Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid

• US 10,159,752 B2
• Filed: 11/14/2012
• Issued: 12/25/2018
• Est. Priority Date: 12/31/2003
• Status: Active Grant

• Current Assignee: CyDex Pharmaceuticals, Inc. (Ligand Pharmaceuticals, Inc.)
• Original Assignee: CyDex Pharmaceuticals, Inc. (Ligand Pharmaceuticals, Inc.)
• Inventors: Pipkin, James D., Zimmerer, Rupert O., Thompson, Diane O., Mosher, Gerold L.
• Primary Examiner(s): Liu, Sue X
• Assistant Examiner(s): Karpinski, Luke E
• Application Number:
  US13/676,744
• Publication Number:
  US 20130303498A1
• Time in Patent Office: 2,232 Days
• Field of Search: None
• 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 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/724 Cyclodextrins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08B 37/0015 Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
• CPC Class Codes: C08L 5/16 : Cyclodextrin; Derivatives thereof

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.

Claims

1. An aqueous liquid formulation comprising a therapeutically effective amount of corticosteroid dissolved therein, a sulfoalkyl ether cyclodextrin, and an aqueous liquid carrier, wherein

i. the corticosteroid is budesonide;

ii. the sulfoalkyl ether cyclodextrin has the structure;

2. The formulation of claim 1, wherein the molar ratio of the sulfoalkyl ether cyclodextrin to corticosteroid is between 14:

1 and 10,000;

1.

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

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

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

7. The formulation of claim 1 further comprising one or more other therapeutic agents independently selected from the group consisting of a β

2-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-lypoxygenase inhibitor, and anti-IgE antibody.

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

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

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

11. A solid composition prepared by drying a formulation according to claim 1.

12. A method of treating a disease or disorder of the airways, in a subject in need thereof, comprising administering via inhalation the formulation of claim 1, the corticosteroid being present in an amount sufficient to provide a mean plasma AUCt of 160-1600 pg*h/ml.

13. A method of providing in a subject:

(a) a mean plasma AUCt of 150-1600 pg*h/ml for the corticosteroid in an individual subject comprising;

administering to the subject, via nebulization, 48-220 μ

g, as dose to subject, of a corticosteroid dissolved in an aqueous liquid carrier comprising sulfoalkyl ether cyclodextrin;

or

(b) a mean plasma AUCt, normalized for dose of corticosteroid to subject, of at least 6 (pg*h/ml)/pg of corticosteroid delivered, as dose to subject, comprising;

administering to the subject, via nebulization, at least 45 μ

g of corticosteroid dissolved in an aqueous liquid carrier comprising sulfoalkyl ether cyclodextrin;

or

(c) a mean AUCi, normalized for dose of corticosteroid to subject, of at least 8 (pg*h/ml)/μ

g of corticosteroid delivered, as dose to subject, comprising;

administering to the subject, via nebulization, at least 45 μ

g of corticosteroid dissolved in an aqueous liquid carrier comprising sulfoalkyl ether cyclodextrin wherein the corticosteroid is administered as the formulation of claim 1.

14. 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 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 corticosteroid is administered as the formulation of claim 1.