Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
View Patent ↗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.
1. An aqueous liquid solution formulation comprising a therapeutically effective amount of corticosteroid dissolved therein, a sulfoalkyl ether cyclodextrin (SAE-CD), and an aqueous liquid carrier, wherein
i. the corticosteroid is budesonide;
ii. 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
iii. the formulation provides an enhanced pharmacokinetic profile over a suspension based formulation administered under similar conditions; wherein the molar ratio of SAE-CD to corticosteroid is greater than 10:1, and wherein more than 50% by weight of the corticosteroid is complexed with the SAE-CD; and wherein the aqueous liquid solution formulation is adapted for pulmonary inhalation.
2. The formulation of claim 1 , wherein the molar ratio of the sulfoalkyl ether cyclodextrin to corticosteroid is from greater than 10:1 to about 1,000:1.
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 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-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 solution based aerosol comprising an aqueous liquid carrier, a sulfoalkyl ether cyclodextrin (SAE-CD), and a dose of corticosteroid dissolved therein, wherein
i. the SAE-CD has the structure:
wherein:
each R is independently 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;
ii. the corticosteroid is budesonide; and
iii. the aerosol provides an enhanced pharmacokinetic profile over a suspension based formulation administered under similar conditions; wherein the molar ratio of SAE-CD to corticosteroid is greater than 10:1, wherein more than 50% by weight of the corticosteroid is complexed with the SAE-CD, and wherein the aerosol comprises nebulized droplets having a particle size of 0.5 to 5 microns; and wherein the solution based aerosol is adapted for pulmonary inhalation.
13. The aerosol of claim 12 , wherein the molar ratio of the sulfoalkyl ether cyclodextrin to corticosteroid is from greater than 10:1 to about 10,000:1.
14. The aerosol of claim 12 , wherein the aerosol comprises less than 5% wt. undissolved corticosteroid.
15. The aerosol of claim 12 , comprising 23.5% wt./wt. or less of the sulfoalkyl ether cyclodextrin.
16. The aerosol of claim 12 , 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 aerosol.
17. The aerosol of claim 12 , wherein the aerosol has a shelf-life of at least 6 months.
18. The aerosol of claim 12 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-lypoxygenase inhibitor, and anti-IgE antibody.
19. The aerosol of claim 18 , wherein the corticosteroid is present in a molar excess over the other therapeutic agent.
20. The aerosol of claim 18 , wherein the other therapeutic agent is present in a molar excess over the corticosteroid.
21. The aerosol of claim 18 , wherein the sulfoalkyl ether cyclodextrin is present in a molar excess over the other therapeutic agent.