Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid prepared from a unit dose suspension

• US 20070020196A1
• Filed: 06/30/2006
• Published: 01/25/2007
• Est. Priority Date: 12/31/2003
• Status: Abandoned Application

• Current Assignee: CyDex Pharmaceuticals, Inc. (Ligand Pharmaceuticals, Inc.)
• Original Assignee: CyDex Pharmaceuticals, Inc. (Ligand Pharmaceuticals, Inc.)
• Inventors: Pipkin, James, Zimmerer, Rupert, Thompson, Diane, Mosher, Gerold
• Application Number:
  US11/479,937
• Publication Number:
  US 20070020196A1
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• 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

Abstract

An inhalable unit dose liquid 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 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 corticosteroid, such as budesonide. A method of administering the formulation by inhalation is provided. The formulation can also be administered by conventional nasal delivery apparatus. The formulation is prepared by mixing SAE-CD, in solid or liquid (dissolved) form, with an inhalable suspension-based unit dose formulation.

Claims

1. A method of improving the administration of an inhalable corticosteroid-containing suspension-based unit dose formulation to a subject by nebulization, the method comprising the steps of:

providing in a unit dose an aqueous suspension formulation comprising water and corticosteroid suspended therein;

combining the suspension with an amount of SAE-CD sufficient to and for a period of time sufficient to increase the amount of solubilized corticosteroid in the formulation to form an altered formulation; and

administering the altered formulation to the subject.

2. The method of claim 1 further comprising one or more therapeutic agents independently selected at each occurrence 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.

3. The method of claim 2, wherein the β

₂-adrenoreceptor agonist is selected from the group consisting of Albuterol (alpha¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedimethanol);

Bambuterol (dimethylcarbamic acid 5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenylene ester);

Bitolterol (4-methylbenzoic acid 4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenyleneester);

Broxaterol (3-bromo-alpha-(((1,1-dimethylethyl)amino)methyl)-5-isoxazolemethanol);

Isoproterenol (4-(1-hydroxy-2-((1-methylethyl-)amino)ethyl)-1,2-benzene-diol);

Trimetoquinol (1,2,3,4-tetrahydro-1-((3,4,5-trimethoxyphenyl)-methyl)-6,7-isoquinolinediol);

Clenbuterol (4-amino-3,5-dichloro-alpha-(((1,1-diemthylethyl)amino)methyl)benzenemethanol);

Fenoterol (5-(1-hydroxy-2-((2-(4-hydroxyphenyl)-1-methylethyl)ami-no)ethyl)-1,3-benzenediol);

Formoterol (2-hydroxy-5-((1 RS)-1-hydroxy-2-((( 1 RS)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl) formanilide);

(R,R)-Formoterol;

Desformoterol ((R,R) or (S,S)-3-amino-4-hydroxy-alpha-(((2-(4-methoxyphenyl)-1-methyl-ethyl)amino)methyl)benzenemethanol);

Hexoprenaline (4,4′

-(1,6-hexane-diyl)-bis(imino( 1-hydroxy-2,1-ethanediyl)))bis-1,2-benzenediol);

Isoetharine (4-(1-hydroxy-2-((1-meth-ylethyl)amino)butyl)-1,2-benzenediol);

Isoprenaline (4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);

Meta-proterenol (5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,3-benzenediol);

Picumeterol (4-amino-3,5-dichloro-alpha-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)methyl) benzenemethanol);

Pirbuterol (.alpha. -(((1,1-dimethylethyl)-amino)methyl)-3-hydroxy-2,6-pyridinemethanol);

Procaterol (((R*,S*)-(.+-.)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino-)butyl)-2(1H)-quinolin-one);

Reproterol ((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione);

Rimiterol (4-(hydroxy-2-piperidinylmethyl)-1,2-benzenediol);

Salbutamol ((.+-.)-alpha¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-b-enzenedimethanol);

(R)-Salbutamol;

Salmeterol ((.+-.)-4-hydroxy-.alpha¹-(((6-(4-phenylbutoxy)hexyl)-amino)methyl)-1,3-benzenedimethanol);

(R)-Salmeterol;

Terbutaline (5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenediol);

Tulobuterol (2-chloro-.alpha.-(((1,1-dimethylethyl)amino)methyl)benzenemethanol); and

TA-2005 (8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)carbostyril hydrochloride).

4. The method of claim 2, wherein the dopamine (D2) receptor agonist is selected from the group consisting of Apomorphine ((r)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo [de,glquinoli-ne-10,11-diol);

Bromocriptine ((5′

.alpha.)-2-bromo-12′

-hydroxy-2′

-(1-methylethyl)-5′

-(2-methylpropyl)ergotaman-3′

,6′

,18-trione);

Cabergoline ((8.beta.)-N-(3-(dimethylamino)propyl)-N-((ethylamino)carbony-l)-6-(2-propenyl)ergoline-8-carboxamide);

Lisuride (N′

-((8-alpha-)-9,10-di-dehydro-6-methylergolin-8-yl)-N,N-diethylurea);

Pergolide ((8-beta-)-8-((methylthio)methyl)-6-propylergoline);

Levodopa (3-hydroxy-L-tryrosine);

Pramipexole ((s)-4,5,6,7-tetrahydro-N.sup.6-prop-yl-2,6-benzothiazolediamine);

Quinpirole hydrochloride (trans-(−

)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride);

Ropinirole (4-(2-(dipropylamino)ethyl)-1,3-dihydro-2H-indol-2-one); and

Talipexole (5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thia-zolo[4,5-d]azepin-2-amine).

5. The method of claim 2, wherein the anticholinergic agent is selected from the group consisting of ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide, homatropine methobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide.

6. The method of claim 1 wherein the topical anesthetic is selected from the group consisting of lidocaine, an N-arylamide, an aminoalkylbenzoate, prilocaine, and etidocaine.

7. The method of claim 1, wherein the corticosteroid is selected from the group consisting of aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, rofleponide, RPR 106541, tixocortol, triamcinolone, and their respective pharmaceutically acceptable derivatives.

8. The method of claim 7, wherein the corticosteroid derivative is selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, dexamethasone 21-isonicotinate, fluticasone propionate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide.

9. The method of claim 1, wherein the corticosteroid is selected from the group consisting of beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide.

10. The method of claim 1, wherein the SAE-CD is present in an amount sufficient to solubilize at least 90% of the corticosteroid.

11. The method of claim 1, wherein the SAE-CD is present in an amount sufficient to solubilize at least 95% of the corticosteroid.

12. The method of claim 11, wherein the SAE-CD is present in an amount sufficient to solubilize enough corticosteroid such that the solution formulation is a substantially clear solution containing less than 5% wt. solid corticosteroid.

13. The method of claim 1, wherein the molar ratio of corticosteroid to SAE-CD is in the range of about 1:

2 to about 1;

10,000.

14. The method of claim 1, wherein the solution formulation further comprises a conventional preservative, an antioxidant, a buffering agent, an acidifying agent, a solubilizing agent, a colorant, a complexation enhancing agent, saline, an electrolyte, another therapeutic agent, an alkalizing agent, a tonicity modifier, surface tension modifier, viscosity modifier, density modifier, volatility modifier, antifoaming agent, flavor, sweetener, hydrophilic polymer, or a combination thereof.

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

16. The method of claim 1 further comprising a liquid carrier other than water.

17. The method of claim 1, wherein the formulation comprises less than or about 21.5%±

5% wt./wt. of SAE-CD.

18. The method of claim 1, wherein the SAE-CD is present in an amount sufficient to dissolve at least 50% wt. of the corticosteroid.

33. The invention according to any one of the above claims, wherein the cyclodextrin is a compound of the Formula 1:

wherein;

n is 4, 5 or 6;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are each, independently, —

O—

or a —

O—

(C₂-C₆ alkylene)—

SO3⁻

group, wherein at least one of R₁-R₉ is independently a —

O—

(C₂-C₆ alkylene)—

SO₃⁻

group, a —

O—

(CH₂)_mSO₃⁻

group wherein m is 2 to 6, —

OCH₂CH₂CH₂SO₃⁻

, or —

OCH₂CH₂CH₂CH₂SO₃⁻

); and

S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ and S₉ are each, independently, a pharmaceutically acceptable cation.

19. A method of preparing a nebulizable corticosteroid-containing liquid unit dose formulation comprising the steps of:

providing a suspension-based unit dose formulation comprising an aqueous liquid carrier and a corticosteroid suspended therein, wherein the corticosteroid is present at a concentration of about 20 mcg to about 30 mg of corticosteroid per ml of suspension; and

mixing SAE-CD with the suspension-based unit dose formulation to form a nebulizable liquid unit dose formulation, wherein the SAE-CD is present in an amount sufficient to solubilize at least a major portion of the corticosteroid.

20. The method of claim 19, wherein the SAE-CD is present in the liquid formulation at a concentration of about 10 to about 500 mg of SAE-CD per ml of liquid formulation.

21. The method of claim 19, wherein the molar ratio of corticosteroid to SAE-CD is in the range of about 1:

1 to about 1;

10,000.

22. A kit adapted for the preparation of an inhalable unit dose liquid formulation, the kit comprising:

a first composition comprising a suspension-based unit dose formulation comprising corticosteroid suspended within an aqueous carrier; and

a separate second composition comprising SAE-CD, wherein the SAE-CD is present in an amount sufficient to increase the amount of dissolved corticosteroid when the first and second compositions are mixed;

wherein the first and/or second composition optionally comprises one or more other components.

23. The kit of claim 22, wherein the second composition is a dry solid, moist solid, semisolid or glass.

24. The kit of claim 22, wherein the second composition comprises a liquid carrier.

25. The kit of claim 22, wherein the unit dose liquid formulation further comprises one or more therapeutic agents independently selected at each occurrence from the group consisting of a β

₂-adrenoreceptor agonist, a dopamine (D₂) receptor agonist, an anticholinergic agent, a topical anesthetic, 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.

26. The kit of claim 25, wherein the β

₂-adrenoreceptor agonist is selected from the group consisting of Albuterol (alpha¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedimethanol);

Bambuterol (dimethylcarbamic acid 5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenylene ester);

Bitolterol (4-methylbenzoic acid 4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenyleneester);

Broxaterol (3-bromo-alpha-(((1,1-dimethylethyl)amino)methyl)-5-isoxazolemethanol);

Isoproterenol (4-(1-hydroxy-2-((1-methylethyl-)amino)ethyl)-1,2-benzene-diol);

Trimetoquinol (1,2,3 ,4-tetrahydro-1-((3,4,5-trimethoxyphenyl)-methyl)-6,7-isoquinolinediol);

Clenbuterol (4-amino-3,5-dichloro-alpha-(((1,1-diemthylethyl)amino)methyl)benzenemethanol);

Fenoterol (5-(1-hydroxy-2-((2-(4-hydroxyphenyl)-1-methylethyl)ami-no)ethyl)-1,3-benzenediol);

Formoterol (2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl) formanilide);

(R,R)-Formoterol;

Desformoterol ((R,R) or (S,S)-3-amino-4-hydroxy-alpha-(((2-(4-methoxyphenyl)-1-methyl-ethyl)amino)methyl)benzenemethanol);

Hexoprenaline (4,4′

-(1,6-hexane-diyl)-bis(imino(1-hydroxy-2,1-ethanediyl)))bis-1,2-benzenediol);

Isoetharine (4-(1-hydroxy-2-((1-meth-ylethyl)amino)butyl)-1,2-benzenediol);

Isoprenaline (4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol);

Meta-proterenol (5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,3-benzenediol);

Picumeterol (4-amino-3,5-dichloro-alpha-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)methyl) benzenemethanol);

Pirbuterol (.alpha.⁶-(((1,1-dimethylethyl)-amino)methyl)-3-hydroxy-2,6-pyridinemethanol);

Procaterol (((R*,S*)-(.+-.)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino-)butyl)-2(1 H)-quinolin-one);

Reproterol ((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione);

Rimiterol (4-(hydroxy-2-piperidinylmethyl)-1,2-benzenediol);

Salbutamol ((.+-.)-alpha¹-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-b-enzenedimethanol);

(R)-Salbutamol;

Saimeterol ((.+-.)-4-hydroxy-.alpha¹-(((6-(4-phenylbutoxy)hexyl)-amino)methyl)-1,3-benzenedimethanol);

(R)-Salmeterol;

Terbutaline (5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1 ,3-benzenediol);

Tulobuterol (2-chloro-.alpha.-(((1,1-dimethylethyl)amino)methyl)benzenemethanol); and

TA-2005 (8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)carbostyril hydrochloride).

27. The kit of claim 25, wherein the dopamine (D2) receptor agonist is selected from the group consisting of Apomorphine ((r)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,glquinoli-ne-10,11-diol);

Bromocriptine ((5′

.alpha.)-2-bromo-12′

-hydroxy-2′

-(1-methylethyl)-5′

-(2-methylpropyl)ergotaman-3′

,6′

,18-trione);

Cabergoline ((8.beta.)-N-(3-(dimethylamino)propyl)-N-((ethylamino)carbony-l)-6-(2-propenyl)ergoline-8-carboxamide);

Lisuride (N′

-((8-alpha-)-9,10-di-dehydro-6-methylergolin-8-yl)-N,N-diethylurea);

Pergolide ((8-beta-)-8-((methylthio)methyl)-6-propylergoline);

Levodopa (3-hydroxy-L-tryrosine);

Pramipexole ((s)-4,5,6,7-tetrahydro-N.sup.6-prop-yl-2,6-benzothiazolediamine);

Quinpirole hydrochirodie (trans-(−

)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride);

Ropinirole (4-(2-(dipropylamino)ethyl)-1,3-dihydro-2H-indol-2-one); and

Talipexole (5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thia-zolo[4,5-d]azepin-2-amine).

28. The kit of claim 25, wherein the anticholinergic agent is selected from the group consisting of ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide, homatropine methobromide, hyoscyamine, isopriopramide, orphenadrine, *benzalkonium chloride, tiotropium bromide and glycopyrronium bromide.

29. The method of claim 25, wherein the topical anesthetic is selected from the group consisting of lidocaine, an N-arylamide, an aminoalkylbenzoate, prilocaine, and etidocaine.

30. The kit of claim 22, wherein the corticosteroid is selected from the group consisting of aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, rofleponide, RPR 106541, tixocortol, triamcinolone, and their respective pharmaceutically acceptable derivatives.

31. The kit of claim 30, wherein the corticosteroid derivative is selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, dexamethasone 21-isonicotinate, fluticasone propionate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide.

32. The kit of claim 22, wherein the corticosteroid is selected from the group consisting of beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide.