Sublingual fentanyl spray

• US 20070261695A1
• Filed: 01/25/2007
• Published: 11/15/2007
• Est. Priority Date: 01/25/2006
• Status: Active Grant

• Current Assignee: BTcP Pharma, LLC
• Original Assignee: INSYS Therapeutics, Inc.
• Inventors: Zhu, Zhongyuan, Parikh, Neha, Kattookaran, Linet, Kottayil, S., Goskonda, Venkat
• Granted Patent: US 8,486,972 B2
• Time in Patent Office: Days
• US Class Current: 128/200.210
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61M 11/00 Sprayers or atomisers specially adapted for therapeutic purposes in general B05B; aerosol containers B65D83/14
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention is directed to sublingual formulations containing fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof, suitable for administration to a patient, and methods for treatment with the formulations.

Claims

1. A sublingual fentanyl formulation comprising discrete liquid droplets of an effective amount of fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof;

in a pharmaceutically acceptable liquid carrier;

said droplets having a mean diameter of at least about 10 microns.

2. The sublingual fentanyl formulation of claim 1, wherein said liquid droplets have a mean diameter of at least about 20 microns.

3. The sublingual fentanyl formulation of claim 1, wherein said liquid droplets have a size distribution of from about 5 microns to about 500 microns.

4. The sublingual fentanyl formulation of claim 1, wherein said liquid droplets have a size distribution of from about 10 microns to about 200 microns.

5. The sublingual fentanyl formulation of claim 1, wherein said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof is included in said formulation in a concentration of from about 0.05 mg/ml to about 15 mg/ml.

6. The sublingual fentanyl formulation of claim 1 which provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 5 minutes to about 120 minutes, after sublingual administration to humans.

7. The sublingual fentanyl formulation of claim 1, which provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 10 to about 60 minutes, after sublingual administration to humans.

8. The sublingual fentanyl formulation of claim 1, which provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 15 to about 35 minutes after sublingual administration to humans.

9. The sublingual fentanyl formulation of claim 1, which provides a mean maximum plasma concentration (C_max) of fentanyl of about 127 pg/ml to about 213 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

10. The sublingual fentanyl formulation of claim 1, which provides a mean maximum plasma concentration (C_max) of fentanyl of about 142 pg/ml to about 195 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

11. The sublingual fentanyl formulation of claim 1, which provides a mean maximum plasma concentration (C_max) of fentanyl of about 158 pg/ml to about 177 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

12. The sublingual fentanyl formulation of claim 1, further comprising an organic solvent.

13. The sublingual fentanyl formulation of claim 12, wherein said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof is dissolved in said organic solvent.

14. The sublingual fentanyl formulation of claim 1, wherein said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof is dispersed in said pharmaceutically acceptable liquid carrier.

15. The sublingual fentanyl formulation of claim 1, further comprising an absorption enhancer.

16. The sublingual fentanyl formulation of claim 15, wherein said absorption enhancer is triacetin.

17. The sublingual fentanyl formulation of claim 15 or 16, wherein said absorption enhancer is in an amount of from about 0.001% to about 10% by weight of the formulation.

18. The sublingual fentanyl formulation of claim 1, which is a non-propellant formulation.

19. The sublingual fentanyl formulation of claim 1, wherein the fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof does not or substantially does not enter the lungs of a human patient after sublingual administration.

127. The fentanyl formulation of claim 1 wherein upon administration to a human patient, at least about 90% of the discrete liquid droplets have a mean diameter equal or greater than about 9 μ

m.

128. The fentanyl formulation of claim 127 wherein not more than about 5% of the discrete liquid droplets have a mean diameter less than 9 μ

m.

129. The fentanyl formulation of claim 127 wherein the formulation provides a respirable dose of not more than about 5% of the total fentanyl dose contained.

20. A unit dose of a sublingual fentanyl formulation comprising discrete liquid droplets of an effective amount of fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof;

in a pharmaceutically acceptable liquid carrier suitable for sublingual spray administration;

said droplets having a mean diameter of at least about 10 microns.

21. The unit dose of claim 20, wherein said liquid spray formulation comprises droplet particles having a mean diameter of at least about 20 microns.

22. The unit dose of claim 20, wherein said liquid spray formulation comprises droplet particles having a size distribution of from about 5 microns to about 500 microns.

23. The unit dose of claim 20, wherein said liquid spray formulation comprises droplet particles having a size distribution of from about 10 microns to about 200 microns.

24. The unit dose of claim 20, which comprises from about 10 pg to about 10 mg of said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

25. The unit dose of claim 20, which comprises from about 25 μ

g to about 5 mg of said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

26. The unit dose of claim 20, which comprises from about 50 μ

g to about 1600 μ

g of said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

27. The unit dose of claim 20, which provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 5 minutes to about 120 minutes, after sublingual administration to humans.

28. The unit dose of claim 20, which provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 10 to about 60 minutes, after sublingual administration to humans.

29. The unit dose of claim 20, which provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 15 to about 35 minutes after sublingual administration to humans.

30. The unit dose of claim 20, which provides a mean maximum plasma concentration (C_max) of fentanyl of about 127 pg/ml to about 213 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

31. The unit dose of claim 20, which provides a mean maximum plasma concentration (C_max) of fentanyl of about 142 pg/ml to about 195 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

32. The unit dose of claim 20, which provides a mean maximum plasma concentration (C_max) of fentanyl of about 158 pg/ml to about 177 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

33. The unit dose of claim 20, wherein said formulation is a non propellant formulation.

34. The unit dose of claim 20, wherein the fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof does not or substantially does not enter the lungs of a human patient after sublingual administration.

35. A method of treating pain comprising sublingually administering a liquid spray formulation in the form of discrete liquid droplets having a mean diameter of at least about 10 microns to a human patient experiencing pain, said liquid spray formulation comprising an effective amount of fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof, dispersed in a pharmaceutically acceptable liquid carrier.

36. The method of claim 35, wherein said liquid droplets have a mean diameter of at least about 20 microns.

39. The method of claim 35-37, or 38, wherein said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof is included in said liquid spray formulation in a concentration of from about 0.05 mg/ml to about 15 mg/ml.

40. The method of claim 35-37, or 38, wherein said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof is administered to said human patient in an amount of from about 10 μ

g to about 10 mg.

41. The method of claim 35-37, or 38, wherein said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof is administered to said human patient in an amount of from about 25 μ

g to about 5 mg.

42. The method of claim 35-37 or 38, wherein said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof is administered to said human patient in an amount of from about 50 μ

g to about 1600 μ

g.

43. The method of claim 35-37 or 38, wherein said liquid spray formulation provides a mean time to maximum plasma concentration (Tmax) of fentanyl at from about 5 minutes to about 120 minutes, after sublingual administration to humans.

44. The method of claim 35-37 or 38, wherein said liquid spray formulation provides a mean time to maximum plasma concentration (Tmax) of fentanyl at from about 10 to about 60 minutes, after sublingual administration to humans.

45. The method of claim 35-37 or 38, wherein said liquid spray formulation provides a mean time to maximum plasma concentration (Tmax) of fentanyl at from about 15 to about 35 minutes after sublingual administration to humans.

46. The method of claim 35-37 or 38, wherein said liquid spray formulation provides a mean maximum plasma concentration (Cmax) of fentanyl of about 127 pg/ml to about 213 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

47. The method of claim 35-37 or 38, wherein said liquid spray formulation provides a mean maximum plasma concentration (Cmax) of fentanyl of about 142 pg/ml to about 195 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

48. The method of claim 35-37 or 38, wherein said liquid spray formulation provides a mean maximum plasma concentration (Cmax) of fentanyl of about 158 pg/ml to about 177 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

49. The method of claim 35-37 or 38, wherein said human patient has cancer which causes said pain.

50. The method of claim 35-37 or 38, wherein said spray formulation further comprises an organic solvent.

52. The method of claim 50, wherein said organic solvent is a cosolvent comprising ethanol, propylene glycol, polyethylene glycol, labrosol, labrafil, transcutol, or combination thereof.

53. The method of claim 35-37 or 38, wherein said carrier is water.

54. The method of claim 35-37 or 38, wherein said carrier is miglyol.

55. The method claim 35-37 or 38, wherein said spray formulation further comprises an absorption enhancer.

56. The method of claim 55, wherein said absorption enhancer is triacetin.

57. The method of claim 55, wherein said absorption enhancer is included in said spray formulation in an amount of from about 0.001% to about 10% by weight of the formulation.

58. The method of claim 35-37 or 38, wherein none or substantially none of the liquid spray formulation enters the lungs of the human patient after administration.

130. The method of treatment of claim 35 wherein upon administration to a human patient, at least about 90% of the discrete liquid droplets have a mean diameter equal or greater than about 9 μ

m.

131. The method of treatment of claim 35 wherein not more than about 5% of the discrete liquid droplets have a mean diameter less than 9 μ

m.

132. The method of treatment of claim 35 wherein the formulation provides a respirable dose of not more than about 5% of the total fentanyl dose contained.

37. A method of treating pain comprising sublingually administering a liquid spray formulation in the form of discrete liquid droplets having a size distribution of from about 5 microns to about 500 microns to a human patient experiencing pain;

said liquid spray formulation comprising an effective amount of fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof, dispersed in a pharmaceutically acceptable liquid carrier.

38. The method of claim 37, wherein said size distribution is from about 10 microns to about 200 microns.

51. The method of claim 51, wherein said organic solvent is ethanol.

59. A method of treating breakthrough pain comprising:

sublingually administering a liquid spray formulation comprising an effective amount of fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof, dispersed in a pharmaceutically acceptable carrier to a human patient who is receiving chronic pain treatment, and is experiencing breakthrough pain.

60. The method of claim 59, wherein said liquid spray formulation is administered in the form of discrete liquid droplets having a mean diameter greater than about 10 microns.

61. The method of claim 59, wherein said liquid spray formulation is administered in the form of discrete liquid droplets having a mean diameter greater than about 20 microns.

62. The method of claim 59, wherein said liquid spray formulation is administered in the form of discrete liquid droplets having a size distribution of from about 5 microns to about 500 microns.

63. The method of claim 59, wherein said liquid spray formulation is administered in the form of discrete liquid droplets having a size distribution of from about 10 microns to about 200 microns.

64. The method of claim 59, wherein said fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof is included in said liquid spray formulation in a concentration of from about 0.05 mg/ml to about 15 mg/ml.

65. The method of claim 59, wherein said liquid spray formulation provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 5 minutes to about 120 minutes, after sublingual administration to humans.

66. The method of claim 59, wherein said liquid spray formulation provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 10 to about 60 minutes, after sublingual administration to humans.

67. The method of claim 59, wherein said liquid spray formulation provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 15 to about 35 minutes after sublingual administration to humans.

68. The method of claim 59, wherein said liquid spray formulation provides a mean maximum plasma concentration (C_max) of fentanyl of about 127 pg/ml to about 213 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

69. The method of claim 59, wherein said liquid spray formulation provides a mean maximum plasma concentration (C_max) of fentanyl of about 142 pg/ml to about 195 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

70. The method of claim 59, wherein said liquid spray formulation provides a mean maximum plasma concentration (C_max) of fentanyl of about 158 pg/ml to about 177 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

71. The method of claim 59, wherein said human patient has cancer which causes said pain.

72. The method of claim 59, wherein said spray formulation further comprises an organic solvent.

73. The method of claim 72, wherein said organic solvent is ethanol.

74. The method of claim 72, wherein said organic solvent is a cosolvent comprising ethanol, propylene glycol, polyethylene glycol, labrosol, labrafil, transcutol, or combination thereof.

75. The method of claim 59, wherein said carrier is water.

76. The method of claim 59, wherein said carrier is miglyol.

77. The method of claim 59, wherein said spray formulation is a non-propellant formulation.

78. The method of claim 59, wherein none or substantially none of the liquid spray formulation enters the lungs of the human patient after administration.

79. A unit dose or bi-dose device for sublingual administration of a drug comprising:

a reservoir containing a unit dose or a bi-dose of a liquid formulation comprising an effective amount of fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof in a pharmaceutically acceptable liquid carrier; and

the device having an actuator which when actuated delivers the unit dose of the liquid formulation in the form of liquid droplets having a mean diameter of at least about 10 microns.

80. The unit dose or bi-dose device of claim 79, wherein said delivered unit dose comprises from about 10 μ

g to about 10 mg fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

81. The unit dose or bi-dose device of claim 79, wherein said delivered unit dose comprises from about 25 μ

g to about 5 mg fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

82. The unit dose or bi-dose device of claim 79, wherein said delivered unit dose comprises from about 50 μ

g to about 1600 μ

g fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

83. The unit dose or bi-dose device of claim 79, the device further comprising a stopper comprising a material that precludes or substantially precludes the absorption of the fentanyl, pharmaceutically acceptable salt thereof or derivative thereof.

84. The unit dose or bi-dose device of claim 83, wherein the stopper is a component of a primary packaging of the device which affects spray characteristics of the liquid formulation.

85. The unit dose or bi-dose device of claim 83, wherein said stopper has the following composition and characteristic:

a) elastomer;

bromobutyl and/or chlorobutyl;

b) reinforcement;

inert material;

inert mineral; and

c) curing system;

unconventional.

92. The device of claim 79-90, or 91, wherein said liquid droplets have a mean diameter of at least about 20 microns.

93. The device of claim 79-90, or 91, wherein said liquid droplets have a size distribution of from about 5 microns to about 500 microns.

94. The device of claim 79-90, or 91, wherein said liquid droplets have a size distribution of about 10 microns to about 200 microns.

95. The device of claim 79-90, or 91, wherein said dose provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 5 minutes to about 120 minutes, after sublingual administration to humans.

96. The device of claim 79-90, or 91, wherein said dose provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 10 to about 60 minutes, after sublingual administration to humans.

97. The device of claim 79-90, or 91, wherein said dose provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 15 to about 35 minutes after sublingual administration to humans.

98. The device of claim 79-90, or 91, wherein said liquid formulation is a non-propellant formulation.

99. The device of claim 79-90, or 91, wherein none or substantially none of the dose enters the lungs of a human patient after sublingual administration.

100. The device of claim 79, wherein after said unit dose is delivered, said device is substantially empty.

101. The device of claim 79, wherein said device is disposable after said unit dose is delivered.

133. The device of claim 79 wherein upon administration to a human patient, at least about 90% of the discrete liquid droplets have a mean diameter equal or greater than about 9 μ

m.

134. The device of claim 79 wherein not more than about 5% of the discrete liquid droplets have a mean diameter less than 9 μ

m.

135. The device of claim 79 wherein the formulation provides a respirable dose of not more than about 5% of the total fentanyl dose contained.

86. A multi-dose device for sublingual administration of a drug comprising:

a reservoir containing a liquid formulation comprising fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof in a pharmaceutically acceptable liquid carrier; and

the device having an actuator which when actuated delivers a therapeutically effective dose of the liquid formulation in the form of liquid droplets having a mean diameter of at least about 10 microns.

87. The multi-dose device of claim 86, wherein said therapeutically effective dose comprises from about 10 μ

g to about 10 mg fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

88. The multi-dose device of claim 86, wherein said therapeutically effective dose comprises from about 25 μ

g to about 5 mg fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

89. The multi-dose device of claim 86, wherein said therapeutically effective dose comprises from about 50 μ

g to about 1600 μ

g fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

90. The multi-dose device of claim 86, wherein the device further comprises a gasket comprising a material which precludes or substantially precludes the absorption of the fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

91. The device of claim 86, wherein said gasket has the following composition and characteristic:

a) elastomer;

bromobutyl and/or chlorobutyl;

b) reinforcement;

inert material;

inert mineral; and

c) curing system;

unconventional.

102. The device of claim 86, which contains two doses of said fentanyl, pharmaceutically acceptable salt thereof, or derivative.

103. The device of claim 102, wherein said device is substantially empty after said two doses are delivered.

104. The device of claim 103, wherein said device is disposable after said two doses are delivered.

105. The device of claim 86, further including a lock-out mechanism which allows for the administration of one dose and locks out of further administration for a certain period of time.

136. The device of claim 86 wherein upon administration to a human patient, at least about 90% of the discrete liquid droplets have a mean diameter equal or greater than about 9 μ

m.

137. The device of claim 86 wherein not more than about 5% of the discrete liquid droplets have a mean diameter less than 9 μ

m.

138. The device of claim 86 wherein the formulation provides a respirable dose of not more than about 5% of the total fentanyl dose contained.

106. A method of treating pain comprising:

utilizing a sublingual spray device comprising a reservoir containing a liquid formulation comprising fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof in a pharmaceutically acceptable liquid carrier; and

the device having an actuator which upon actuation delivers a therapeutically effective amount of liquid droplets to be sprayed from the device having a mean diameter of at least about 10 microns.

107. The method of claim 106, wherein said liquid droplets have a mean diameter greater than about 20 microns.

108. The method of claim 106, wherein said liquid droplets have a size distribution of from about 5 microns to about 500 microns.

109. The method of claim 106, wherein said liquid droplets have a size distribution of from about 10 microns to about 200 microns.

110. The method of claim 106, wherein said therapeutically effective amount comprises from about 10 pg to about 10 mg fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

111. The method of claim 106, wherein said therapeutically effective amount comprises from about 25 μ

g to about 5 mg fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

112. The method of claim 106, wherein said therapeutically effective dose comprises from about 50 μ

g to about 1600 μ

g fentanyl, pharmaceutically acceptable salt thereof, or derivative thereof.

113. The method of claim 106, wherein said therapeutically effective amount provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 5 minutes to about 120 minutes, after sublingual administration to humans.

114. The method of claim 106, wherein said therapeutically effective amount provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 10 to about 60 minutes, after sublingual administration to humans.

115. The method of claim 106, wherein said therapeutically effective amount provides a mean time to maximum plasma concentration (T_max) of fentanyl at from about 15 to about 35 minutes after sublingual administration to humans.

116. The method of claim 106, wherein said therapeutically effective amount provides a mean maximum plasma concentration (C_max) of fentanyl of about 127 pg/ml to about 213 pg/ml per 100 μ

g fentanyl after sublingual administration to humans.

117. The method of claim 106, wherein said a liquid formulation is a non-propellant formulation.

118. The method of claim 106, wherein none or substantially none of the liquid droplets enter the lungs of a human patient after sublingual administration.

119. A method of preparing a pharmaceutical composition for sublingual administration comprising:

preparing a mixture of a therapeutically active agent in a pharmaceutically acceptable carrier,

incorporating a sufficient amount of said mixture into a unit dose device to provide at least one therapeutic dose, said device being capable of being actuated to deliver liquid droplets of said at least one therapeutic dose having a mean diameter of at least about 10 microns to the sublingual region of a human.

120. A sublingual pharmaceutical formulation comprising discrete liquid droplets of an effective amount of a therapeutically active agent in a pharmaceutically acceptable liquid carrier;

said droplets having a mean diameter of at least about 10 microns.

121. A unit dose of a sublingual pharmaceutical formulation comprising discrete liquid droplets of an effective amount of a therapeutically active agent, in a pharmaceutically acceptable liquid carrier suitable for sublingual spray administration;

said droplets having a mean diameter of at least about 10 microns.

122. A method of treating a human patient comprising sublingually administering a liquid spray formulation in the form of discrete liquid droplets having a mean diameter of at least about 10 microns to a human patient, said liquid spray formulation comprising an effective amount of therapeutically active agent, dispersed in a pharmaceutically acceptable liquid carrier.

123. A method of treating a human patient comprising sublingually administering a liquid spray formulation in the form of discrete liquid droplets having a size distribution of from about 5 microns to about 500 microns to a human patient;

said liquid spray formulation comprising an effective amount of therapeutically active agent, dispersed in a pharmaceutically acceptable liquid carrier.

124. A unit dose or bi-dose device for sublingual administration of a drug comprising:

a reservoir containing a unit dose or a bi-dose of a liquid formulation comprising an effective amount of a therapeutically active agent in a pharmaceutically acceptable liquid carrier; and

the device having an actuator which when actuated delivers the unit dose of the liquid formulation in the form of liquid droplets having a mean diameter of at least about 10 microns.

125. A multi-dose device for sublingual administration of a drug comprising:

a reservoir containing a liquid formulation comprising a therapeutically active agent; and

the device having an actuator which when actuated delivers a therapeutically effective dose of the liquid formulation in the form of liquid droplets having a mean diameter of at least about 10 microns.

126. A method of treating a human patient comprising:

utilizing a sublingual spray device comprising a reservoir containing a liquid formulation comprising a therapeutically active agent in a pharmaceutically acceptable liquid carrier; and

the device having an actuator which upon actuation delivers a therapeutically effective amount of liquid droplets to be sprayed from the device having a mean diameter of at least about 10 microns.