Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid

• US 20070020299A1
• 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:
  US11/479,979
• Publication Number:
  US 20070020299A1
• Time in Patent Office: Days
• US Class Current: 424/400
• 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, SAE-CD, and an aqueous liquid carrier, wherein the molar ratio of SAE-CD to corticosteroid is greater than 10:

1.

2. The formulation of claim 1, wherein the molar ratio of SAE-CD to corticosteroid required by the corticosteroid at the saturated solubility of the corticosteroid in the presence of SAE-CD is greater than 10:

1.

3. The formulation of claim 2, wherein the corticosteroid is at least as lipophilic as or more lipophilic than flunisolide.

4. The formulation of claim 3, wherein the corticosteroid is selected from the group consisting of beclomethasone, beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyryl-ciclesonide, flunisolide, fluticasone, fluticasone propionate, mometasone, mometasone furoate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide.

5. The formulation of claim 3, wherein the corticosteroid is selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyryl-ciclesonide, flunisolide, fluticasone propionate, mometasone furoate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide.

6. The formulation of claim 3, wherein the corticosteroid is present at a concentration that is less than its saturated solubility as determined in the presence of SAE-CD.

7. The formulation of claim 6, wherein the molar ratio of SAE-CD to corticosteroid in the composition or formulation is at least 1% greater than the molar ratio at the saturated solubility of the corticosteroid as determined in the presence of SAE-CD.

8. The formulation of claim 7, wherein the molar ratio of SAE-CD to corticosteroid is in the range of greater than 10:

1 to about 10,000;

1 or in the range of greater than 10;

1 to about 1000;

1.

9. The formulation of claim 7, wherein the molar ratio of SAE-CD to corticosteroid at the saturated solubility of the corticosteroid in the presence of SAE-CD is at least 14:

1.

10. The formulation of claim 9, wherein the formulation is a substantially clear solution comprising less than 5% wt. undissolved corticosteroid.

11. The formulation of claim 10 comprising 21.5±

2% wt./wt. or less of SAE-CD.

12. The formulation of claim 2, wherein the corticosteroid is present at a concentration that is less than its saturated solubility as determined in the presence of SAE-CD.

13. The formulation of claim 12, wherein the corticosteroid is present at a concentration that is 95% or less of its saturated solubility as determined in the presence of SAE-CD.

14. The formulation of claim 2, wherein the molar ratio of SAE-CD to corticosteroid in the composition or formulation is at least 1% greater than the molar ratio at the saturated solubility of the corticosteroid as determined in the presence of SAE-CD.

15. The formulation of claim 14, wherein the molar ratio of SAE-CD to corticosteroid in the composition or formulation is at least 5% greater than the molar ratio at the saturated solubility of the corticosteroid as determined in the presence of SAE-CD.

16. The formulation of claim 1, wherein the formulation is a substantially clear solution comprising less than 5% wt. undissolved corticosteroid.

17. The formulation of claim 1, wherein the molar ratio of SAE-CD to corticosteroid at the saturated solubility of the corticosteroid in the presence of SAE-CD is at least 14:

1.

18. The formulation of claim 1, wherein the aqueous liquid carrier comprises water, buffer, alcohol, organic solvent, glycerin, poly(ethylene glycol), poloxamer, surfactant or a combination thereof.

19. The formulation of claim 1 comprising 21.5±

2% wt./wt. or less of SAE-CD.

20. The formulation of claim 1, wherein the molar ratio of SAE-CD to corticosteroid is in the range of greater than 10:

1 to about 10,000;

1 or in the range of greater than 10;

1 to about 1,000;

1.

21. The formulation of claim 20, wherein the molar ratio of SAE-CD to corticosteroid is in the range of greater than 10:

1 to about 333;

1, from >

10;

1 to about 1000;

1, about from >

10;

1 to about 100;

1, from >

10;

1 to about 50;

1, from >

10;

1 to about 30;

1, or from >

10;

1 to about 500;

1.

22. The formulation of claim 1, wherein the corticosteroid excludes any corticosteroid having a lipophilicity less than that of flunisolide.

23. The formulation of claim 22 excluding hydrocortisone, prednisolone, prednisone, dexamethasone, betamethasone, methylprednisolone, triamcinolone, and fluocortolone.

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

25. The formulation of claim 1, wherein the corticosteroid possesses an intrinsic solubility in water that approximates or is less than the intrinsic solubility of flunisolide in water.

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

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

28. The formulation of claim 1, wherein the SAE-CD is present at a concentration of about 10 mg to about 500 mg of SAE-CD per ml of formulation.

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

30. The formulation of claim 1 further comprising 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, surfactant or a combination thereof.

31. The formulation 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.

32. The formulation of claim 31, 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)amino)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(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).

33. The formulation of claim 31, 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,glquinoline-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-1)-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).

34. The formulation of claim 31, 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.

35. The formulation of claim 31 wherein the topical anesthetic is selected from the group consisting of lidocaine, an N-arylamide, an aminoalkylbenzoate, prilocaine, and etidocaine.

36. The formulation of claim 31 comprising:

a corticosteroid selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyryl-ciclesonide, flunisolide, fluticasone propionate, mometasone furoate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide; and

a therapeutic agent selected from the group consisting of salmeterol, formoterol, albuterol, ipatropium, a pharmaceutically acceptable salt thereof, and an isomer thereof.

37. The formulation of claim 31, wherein the corticosteroid is present in a molar excess over the other therapeutic agent.

38. The formulation of claim 31, wherein the other therapeutic agent is present in a molar excess over the corticosteroid.

39. The formulation of claim 31, wherein the SAE-CD is present in a molar excess over the other therapeutic agent.

40. The formulation of claim 31, wherein the SAE-CD has a higher equilibrium binding constant for the corticosteroid than for the other therapeutic agent.

41. The formulation of claim 31, wherein the SAE-CD has a higher equilibrium binding constant for the other therapeutic agent than for the corticosteroid.

42. The formulation of claim 31, wherein the SAE-CD has an equilibrium binding constant approximating that for the other therapeutic agent.

43. The formulation 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.

44. The formulation according to any one of claims claims 1-42 or 43, wherein the cyclodextrin is a compound of the Formula II (SAEx-α

-CD), wherein “

x”

ranges from 1 to 18;

of the Formula III (SAEy-β

-CD), wherein “

y”

ranges from 1 to 21;

or of the Formula IV (SAEz-γ

-CD), wherein “

z”

ranges from 1 to 24, and wherein “

SAE”

represents a sulfoalkyl ether substituent, and the values “

x”

, “

y” and

“

z”

represent the average degree of substitution in terms of the number of sulfoalkyl ether groups per CD molecule.

45. The invention according to claim 22, wherein the cyclodextrin is selected from the group consisting of:

SAEx-α

-CD SAEy-β

-CD SAEz-γ

-CD SEEx-α

-CD SEEy-β

-CD SEEz-γ

-CD SPEx-α

-CD SPEy-β

-CD SPEz-γ

-CD SBEx-α

-CD SBEy-β

-CD SBEz-γ

-CD SPtEx-α

-CD SPtEy-β

-CD SPtEz-γ

-CD SHEx-α

-CD SHEy-β

-CD SHEz-γ

-CD.

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

47. A liquid formulation according to claim 1, wherein the formulation is adapted for nasal, oral, ophthalmic, otic or topical administration.

48. A method of treating a disease or disorder of the airways, in a subject in need thereof, comprising administering via inhalation a liquid formulation comprising an aqueous liquid carrier, a sulfoalkyl ether cyclodextrin, and a therapeutically effective amount of corticosteroid dissolved therein, the corticosteroid being present in an amount sufficient to provide a mean plasma AUCt of 160-1600 pg*h/ml, wherein the molar ratio of SAE-CD to corticosteroid is greater than 10:

1.

49. The method of claim 48, wherein the therapeutically effective amount comprises 45-1000 μ

g of corticosteroid.

50. The method of claim 49, wherein the molar ratio of SAE-CD to corticosteroid required by the corticosteroid at the saturated solubility of the corticosteroid in the presence of SAE-CD is greater than 10:

1.

51. The method of claim 50, wherein the liquid formulation is administered via nebulization.

52. The method of claim 51, wherein the formulation comprises less than or about 5 ml of aqueous liquid carrier.

53. The method of claim 52, wherein the formulation comprises 0.05 to 2 ml of aqueous liquid carrier.

54. The method of claim 51, wherein the liquid formulation is administered with an ultrasonic nebulizer, air jet nebulizer, electronic nebulizer, vibrating membrane nebulizer, vibrating mesh nebulizer, forced carrier/perforated disc combination nebulizer or vibrating plate nebulizer.

55. The method of claim 50, wherein the corticosteroid is selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyryl-ciclesonide, flunisolide, fluticasone propionate, mometasone furoate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide.

56. A method of providing 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.

57. The method of claim 56, wherein nebulization is conducted with a nebulizer selected from the group consisting of an air jet nebulizer, ultrasonic nebulizer, electronic nebulizer, vibrating membrane nebulizer, vibrating mesh nebulizer and vibrating plate nebulizer.

58. The method of claim 57, wherein the corticosteroid is budesonide.

59. A method of providing in a subject a mean plasma AUCt, normalized for dose of corticosteroid to subject, of at least 6 (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.

60. The method of claim 59, wherein nebulization is conducted with a nebulizer selected from the group consisting of an air jet nebulizer, ultrasonic nebulizer, electronic nebulizer, vibrating membrane nebulizer, vibrating mesh nebulizer and vibrating plate nebulizer.

61. The method of claim 60, wherein the unit dose is from 45-1000 μ

g.

62. The method of claim 60, wherein the corticosteroid is budesonide.

67. The method of claim 59, wherein the method provides a two- to less than four-fold increase in the mean plasma AUCt per μ

g of corticosteroid delivered to a subject as compared to administration via nebulization of a reference unit dose aqueous suspension-based liquid formulation.

68. The method of claim 59, wherein the method provides a 1.5 to 5-fold increase in the individual plasma AUCt per μ

g of corticosteroid delivered to a subject as compared to administration via nebulization of a reference unit dose aqueous suspension-based liquid formulation.

63. A method of providing in a subject 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.

64. The method of claim 63, wherein nebulization is conducted with a nebulizer selected from the group consisting of an air jet nebulizer, ultrasonic nebulizer, electronic nebulizer, vibrating membrane nebulizer, vibrating mesh nebulizer and vibrating plate nebulizer.

65. The method of claim 64, wherein the corticosteroid is budesonide.

66. The method of claim 64, wherein the unit dose is from 45-1000 μ

g.

69. The method of claim 63, wherein the method provides a two- to less than four-fold increase in the mean plasma AUCi per μ

g of corticosteroid delivered to a subject as compared to administration via nebulization of a reference unit dose aqueous suspension-based liquid formulation.

70. The method of claim 63, wherein the method provides a 1.5 to 5-fold increase in the individual plasma AUCi per μ

g of corticosteroid delivered to a subject as compared to administration via nebulization of a reference unit dose aqueous suspension-based liquid formulation.

71. A method of reducing the amount of time required to provide a therapeutically effective amount of corticosteroid to a subject by inhalation of an corticosteroid-containing composition with a nebulizer, the method comprising the steps of:

including SAE-CD 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.