Pharmaceutical aerosol composition

• US 20050244339A1
• Filed: 04/14/2005
• Published: 11/03/2005
• Est. Priority Date: 10/15/2003
• Status: Active Grant

• Current Assignee: PARI Pharma GmbH (PARI MEDICAL HOLDING GmbH)
• Original Assignee: PARI GMBH (PARI MEDICAL HOLDING GmbH)
• Inventors: Friedrich, Ingo, Keller, Manfred, Jauernig, Jurgen, Lintz, Frank-Christophe
• Granted Patent: US 7,758,886 B2
• Time in Patent Office: Days
• US Class Current: 424/45
• 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: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Sterile compositions for administration as aerosols are described. They contain an active agent which is poorly water-soluble, a non-ionic surfactant acomponent and a phospholipid component. The compositions are suitable for oral or nasal inhalation, but also for topical or oromucosal administration. They are particulary useful for the efficient pulmonary administration of poorly soluble corticosteroids and can be aerosolized with common nebulizers.

Claims

1. Sterile composition for administration as an aerosol, comprising a poorly water-soluble active agent, a non-ionic surfactant component and a phospholipid component, wherein the active agent is not a surfactant.

2. The composition of claim 1, wherein the non-ionic surfactant component comprises at least one member from the group consisting of tyloxapol, polysorbates, vitamin E TPGS, and macrogol-hydroxystearates.

3. The composition of claim 1, wherein the phospholipid component comprises a zwitterionic or saturated phospholipid, or a mixture of such phospholipids, and is preferably selected from the group consisting of lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC) and distearoyl phosphatidylcholine (DSPC).

4. The composition of claim 1, wherein the weight ratio between the non-ionic surfactant component and the phospholipid component is from about 5:

1 and about 1;

20.

5. The composition of claim 1, further comprising one or more excipients selected from solvents, co-solvents, acids, bases, buffering agents, osmotic agents, stabilizers, antioxidants, taste-masking agents, flavors, sweetening agents, ionic surfactants, thickeners, coloring agents, fillers, and bulking agents.

6. The composition of claim 5, wherein the antioxidant is selected from the group of vitamin E acetate, EDTA (di)sodium salt and a mixture thereof.

7. The composition of claim 1, wherein the composition is in the form of an aqueous liquid.

8. The composition of claim 7, wherein the aqueous liquid is an isotropic or anisotropic colloidal solution or dispersion.

9. The composition of claim 8, comprising colloidal structures selected from the group of liposomes, micelles, mixed micelles, anisotropic liquid crystals, liquid crystalline mesophases, and complexes.

10. The composition of claim 9, wherein the average particle size of the colloidal structures is from about 10 nm to about 200 nm, and preferably from about 10 nm to about 100 nm, with a polydispersity index of not more than about 0.5, in particular of not more than about 0.3, the composition being substantially free of solid particles capable of sedimentation.

11. The composition of claim 7, having a non-ionic surfactant component content of about 0.01 to about 5.0 wt-%, and in particular of about 0.05 to about 2.0 wt.-%.

12. The composition of claim 7, having a phospholipid component content of 0.5 to about 5 wt.-%, and in particular of about 0.5 to about 3 wt.-%.

13. The composition of claim 7, wherein the aqueous liquid has a surface tension of about 30 to about 75 mN/m, and preferably of about 40 to about 70 mN/m.

14. The composition of claim 7, wherein the aqueous liquid has a dynamic viscosity of about 0.8 to about 3.0 mPas, preferably of about 1.0 to about 2.0 mPas.

15. The composition of claim 7, wherein the aqueous liquid has a pH of about 4 to about 8, preferably of about 4 to about 6.

16. The composition of claim 7, wherein the aqueous liquid has an osmolality of about 200 to about 500 mOsmol/kg, and preferably of about 220 to about 350 mOsmol/kg.

17. The composition of claim 7, wherein the composition is substantially free of (a) propylene glycol, glycerol and polyethylene glycol;

and/or (b) a preservative.

18. The composition of claim 7, wherein the composition has a content of the poorly water-soluble active agent of between about 0.001 wt-% and about 1 wt-%.

19. The composition of claim 1, wherein the poorly water-soluble active agent is selected from the group of corticosteroids, betasympathomimetics, anticholinergics, immunomodulators, anti-infectives, and cytostatics.

20. The composition of claim 1, wherein the poorly water-soluble active agent has (a) a poor taste, and/or (b) a mucosal irritation potential, and/or (c) a cough-inducing potential, and/or (d) a potential to induce bronchoconstriction.

21. The composition of claim 1, wherein the poorly water-soluble active agent is a corticosteroid and/or cyclosporine.

22. The composition of claim 21, wherein the corticosteroid is selected from budesonide, fluticasone, ciclesonide and compounds comprising the active moiety of any of these corticosteroids, such as salts, derivatives, and prodrugs thereof.

23. The composition of claim 22, wherein the corticosteroid is budesonide.

24. The composition of claim 23, wherein the budesonide content is about 0.10 to about 0.5 mg/ml.

25. The composition of claim 22, wherein the corticosteroid is present in a colloidally dissolved or dispersed state.

26. The composition of claim 1, comprising a further active agent.

27. The composition of claim 26, wherein at least one of the active agent is selected from the group consisting of anti-inflammatory drugs, such as corticosteroids, non steroidal anti-inflammatory drugs (NSAIDs), Leukotriene-Antagonists, Betasympathomimetics, Anticholinergics, Phosphodiesterase-inhibitors, potassium channel openers, Tachikinin and kinin antagonists, IgE-synthesis inhibitors, endothelin-receptor antagonists, anesthetics, immunomodulators, antiinfectives, interferones, Vasodilatators, Angiotension Converting Enzyme (ACE) inhibitors, Cytostatics, in particular:

budesonide, ciclesonide, fluticasone, mometasone, beclomethasone, flunisolide;

ibuprofen, ketoprofen, valdecoxib, celecoxib;

zileuton, montelukast, pranlukast, roflumilast, cilomilast, zafirlukast;

albuterol, formoterol, salmeterole, levalbuterole, terbutaline, pirbuterol;

tiotropium, oxitropium, ipratropium;

theophyllin, pentoxyphyllin, cilomast, rolipram, amrinone, cilostazol, zardaverine, benzafentrine;

cromakalim, levocromakalim, pinacidil;

Nolpitantium, Saredutant, Nepadutant, Osanetant;

Icatibant;

Cromoglicate, nedocromil, glucan-sulfates, suplatast, batimastat, omalizumab;

idocaine, prolocaine, mepivacaine, bupivacaine, articaine, cyclosporine, tacrolimus, sirolimus, everolimus, rapamycine, leflunomide, midostaurin, azathioprine;

chloroquin, hydroxychlorquine;

trimethoprim, tetracycline, doxycycline, ciprofloxacine, moxifloxacine, gatifloxacine, carbapenems, azithromycine, clarithromycine, erythromycine, ketolides, penems, aminoglycosides, tobramyicin, filgrastim, pentamidine, microcidin, clerocidin;

metronidazole, ketoconazole, itraconazole, voriconazole, clotrimazole, bifonazole, fluconazole, amphotericine B, natamycine, nystatine, amikacine, aciclovir, famciclovir, valaciclovir, didanosine, saquinavir, ritonavir, lamivudine, stavudine, zidovudine, ribivarine, captoprile, lisinoprile, perindoprile, trandolaprile, cilazaprile, lovastatin, relaxin;

suramin;

sildenfafil, tardalafil, vardenafil, nitrendipin, amlodipine, prostacyclins, beraprost, lloprost, bosentane, carmustine, lomustine, taxol, etopside, cisplatin;

reduced glutathione, TNF-alpha-antibodies including the pharmaceutically acceptable derivatives of these substances such as, for example, the salts, conjugates, enantiomeres, racemates, epimeres, diastereomeres or complexes of any one of these active agents.

28. The composition of claim 27, comprising a combination of two active agents, selected from the combinations of:

(a) a corticosteroid and an immunomodulator;

(b) a corticosteroid and a beta-agonist;

(c) a corticosteroid and an anticholinergic agent;

(d) an immunomodulator and a beta-agonist;

(e) an immunomodulator and an anticholinergic agent; and

(f) a beta-agonist and an anticholinergic agent;

29. The composition of claim 28, comprising a combination of two active agents, selected from the combinations of:

(a) budesonide and formoterol;

(b) budesonide and tiotropium;

(c) fluticasone and formoterol;

(d) fluticasone and tiotropium;

(e) ciclesonide and and formoterol;

(f) ciclesonide and tiotropium;

(g) mometasone and formoterol;

(h) mometasone and tiotropium.

30. The composition of claim 1, wherein the composition is in the form of a dry solid material adapted for preparing an aqueous liquid composition.

31. A dry solid composition which is obtainable by freeze-drying the composition of claim 7.

32. A medicament comprising the composition of claim 1.

33. The medicament of claim 32, being packaged in one or more single dose primary packaging means, from which it is dispensable, such as, by dropwise dosing, with a dispensing variability of less than about 20%, preferably less than about 10%, wherein the packaging means is adapted to hold a fill volume of about 0.2 ml to about 5 ml.

34. The medicament of claim 33, wherein each packaging means is a plastic container comprising a removable closure element, and wherein the container is optionally manufactured using an aseptic blow-fill-seal process design.

35. The medicament of claim 34, wherein the composition is in aqueous liquid form, and wherein the removal of the closure element yields an opening in the container of a diameter approximately corresponding to the inner or outer diameter of a male luer connection.

36. The medicament of claim 34, wherein the plastic container is designed to be, upon removal of the removable closure elements, tightly connectable to a connecting member of a nebulizer.

37. The medicament of claim 34, wherein the composition is in the form of an aqueous liquid, and wherein the plastic container comprises one or more volume or dosing marks and/or one or more imprints.

38. The medicament of claim 32, being packaged in one or more multiple dose primary packaging means which is adapted to hold a fill volume of about 2 ml to about 50 ml.

39. The medicament of claim 38, wherein the composition is in the form of an aqueous liquid, and wherein the plastic container comprises one or more volume or dosing marks and/or one or more imprints.

40. The medicament of claim 32, wherein the composition is in the form of a dry solid material.

41. The medicament of claim 40, wherein one or more single dose primary packaging means are combined with one or more further containers within one secondary package, said further containers comprising a sterile aqueous liquid for reconstituting the dry solid material to form a liquid suitable for oral or nasal inhalation.

42. Use of the medicament of claim 32 for the diagnosis, prophylaxis or therapy of a symptom, disease or condition in an animal, preferably a mammal, said use comprising topical or oromucosal administration, and/or oral or nasal inhalation.

43. The use of claim 42, wherein the mammal is a human baby, infant, child or youth, and wherein the use comprises oral or nasal inhalation.

44. The use of claim 42, wherein the medicament is administered at a once-daily dosing regimen.

45. The use of claim 42, wherein the medicament is intended for the prophylaxis and/or treatment of one or more diseases, symptoms or conditions affecting the upper or lower airways.

46. The use of claim 45 wherein the one or more diseases, symptoms or conditions affect the mucosa of the nasal and/or oral cavity, such as stomatitis, aphthae, allergic rhinitis, vasomotoric rhinitis, seasonal rhinitis, perennial rhinitis, chronic rhinitis, or nasal polyps.

47. The use of claim 46 wherein the medicament is nebulized by means of a mechanical atomizer or a nebulizer for spraying into the nose or the mouth or for inhalation.

48. The use of claim 45 wherein the one or more diseases, symptoms or conditions affect the mucosa of the frontal, maxillary and/or paranasal sinuses, such as chronic or allergic sinusitis, or polyps.

49. The use of claim 48 wherein the medicament is nebulized by means of a jet nebulizer and inhaled through the nose, wherein said jet nebulizer contains a nose piece for directing the aerosol into one or both nostrils of a patient and generates an aerosol output with pulsating pressure changes, such as the PARI Sinus nebulizer.

50. The use of claim 45 wherein the one or more diseases, symptoms or conditions are selected from the group consisting of asthma, pediatric asthma, obstructive bronchitis, chronic obstructive bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, lung infections, vascular, parenchymal lung disease, sarcosidosis, pulmonary fibrosis, cystic fibrosis, bonchiolitis obliterans, pulmonary hypertension, and lung cancer.

51. The use of claim 50 wherein the medicament is nebulized with a nebulizer of the ultrasonic, jet or electro hydrodynamic type and/or with a nebulizer operating with a vibrating membrane or with pores of defined size, such as eFlow™

, eFlow™

Baby, AeroNeb™

, AeroDose™

or AERx™

.

52. The use of claim 50 wherein the medicament is administered in single doses having a liquid volume of about 0.2 to about 5 ml, and in particular of about 0.5 to about 1.0 ml.

53. The use of claim 50 wherein the medicament is delivered to the human at a total output rate of about 0.2 to about 0.8 ml, or of about 200 to about 800 mg per minute.

54. The use of claim 50 wherein the medicament is administered within about 5 minutes or less, and in particular within about 2 minutes or less, per single dose.

65. Method for the manufacture of the composition of claim 1, comprising the following steps:

(a) providing the ingredients;

(b) preparing an aqueous liquid composition from the ingredients provided in step (a);

(c) sterile filtration of the composition obtained in step (b); and

(d) filling the sterile filtered composition from step (c) into sterile containers under aseptic conditions.

66. The method of claim 65, wherein at least one of the ingredients provided in step (a) is sterile.

67. The method of claim 65, wherein step (b) comprises a substep of homogenization under increased pressure, of ultrasonication and/or of heating to at least 45°

C.

68. The method of claim 65, wherein the sterile containers of step (d) are plastic vials manufactured by an aseptic blow-fill-seal process.

69. The method of claim 65, further characterized by the absence of any steps or substeps in which the poorly water-soluble active agent is present in solid form and wherein its particle size is reduced mechanically.

55. Method for treating a human subject suffering from a disease or condition selected from the group of asthma, pediatric asthma, obstructive bronchitis, and chronic obstructive bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, lung infections, vascular or parenchymal lung disease, sarcosidosis, lung and cystic fibrosis, bronchiolitis obliterans, pulmonary hypertension, and lung cancer, said method comprising the repeated administration of a sterile aqueous composition comprising a poorly water-soluble corticosteroid or immunomodulator, a non-ionic surfactant component and a phospholipid component, wherein the administration is achieved by nebulizing said composition by means of a nebulizer having a vibrating membrane with pores of defined size, and wherein the medicament is delivered from said nebulizer in aerosol form at a total output rate of about 0.2 to about 0.8 ml per minute.

56. The method of claim 55, wherein the aerosol has a mass median diameter of about 1 to about 5 μ

m, and more particularly of about 2 to about 4 μ

m.

57. The method of claim 55, wherein at least about 60% of the aerosol consists of aerosol particles having a diameter from about 2 to about 5 μ

m.

58. The method of claim 55, wherein the poorly water-soluble corticosteroid is budesonide.

59. The method of claim 55, wherein the poorly water-soluble immunomodulator is cyclosporin, and wherein the cyclosporin is optionally administered in combination with budesonide.

60. The method of claim 55, wherein the non-ionic surfactant component comprises at least one member from the group consisting of tyloxapol, polysorbates, vitamin E-TPGS, and macrogol hydroxystearates.

61. The method of claim 55, wherein the phospholipid component comprises a zwitterionic or saturated phospholipid, or a mixture of such phospholipids, and is preferably selected from the group consisting of lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC) and distearoyl phosphatidylcholine (DSPC).

62. The method of claim 55, wherein the administration is repeated about once a day.

63. Method for treating a human subject suffering from asthma or pediatric asthma, said method comprising the once-daily or twice-daily administration of a sterile aqueous composition comprising:

(a) Budesonide

(b) a non-ionic surfactant component selected from the group consisting of tyloxapol, polysorbates, vitamin E TPGS, and macrogol hydroxystearates, and

(c) lecithin,

wherein the administration is achieved by nebulizing said composition by means of a nebulizer having a vibrating membrane with pores of defined size;

wherein a single dose of the medicament has a volume of about 0.2 ml to about 1 ml and a budesonide content of about 0.2 to about 0.5 mg/ml; and

wherein the composition is delivered from said nebulizer in aerosol form at a total output rate of about 0.2 to about 0.8 ml per minute.

64. The method of claim 63, wherein the human subject is a pediatric patient, and wherein a total daily dose of budesonide from about 50 μ

g to about 400 μ

g is administered.