticles of the diketopiperazine with acidic or basic side chains.

6 . The method of claim 4 , wherein the active agent is insulin, calcitonin, parathyroid hormone 1-34, bioactive fragment of parathyroid hormone, octreotide, leuprolide, RSV peptide, felbamate, cannabinoid antagonists and/or agonists, muscurinic antagon and/or agonists, heparin, low molecular weight heparin, cromolyn, sildenafil, vardenafil, tadalafil, growth hormone, AZT, DDI, GCSF, lamotrigine, chorionic gonadotropin releasing factor, luteinizing release hormone, β-galactosidase, GLP-1, exendins 1-4, or ghrelin.

7 . The method of claim 4 , wherein the active agent is a peptide or protein.

8 . The method of claim 6 , wherein the active agent is insulin or an analogue thereof.

9 . The method of claim 8 , wherein the active agent is human insulin.

10 . The method of claim 1 , wherein said improved pharmaceutic property is improved aerodynamic performance of the microparticle.

11 . The method of claim 1 , wherein said improved pharmaceutic property is increased density of the powder.

12 . The method of claim 4 , wherein said improved pharmaceutic property is improved stability of the active agent of the microparticle.

13 . The method of claim 10 , wherein said aerodynamic performance is measured by the percent respirable fraction on a cartridge fill.

14 . The method of claim 13 , wherein the percent respirable fraction is greater than about 40%.

15 . The method of claim 12 , wherein the percent respirable fraction is greater than about 60%.

16 . The method of claim 9 , wherein the insulin content of the microparticle is about 3% to about 50% by weight of the dry powder formulation.

17 . The method of claim 16 , wherein the insulin content of the microparticle is about 7% to about 25% by weight of the dry powder formulation.

18 . The method of claim 17 , wherein the insulin content of the microparticle is about 11% by weight of the dry powder formulation.

19 . A method for delivering an active agent to a patient in need thereof, comprising administering by inhalation to the patient an effective amount of the dry powder made by the method of claim 4 .

20 . The method of claim 10 , wherein said increased density is 1.7 to 2.3 times the density of said dry powder obtained by removing solvent by lyophilization.

21 . The method of claim 20 , wherein said increased density comprises greater tapped density.

22 . The method of claim 20 , wherein said increased density comprises greater bulk density.

23 . The method of claim 21 , wherein said greater tapped density is from 0.25 to 0.30 g/cc.

24 . The method of claim 22 , wherein said greater bulk density is from 0.15 to 0.20 g/cc.

25 . The method of claim 1 , wherein the step for forming microparticles comprises adjusting the pH of a solution comprising a diketopiperazine with acidic or basic side chains.

Assignees

• Mannkind Corp

Inventors

• Wilson Bryan R
• Grant Marshall

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K9/1617

  Organic compounds, e.g. phospholipids, fats · CPC title

• A61K9/1694

  resulting in granules or microspheres of the matrix type containing more than 5% of excipient · CPC title

• A61K9/145 Primary

  with organic compounds · CPC title

• A61K9/0075 Primary

  for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles · CPC title