NASAL DELIVERY

• US 20090304802A1
• Filed: 03/05/2007
• Published: 12/10/2009
• Est. Priority Date: 03/03/2006
• Status: Abandoned Application

• Current Assignee: OptiNose AS (OptiNose, Inc.)
• Original Assignee: OptiNose AS (OptiNose, Inc.)
• Inventors: Djupesland, Per Gisle, Hafner, Roderick Peter
• Application Number:
  US12/281,547
• Publication Number:
  US 20090304802A1
• Time in Patent Office: Days
• US Class Current: 424/495
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61M 15/0091 mechanically breath-triggered
• CPC Class Codes: A61M 15/0098 Activated by exhalation
• CPC Class Codes: A61M 15/08 Inhaling devices inserted into the nose
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Abstract

A sustained release nasal formulation for delivery to a nasal cavity of a subject, wherein the formulation provides for sustained release of a substance, in particular nitric oxide (NO), to nasal mucosa within the nasal cavity so as to provide one or both of a therapeutic effect and promote normal nasal function, and a nasal delivery device and method relating thereto.

Claims

1. A sustained release nasal formulation for delivery to a nasal cavity of a subject, wherein the formulation provides for sustained release of a substance to nasal mucosa within the nasal cavity.

2. The formulation of claim 1, wherein the formulation contains a substance-generating agent which generates the substance on exposure to the nasal mucosa.

3. The formulation of claim 1, where formulated as a liquid, such as a viscous liquid, a gel, such as a hydrogel, including a chitosan hydrogel, or a powder, such as a micropowder.

6. The formulation of claim 3, where formulated as microspheres or microparticles, such as coated microparticles.

7. The formulation of claim 6, where formulated as polymer-coated microparticles, wherein the polymer coating preferably comprises one or more of ethylcellulose, methacrylic acid-methyl methacrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose and cellulose acetate phthalate.

9. The formulation of claim 6, where formulated as microparticles of a lipid structural matrix which encapsulates the substance or a substance-generating agent.

10. The formulation of claim 3, wherein the powder comprises a significant fraction of particles having sizes over the entire range of from about 1 μ

m to about 100 μ

m, preferably the powder has a major fraction of particles having a size greater than about 20 μ

m, and preferably a major fraction of particles having a size greater than about 50 μ

m.

12. The formulation of claim 1, wherein the formulation provides for release of the substance at such a rate that the local concentration of the substance does not cause a significant change in the diastolic blood pressure, and preferably a change in the diastolic blood pressure of not more than about 20 mm Hg.

13. The formulation of claim 1, wherein the formulation provides for an effective concentration in the nasal mucosa for a period greater than 30 minutes, preferably for a period greater than 1 hour, more preferably for a period greater than 2 hours, still more preferably for a period greater than 4 hours, yet more preferably for a period greater than 6 hours, yet still more preferably for a period greater than 12 hours, and yet further more preferably for a period greater than 24 hours.

14. The formulation of claim 1, wherein the substance comprises nitric oxide.

15. The formulation of claim 14, wherein the formulation comprises one or more of sodium nitroprusside, isosorbide dinitrate and glyceryl trinitrate as a nitric oxide generator which generates nitric oxide on exposure to the nasal mucosa.

16. The formulation of claim 14, wherein the formulation provides for (i) the sustained release of nitric oxide to the ciliated nasal mucosa to promote, and preferably restore, mucociliary function, such as in subjects suffering from rhinosinusitis and other infectious and inflammatory diseases, in particular of the sinuses, middle ears and adjacent structures, (ii) the sustained release of nitric oxide to the nasal mucosa to inhibit expression and liberation of pro-inflammatory cyokines and mediators, (iii) the sustained release of nitric oxide to the nasal mucosa to at least reduce replication of one or more of viruses, bacteria and fungi, (iv) the sustained release of nitric oxide to the nasal mucosa to prevent progression of a localized disease, in particular to otitis media, acute sinusitis, recurrent sinusitis or chronic rhinosinusitis, (v) the sustained release of nitric oxide to the nasal mucosa to prevent development or reduce a severity of secondary complications, such as observed in subjects with asthma, cystic fibrosis, COPD and a variety of hereditary and acquired immune deficiencies, or (vi) the sustained release of nitric oxide to the nasal mucosa to provide therapeutic benefits in subjects with rhinosinusitis, polyposis, acute and recurrent sinusitis, common cold, cystic fibrosis and other infectious or inflammatory diseases, in particular of the sinuses, middle ears and adjacent organs and structures, such as through promoting mucociliary clearance in the ciliated nasal mucosa, inhibiting expression and liberation of pro-inflammatory cyokines and mediators and reducing replication of one or more of viruses, bacteria and fungi.

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22. A method of providing for sustained release of a substance to nasal mucosa within a nasal cavity of a subject, the method comprising the steps of:

fitting a nosepiece unit to one nostril of a subject, the nosepiece unit including a nosepiece which is inserted into the one nostril of a subject and a nozzle through which a sustained release formulation is delivered to the respective nasal cavity; and

delivering a sustained release formulation from the nozzle to the nasal cavity of the subject, wherein the formulation provides for sustained release of a substance to nasal mucosa within the nasal cavity.

23. The method of claim 22, wherein the nosepiece is configured to extend into the nasal valve.

24. The method of claim 22, further comprising the step of:

the subject exhaling through a mouthpiece unit such as to cause closure of the oropharyngeal velum of the subject.

25. The method of claim 24, wherein the nosepiece is fluidly connected to the mouthpiece unit, such that exhaled air from an exhalation breath is delivered through the nosepiece, or further comprising the step of:

delivering a gas flow, separate to an exhaled air flow from an exhalation breath of the subject, through the nosepiece.

27. The method of claim 22, wherein the nozzle provides for the delivery of a single jet or a plurality of jets, wherein the one or more jets comprise a liquid jet or a powder jet.

31. The method of claim 22, wherein the nozzle provides for the delivery of an aerosol spray, wherein the aerosol spray comprises a liquid spray or a powder spray.

34. The method of claim 22, further comprising the step of:

(i) manually actuating the delivery unit;

or

(ii) actuating the delivery unit in response to oral exhalation by the subject.

36. The method of claim 22, wherein at least 50%, preferably at least 55%, more preferably at least 60%, still more preferably at least 65% and yet more preferably at least 70% of the formulation as initially deposited in the nasal airway is deposited in a region of the nasal cavity which is posterior of the nasal valve.

37. The method of claim 36, wherein the nosepiece is configured such as to obstruct the nasal valve, and preferably the nosepiece is configured such as to close the nasal valve, and thereby prevent deposition of the formulation anteriorly of the same.

39. The method of claim 22, wherein at least 30%, preferably at least 35%, more preferably at least 40%, still more preferably at least 45% and yet more preferably at least 50% of the formulation as initially deposited in the nasal cavity is deposited in an upper posterior region of the nasal cavity which is posterior of the nasal valve and above the inferior meatus.

40. The method of claim 22, wherein the nosepiece unit includes a further nosepiece, and the nosepiece unit fitting step further comprises the step of:

fitting the further nosepiece to the other nostril of the subject, such as to at least partially obstruct the same, and preferably close the same.

42. The method of claim 22, further comprising the step of:

fitting a further nosepiece unit to the other nostril of the subject, the nosepiece unit including a nosepiece for insertion into the other nostril of a subject and a nozzle through which the formulation is delivered to the respective nasal cavity.

43. The method of claim 22, wherein the formulation contains a substance-generating agent which generates the substance on exposure to the nasal mucosa.

44. The method of claim 22, where formulated as a liquid, such as a viscous liquid, a gel, such as a hydrogel, including a chitosan hydrogel, or a powder, such as a micropowder.

47. The method of claim 44, where formulated as microspheres or microparticles, such as coated microparticles.

48. The method of claim 47, where formulated as polymer-coated microparticles, wherein the polymer coating preferably comprises one or more of ethylcellulose, methacrylic acid-methyl methacrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose and cellulose acetate phthalate.

50. The method of claim 47, where formulated as microparticles of a lipid structural matrix which encapsulates the substance or a substance-generating agent.

51. The method of claim 47, wherein the powder comprises a significant fraction of particles having sizes over the entire range of from about 1 μ

m to about 100 μ

m, preferably the powder has a major fraction of particles having a size greater than about 20 μ

m, and preferably a major fraction of particles having a size greater than about 50 μ

m.

53. The method of claim 22, wherein the formulation provides for release of the substance at such a rate that the local concentration of the substance does not cause a significant change in the diastolic blood pressure, and preferably a change in the diastolic blood pressure of not more than about 20 mm Hg.

54. The method of claim 22, wherein the formulation provides for an effective concentration in the nasal mucosa for a period greater than 30 minutes, preferably for a period greater than 1 hour, more preferably for a period greater than 2 hours, still more preferably for a period greater than 4 hours, yet more preferably for a period greater than 6 hours, yet still more preferably for a period greater than 12 hours, and yet further more preferably for a period greater than 24 hours.

55. The method of claim 22, wherein the substance comprises nitric oxide.

56. The method of claim 55, wherein the formulation comprises one or more of sodium nitroprusside, isosorbide dinitrate and glyceryl trinitrate as a nitric oxide generator which generates nitric oxide on exposure to the nasal mucosa.

57. The method of claim 55, wherein the formulation provides for the sustained release of nitric oxide to the ciliated nasal mucosa to promote, and preferably restore, mucociliary function, such as in subjects suffering from rhinosinusitis and other infectious and inflammatory diseases, in particular of the sinuses, middle ears and adjacent structures.

58. The method of claim 55, wherein the formulation provides for the sustained release of nitric oxide to the nasal mucosa to inhibit expression and liberation of pro-inflammatory cyokines and mediators.

59. The method of claim 55, wherein the formulation provides for the sustained release of nitric oxide to the nasal mucosa to at least reduce replication of one or more of viruses, bacteria and fungi.

60. The method of claim 55, wherein the formulation provides for the sustained release of nitric oxide to the nasal mucosa to prevent progression of a localized disease, in particular to otitis media, acute sinusitis, recurrent sinusitis or chronic rhinosinusitis, and preferably the formulation provides for the sustained release of nitric oxide to the nasal mucosa to prevent development or reduce a severity of secondary complications, such as observed in subjects with asthma, cystic fibrosis, COPD and a variety of hereditary and acquired immune deficiencies.

62. The method of claim 55, wherein the formulation provides for the sustained release of nitric oxide to the nasal mucosa to provide therapeutic benefits in subjects with rhinosinusitis, polyposis, acute and recurrent sinusitis, common cold, cystic fibrosis and other infectious or inflammatory diseases, in particular of the sinuses, middle ears and adjacent organs and structures, such as through promoting mucociliary clearance in the ciliated nasal mucosa, inhibiting expression and liberation of pro-inflammatory cyokines and mediators and reducing replication of one or more of viruses, bacteria and fungi.

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63. A nasal delivery device for delivering a sustained release formulation to a nasal cavity of a subject, which provides for sustained release of a substance to nasal mucosa within the nasal cavity, the delivery device comprising:

a nosepiece unit including a nosepiece for fitting to a nostril of a subject and a nozzle through which the formulation is in use delivered to the respective nasal cavity; and

a delivery unit for delivering the formulation through the nozzle of the nosepiece.

64. The delivery device of claim 63, wherein the nosepiece is configured, when inserted into the nasal cavity, to extend into the nasal valve.

65. The delivery device of claim 63, further comprising:

a mouthpiece unit through which the subject in use exhales to cause closure of the oropharyngeal velum of the subject.

66. The delivery device of claim 65, further comprising:

(i) a flow channel fluidly connecting the nosepiece and the mouthpiece unit, whereby exhaled air from an exhalation breath is delivered through the nosepiece;

or

(ii) a flow channel fluidly connected to the nosepiece through which a gas flow, separate to an exhaled air flow from an exhalation breath of the subject, is in use delivered to the nosepiece; and

a gas supply unit for supplying a gas flow to the flow channel.

68. The delivery device of claim 63, wherein the nozzle provides for the delivery of a single jet or a plurality of jets, wherein the one or more jets comprise a liquid jet or a powder jet.

72. The delivery device of any of claim 63, wherein the nozzle provides for the delivery of an aerosol spray, wherein the aerosol spray comprises a liquid spray or a powder spray.

75. The delivery device of claim 63, wherein the delivery unit is manually actuatable, or further comprising:

an actuation mechanism for actuating the delivery unit in response to oral exhalation by the subject, wherein the actuation mechanism is preferably configured such as to be actuated in response to generation of a predeterminable pressure in the nasal cavity.

78. The delivery device of claim 63, wherein the delivery device is configured such that at least 50%, preferably at least 55%, more preferably at least 60%, still more preferably at least 65% and yet more preferably at least 70% of the formulation as initially deposited in the nasal cavity is deposited in the region posterior of the nasal valve.

79. The delivery device of claim 78, wherein the nosepiece is configured such as to obstruct the nasal valve, and preferably close the nasal valve, and thereby prevent deposition of the formulation anteriorly of the same.

81. The delivery device of claim 63, wherein the delivery device is configured such that at least 30%, preferably at least 35%, more preferably at least 40%, still more preferably at least 45% and yet more preferably at least 50% of the formulation as initially deposited in the nasal cavity is deposited in the upper posterior region thereof.

82. The delivery device of claim 63, wherein the nosepiece unit includes a further nosepiece for fitting to the other nostril of the subject and at least partially obstructing the same, and preferably close the same.

84. The delivery device of claim 63, further comprising:

a further nosepiece unit including a nosepiece for fitting to the other nostril of the subject and a nozzle through which the formulation is in use delivered to the respective nasal cavity.

85. The delivery device of claim 63, wherein the formulation contains a substance-generating agent which generates the substance on exposure to the nasal mucosa.

86. The delivery device of claim 63, where formulated as a liquid, such as a viscous liquid, a gel, such as a hydrogel, including a chitosan hydro gel, or a powder, such as a micropowder.

89. The delivery device of claim 86, where formulated as microspheres or microparticles, such as coated microparticles.

90. The delivery device of claim 89, where formulated as polymer-coated microparticles, wherein the polymer coating preferably comprises one or more of ethylcellulose, methacrylic acid-methyl methacrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose and cellulose acetate phthalate.

92. The delivery device of claim 89, where formulated as microparticles of a lipid structural matrix which encapsulates the substance or a substance-generating agent.

93. The delivery device of claim 86, wherein the powder comprises a significant fraction of particles having sizes over the entire range of from about 1 μ

m to about 100 μ

m, preferably the powder has a major fraction of particles having a size greater than about 20 μ

m, and preferably a major fraction of particles having a size greater than about 50 μ

m.

95. The delivery device of claim 63, wherein the formulation provides for release of the substance at such a rate that the local concentration of the substance does not cause a significant change in the diastolic blood pressure, and preferably a change in the diastolic blood pressure of not more than about 20 mm Hg.

96. The delivery device of claim 63, wherein the formulation provides for an effective concentration in the nasal mucosa for a period greater than 30 minutes, preferably for a period greater than 1 hour, more preferably for a period greater than 2 hours, still more preferably for a period greater than 4 hours, yet more preferably for a period greater than 6 hours, yet still more preferably for a period greater than 12 hours, and yet further more preferably for a period greater than 24 hours.

97. The delivery device of claim 63, wherein the substance comprises nitric oxide.

98. The delivery device of claim 97, wherein the formulation comprises one or more of sodium nitroprusside, isosorbide dinitrate and glyceryl trinitrate as a nitric oxide generator which generates nitric oxide on exposure to the nasal mucosa.

99. The delivery device of claim 97, wherein the formulation provides for (i) the sustained release of nitric oxide to the ciliated nasal mucosa to promote, and preferably restore, mucociliary function, such as in subjects suffering from rhinosinusitis and other infectious and inflammatory diseases, in particular of the sinuses, middle ears and adjacent structures, (ii) the sustained release of nitric oxide to the nasal mucosa to inhibit expression and liberation of pro-inflammatory cyokines and mediators, (iii) the sustained release of nitric oxide to the nasal mucosa to at least reduce replication of one or more of viruses, bacteria and fungi, (iv) the sustained release of nitric oxide to the nasal mucosa to prevent progression of a localized disease, in particular to otitis media, acute sinusitis, recurrent sinusitis or chronic rhinosinusitis, (v) the sustained release of nitric oxide to the nasal mucosa to prevent development or reduce a severity of secondary complications, such as observed in subjects with asthma, cystic fibrosis, COPD and a variety of hereditary and acquired immune deficiencies, or (vi) the sustained release of nitric oxide to the nasal mucosa to provide therapeutic benefits in subjects with rhinosinusitis, polyposis, acute and recurrent sinusitis, common cold, cystic fibrosis and other infectious or inflammatory diseases, in particular of the sinuses, middle ears and adjacent organs and structures, such as through promoting mucociliary clearance in the ciliated nasal mucosa, inhibiting expression and liberation of pro-inflammatory cyokines and mediators and reducing replication of viruses, bacteria and fungi.

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