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1. (WO2005065651) FORMULATION POUR INHALATION CONTENANT DU SULFOALKYLE ETHER CYCLODEXTRINE ET UN CORTICOSTEROIDE, A BASE D'UNE SUSPENSION EN DOSES UNITAIRES
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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 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-carbonifrile); milrinone lactate; tryptase inhibitor, tachykinin receptor antagonist, leukofriene receptor antagonist, 5- lypoxygenase inhibitor, and anti-IgE antibody.
3. The method of claim 2, wherein the β2-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-((l,l dimethylethyl)amino)-l-hydroxyethyl)-l,3-phenylene ester); Bitolterol (4- methylbenzoic acid 4-(2-(( 1 , 1 -dimethylethyl)amino)- 1 -hydroxyethyl)- 1,2- phenyleneester); Broxaterol (3-bromo-alpha-(((l,l-dimethylethyl)amino)methyl)-5- isoxazolemethanol); Isoproterenol (4-(l-hydroxy-2-((l-methylethyl- )amino)ethyl)- 1,2-benzene-diol); Trimetoquinol (l,2,3,4-tetrahydro-l-((3,4,5-trimethoxyphenyl)- methyl)-6,7-isoquinolinediol); Clenbuterol (4-amino-3,5-dichloro-alpha-(((l,l- diemthylethyl)amino)methyl)benzenemethanol); Fenoterol (5-(l-hydroxy-2-((2-(4- hydroxyphenyl)-l -methy lethyl)ami- no)ethyl)-l,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'-(l,6-hexane-diyl)- bis(imino( l-hydroxy-2, l-ethanediyl)))bis-l,2-benzenediol); Isoetharine (4-(l- hydroxy-2-((l-meth- ylethyl)amino)butyl)-l,2-benzenediol); Isoprenaline (4-(l- hydroxy-2-((l-methylethyl)amino)ethyl)-l,2-benzenediol); Meta-proterenol (5-(l- hydroxy-2-((l-methylethyl)amino)ethyl)-l,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-(l-hydroxy-2-((l- methylethyl)amino-)butyl)-2( 1 H)-quinolin-one) ; Reproterol ((7-(3 -((2-(3 ,5 - dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro-l,3-dimethyl-lH- purine-2,6-dione); Rimiterol (4-(hydroxy-2-piperidinylmethyl)-l,2-benzenediol); Salbutamol ((.+-.)-alpha1-(((l,l-dimethylethyl)amino)methyl)-4-hydroxy-l,3-b- enzenedimethanol); (R)-Salbutamol; Salmeterol ((.+-.)-4-hydroxy-.alpha1-(((6-(4- phenylbutoxy)hexyl)-amino)methyl)-l,3-benzenedimethanol); (R)-Salmeterol; Terbutaline (5 -(2-(( 1 , 1 -dimethylethyl)amino)- 1 -hydroxyethyl)- 1 ,3-benzenediol) ;

Tulobuterol (2-chloro-.alpha.-(((l,l-dimethylethyl)amino)methyl)benzenemethanol); and TA-2005 (8-hydroxy-5-((lR)-l-hydroxy-2-(N-((lR)-2-(4-methoxyphenyl)-l- methylethy l)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-tefrahydro-6-methyl-4H- dibenzo[de,glquinoli- ne-10,11 -diol); Bromocriptine ((5'.alpha.)-2-bromo-12'- hydroxy-2,-(l-methylethyl)-5'-(2-methylpropyl)ergotaman-3',6',18-frione);
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-fryrosine); Pramipexole ((s)-4,5,6,7- tetrahydro-N.sup.6-prop- yl-2,6-benzothiazolediamine); Quinpirole hydrochloride (frans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-lH-pyrazolo[3,4-g]quinoline hydrochloride); Ropinirole (4-(2-(dipropylamino)ethyl)-l,3-dihydro-2H-indol-2-one); and Talipexole (5,6,7,8-tefrahydro-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, oxifropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide, homafropine methobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiofropium 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.
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 meg 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 concenfration 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 β2-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 β2-adrenoreceptor agonist is selected from the group consisting of Albuterol (alpha1 -(((1,1 -dimethylethyl)amino)methyl)-4-hydroxy-l,3- benzenedimethanol); Bambuterol (dimethylcarbamic acid 5-(2-((l,l dimethylethyl)amino)-l -hydroxyethyl)- 1,3-phenylene ester); Bitolterol (4- methy lbenzoic acid 4-(2-(( 1 , 1 -dimethylethy l)amino)- 1 -hydroxyethyl)- 1 ,2- phenyleneester); Broxaterol (3-bromo-alpha-(((l, l-dimethylethyl)amino)methyl)-5- isoxazolemethanol); Isoproterenol (4-(l-hydroxy-2-((l-methylethyl- )amino)ethyl)- 1,2-benzene-diol); Trimetoquinol (l,2,3,4-tetrahydro-l-((3,4- , 5-frimethoxyphenyl)- methyl)-6,7-isoquinolinediol); Clenbuterol (4-amino-3,5-dichloro-alpha-(((l,l- diemthylethyl)amino)methyl)benzenemethanol) ; Fenoterol (5 -( 1 -hydroxy-2-((2-(4- hydroxyphenyl)-l -methy lethyl)ami- no)ethyl)-l,3-benzenediol); Formoterol (2- hydroxy-5-((lRS)- 1 -hydroxy-2-(((lRS)-2-(p-methoxyphenyl)- 1 - methy lethyl)amino)ethyl) formanilide); (R,R)-Formoterol; Desformoterol ((R,R) or (S, S)-3 -amino-4-hydroxy-alpha-(((2-(4-methoxyphenyl)- 1 -methy 1- ethyl)amino)methyl)benzenemethanol); Hexoprenaline (4,4'-(l,6-hexane-diyl)- bis(imino( l-hydroxy-2, l-ethanediyl)))bis-l,2-benzenediol); Isoetharine (4-(l- hydroxy-2-((l-meth- ylethyl)amino)butyl)-l,2-benzenediol); Isoprenaline (4-(l- hydroxy-2-(( 1 -methy lethyl)amino)ethyl)- 1 ,2-benzenediol) ; Meta-proterenol (5-( 1 - hydroxy-2-((l-methylethyl)amino)ethyl)-l,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-(l-hydroxy-2-((l- methylethyl)amino-)butyl)-2(lH)-quinolin-one); Reproterol ((7-(3-((2-(3,5- dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro-l,3-dimethyl-lH- purine-2,6-dione); Rimiterol (4-(hydroxy-2-piperidinylmethyl)-l,2-benzenediol);

Salbutamol (C+^-alpha1 -((( 1 , 1 -dimethylethyl)amino)methyl)-4-hydroxy- 1 ,3 -b- enzenedimethanol); (R)-Salbutamol; Salmeterol ((.+-.)-4-hydroxy-.alpha1-(((6-(4- phenylbutoxy)hexyl)-amino)methyl)-l,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-((lR)-l-hydroxy-2-(N-((lR)-2-(4-methoxyphenyl)-l- 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'-(l-methylethyl)-5'-(2-methylpropyl)ergotaman-3',6',18-frione);
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-fryrosine); Pramipexole ((s)-4,5,6,7- tefrahydro-N.sup.6-prop- yl-2,6-benzothiazolediamine); Quinpirole hydrochirodie (frans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-lH-pyrazolo[3,4-g]qui- noline hydrochloride); Ropinirole (4-(2-(dipropylamino)ethyl)-l,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, oxifropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide, homatropine methobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiofropium 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.

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



Formula 1
wherein:
n is 4, 5 or 6;
Ri, R2, R3, R , R5, Re, R7, R8 and R9 are each, independently, -O- or a-O-(C2 - C6
alkylene)-SO3~ group, wherein at least one of Rn - R is independently a -O-(C2 - C6 alkylene)-SO3" group, a -O-(CH2)mSO3~ group wherein m is 2 to 6,
-OCH2CH2CH2SO3", or-OCH2CH2CH2CH2SO3 ); and
Si, S2, S3, S4, S5, S6, S7, S8 and S are each, independently, a pharmaceutically acceptable cation.