Intranasal opioid compositions, delivery devices and methods of using same

• US 20060083691A1
• Filed: 10/05/2005
• Published: 04/20/2006
• Est. Priority Date: 05/10/2000
• Status: Abandoned Application

• Current Assignee: University of Kentucky, University Of Kentucky Research Foundation (University of Kentucky)
• Original Assignee: University Of Kentucky Research Foundation (University of Kentucky)
• Inventors: Wermeling, Daniel P.
• Application Number:
  US11/243,613
• Publication Number:
  US 20060083691A1
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61M 15/0045 using multiple prepacked dosages on a same carrier, e.g. blisters
• CPC Class Codes: A61M 15/08 Inhaling devices inserted into the nose
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 9/00 Drugs for disorders of the cardiovascular system

Abstract

The present invention relates to pharmaceutical compositions comprising opioids and a liquid nasal carrier, to delivery devices comprising such compositions, and to methods of manufacture and use of such compositions.

Claims

1. A method for providing analgesia to a subject in need thereof, the method comprising intranasally administering to the subject, using an intranasal unit dose delivery device, a pharmaceutical composition comprising:

an effective amount of butorphanol or a pharmaceutically acceptable salt thereof, and a liquid nasal carrier, wherein upon intranasal administration of the composition to a subject, the subject exhibits one or more of;

a T_max butorphanol plasma concentration of at most about 0.75 hr;

a C_max butorphanol plasma concentration of about 1000 pg/ml to about 10,000 pg/ml; and

/or an AUC butorphanol plasma concentration of about 5000 pg*hr/ml to about 18,000 pg*hr/ml.

2. The method of claim 1, wherein upon the liquid nasal carrier comprises anhydrous citric acid, purified water and the composition has a pH of about 3 to about 6.

3. The method of claim 2, wherein the composition is a sterile solution or suspension.

4. The method of claim 2, wherein the composition has a pH of about 5.0.

5. The pharmaceutical composition of claim 4, wherein the liquid nasal carrier comprises water for injection.

6. The method of claim 1, wherein the subject exhibits a C_max butorphanol plasma concentration of about 1500 pg/ml to about 9000 pg/ml.

7. The method of claim 1, wherein the subject exhibits a T_max butorphanol plasma concentration of about 0.05 to about 0.5 hours.

8. The method of claim 1, the subject exhibits an AUC(O-t) butorphanol plasma concentration of about 3000 to about 7000 pg*hr/ml.

9. The method of claim 1, wherein the subject exhibits a C_max butorphanol plasma concentration of about 2500 pg/ml to about 5500 pg/ml;

a T_max butorphanol plasma concentration of at most about 0.5 hr; and

an AUC(0-t) butorphanol plasma concentration of about 5200 to about 18000 pg*hr/ml.

10. An intranasal unit-dose delivery device comprising one or more sealed vessels containing a sterilized, preservative-free pharmaceutical composition, said composition comprising an effective amount of butorphanol tartrate and liquid nasal carrier, wherein upon positioning the device 1 cm away from a detection laser beam, actuating the device to produce a spray plume perpendicular to said laser beam, and detecting droplet size distribution of the spray plume with said laser beam, the spray plume has a maximum droplet size of about 1 to about 4 μ

m.

11. The intranasal unit-dose delivery device of claim 10 wherein the butorphanol tartrate is present in the composition in a total amount about 0.1 to about 10 mg.

12. The intranasal unit-dose delivery device of claim 10 wherein the composition comprises a buffering agent.

13. The intranasal unit-dose delivery device of claim 10 wherein the buffering agent is a salt of citrate, acetate or phosphate or combination thereof.

14. The intranasal unit-dose delivery device of claim 10 wherein the buffering agent is present in the composition in a total amount of about 0.01% to about 3%, by weight.

15. The intranasal unit-dose delivery device of claim 10 wherein the liquid nasal carrier comprises an aqueous diluent.

16. The intranasal unit-dose delivery device of claim 10 wherein the aqueous diluent is selected from the group consisting of saline, water, dextrose or combinations thereof.

17. The intranasal unit-dose delivery device of claim 10 wherein the composition further comprises a sweetening agent.

18. The intranasal unit-dose delivery device of claim 17 wherein the sweetening agent is selected from the group consisting of acacia syrup, anethole, anise oil, aromatic elixir, benzaldehyde, benzaldehyde elixir, caraway, caraway oil, cardamom oil, cardamom seed, cardamom spirit, cardamom tincture, cherry juice, cherry syrup, cinnamon, cinnamon oil, cinnamon water, citric acid, citric acid syrup, clove oil, cocoa, cocoa syrup, coriander oil, dextrose, eriodictyon, eriodictyon fluidextract, eriodictyon syrup, aromatic, ethylacetate, ethyl vanillin, fennel oil, ginger, ginger fluidextract, ginger oleoresin, dextrose, glucose, sugar, maltodextrin, glycerin, glycyrrhiza, glycyrrhiza elixir, glycyrrhiza extract, glycyrrhiza extract pure, glycyrrhiza fluidextract, glycyrrhiza syrup, honey, iso-alcoholic elixir, lavender oil, lemon oil, lemon tincture, mannitol, methyl salicylate, nutmeg oil, orange bitter, elixir, orange bitter, oil, orange flower oil, orange flower water, orange oil, orange peel, bitter, orange peel sweet, tincture, orange spirit, compound, orange syrup, peppermint, peppermint oil, peppermint spirit, peppermint water, phenylethyl alcohol, raspberry juice, raspberry syrup, rosemary oil, rose oil, rose water, stronger, saccharin, saccharin calcium, saccharin sodium, sarsaparilla syrup, sarsaparilla compound, sorbitol solution, spearmint, spearmint oil, sucrose, sucralose, syrup, thyme oil, tolu balsam, tolu balsam syrup, vanilla, vanilla tincture, vanillin, wild cherry syrup, or combinations thereof.

19. The intranasal unit-dose delivery device of claim 10 wherein upon positioning the device 1 cm away from an impaction plate, actuating the device to produce a spray pattern onto the impaction plate, and measuring the diameter of the spray pattern, the spray pattern has a minimum diameter of about 1 to about 3 cm.

20. The intranasal unit-dose delivery device of claim 10 wherein upon positioning the device 1 cm away from a detection laser beam, actuating the device to produce a spray plume perpendicular to said laser beam, and detecting droplet size distribution of the spray plume, the spray plume has a Dv10 of about 10 to about 25 μ

m.

21. The intranasal unit-dose delivery device of claim 10 wherein upon positioning the device 1 cm away from a detection laser beam, actuating the device to produce a spray plume perpendicular to said laser beam, and detecting droplet size distribution of the spray plume, the spray plume has a Dv50 of about 20 to about 60 μ

m.

22. The intranasal unit-dose delivery device of claim 10 wherein upon positioning the device 1 cm away from an impaction plate, actuating the device to produce a spray pattern onto the impaction plate, and measuring the diameter of the spray pattern, the spray pattern has a span of about 1 to about 5.

23. The intranasal unit-dose delivery device of claim 10 wherein upon positioning the device 5 cm away from an impaction plate, actuating the device to produce a spray pattern onto the impaction plate, and measuring the diameter of the spray pattern, the spray pattern has a maximum diameter of about 6 to about 9 cm.

24. The intranasal unit-dose delivery device of claim 10 wherein upon positioning the device 5 cm away from an impaction plate, actuating the device to produce a spray pattern onto the impaction plate, and measuring the diameter of the spray pattern, the spray pattern has a minimum diameter of about 6 to about 8 cm.

25. The intranasal unit-dose delivery device of claim 10 wherein upon positioning the device 5 cm away from a detection laser beam, actuating the device to produce a spray plume perpendicular to said laser beam, and detecting droplet size distribution of the spray plume, the spray plume has a Dv10 of about 9 to about 20 μ

m.

26. The intranasal unit-dose delivery device of claim 10 wherein upon positioning the device 5 cm away from a detection laser beam, actuating the device to produce a spray plume perpendicular to said laser beam, and detecting droplet size distribution of the spray plume, the spray plume has a span of about 1 to about 4.