Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid

Patent metadata

Field	Value
Publication number	US-10799599-B2
Application number	US-201816210561-A
Country	US
Kind code	B2
Filing date	Dec 5, 2018
Priority date	Dec 31, 2003
Publication date	Oct 13, 2020
Grant date	Oct 13, 2020

Abstract

An inhalable formulation containing SAE-CD and corticosteroid is provided. The formulation is adapted for administration to a subject by nebulization with any known nebulizer. The formulation can be included in a kit. The formulation is administered as an aqueous solution, however, it can be stored as a dry powder, ready-to-use solution, or concentrated composition. The formulation is employed in an improved nebulization system for administering corticosteroid by inhalation. SAE-CD present in the formulation significantly enhances the chemical stability of budesonide. A method of administering the formulation by inhalation is provided. The formulation can also be administered by conventional nasal delivery apparatus.

First claim

The invention claimed is:

1. A method of reducing the amount of time required to provide a therapeutically effective amount of corticosteroid to a subject by inhalation of a corticosteroid-containing composition with a nebulizer, the method comprising the steps of: including a sulfoalkyl ether cyclodextrin in the composition in an amount sufficient to solubilize the corticosteroid to form an inhalable aqueous corticosteroid-containing solution; and administering the solution to the subject by inhalation with a nebulizer, wherein the amount of time required to provide a therapeutically effective amount of corticosteroid to the subject with the solution is reduced as compared to the amount of time required to provide a therapeutically effective amount of corticosteroid to the subject with a corticosteroid-containing suspension comprising the same amount or concentration of corticosteroid when the suspension and solution are administered under otherwise similar nebulization conditions;
wherein the sulfoalkyl ether cyclodextrin in the aqueous corticosteroid-containing solution has the structure:

wherein:
each R is —H or —(CH 2 ) 4 SO 3 Na;
wherein the average degree of substitution of —(CH 2 ) 4 SO 3 Na is 6.0 to 7.1 per cyclodextrin molecule; and
wherein the molar ratio of the sulfoalkyl ether cyclodextrin to the corticosteroid in the aqueous corticosteroid-containing solution is between 14:1 and 10,000:1.

2. The method of claim 1 , wherein
the corticosteroid in the aqueous corticosteroid-containing solution is budesonide.

3. The method of claim 1 , wherein the formulation comprises less than 5% wt. undissolved corticosteroid.

4. The method of claim 1 , comprising 23.5% wt./wt. or less of the sulfoalkyl ether cyclodextrin.

5. The method of claim 1 , wherein the sulfoalkyl ether cyclodextrin is present at a concentration of about 10 mg to about 500 mg of sulfoalkyl ether cyclodextrin per ml of formulation.

6. The method of claim 1 , wherein the formulation has a shelf-life of at least 6 months.

7. The method of claim 1 further comprising one or more other therapeutic agents independently selected from the group consisting of a β2-adrenoreceptor agonist, a dopamine (D2) receptor agonist, a topical anesthetic, an anticholinergic agent, IL-5 inhibitor, antisense modulator of IL-5, milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4′-bipyridine]-5-carbonitrile), milrinone lactate, tryptase inhibitor, tachykinin receptor antagonist, leukotriene receptor antagonist, 5-lipoxygenase inhibitor, and anti-IgE antibody.

8. The method of claim 7 , wherein the corticosteroid is present in a molar excess over the other therapeutic agent.

9. The method of claim 7 , wherein the other therapeutic agent is present in a molar excess over the corticosteroid.

10. The method of claim 7 , wherein the sulfoalkyl ether cyclodextrin is present in a molar excess over the other therapeutic agent.

11. The method of claim 1 , wherein the corticosteroid in the aqueous corticosteroid-containing solution is present in an amount sufficient to provide a mean plasma AUCt of 160-1600 pg*h/ml.

12. A method of providing in a subject:
(a) a mean plasma AUCt of 150-1600 pg*h/ml for budesonide in an individual subject comprising: administering by inhalation to the subject a dose of 48-220 μg of budesonide dissolved in an aqueous budesonide solution, wherein the aqueous budesonide solution comprises a sulfoalkyl ether cyclodextrin; or
(b) a mean plasma AUCt, normalized for dose of budesonide, of at least 6 (pg*h/ml)/μg of budesonide, comprising: administering by inhalation to the subject a dose of 45 μg to 1000 μg of budesonide dissolved in an aqueous budesonide solution, wherein the aqueous budesonide solution comprises a sulfoalkyl ether cyclodextrin; or
(c) a mean AUCi, normalized for dose of budesonide, of at least 8 (pg*h/ml)/ug of budesonide, comprising: administering by inhalation to the subject 45 μg to 1000 μg of budesonide dissolved in an aqueous budesonide solution, wherein the aqueous budesonide solution comprises a sulfoalkyl ether cyclodextrin;
wherein the sulfoalkyl ether cyclodextrin has the structure:

wherein:
each R is —H or —(CH 2 ) 4 SO 3 Na;
wherein the average degree of substitution of —(CH 2 ) 4 SO 3 Na is 6.0 to 7.1 per cyclodextrin molecule; and
wherein the molar ratio of the sulfoalkyl ether cyclodextrin to budesonide in the aqueous budesonide solution is between 14:1 and 10,000:1.

Assignees

• Cydex Pharmaceuticals Inc

Inventors

• Pipkin James D
• Zimmerer Rupert O
• Thompson Diane O
• Mosher Gerold L

Classifications

• A61K9/0078 Primary

  for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C08B37/0015

  Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes · CPC title

• A61K31/724

  Cyclodextrins · CPC title

• A61K47/61

  the organic macromolecular compound being a polysaccharide or a derivative thereof · CPC title