Intranasal Benzodiazepine compositions

• US 20040176359A1
• Filed: 03/17/2004
• Published: 09/09/2004
• Est. Priority Date: 02/20/2001
• Status: Abandoned Application

• Current Assignee: University Of Kentucky Research Foundation (University of Kentucky)
• Original Assignee: University Of Kentucky Research Foundation (University of Kentucky)
• Inventors: Wermeling, Daniel P.
• Application Number:
  US10/803,521
• Publication Number:
  US 20040176359A1
• Time in Patent Office: Days
• US Class Current: 514/221
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• 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 9/0043 Nose
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

A pharmaceutical composition for intranasal administration to a mammal. The pharmaceutical composition comprises an effective amount of a benzodiazepine or pharmaceutically acceptable salt thereof; and a nasal carrier. In some embodiments, the pharmaceutical composition when administered intranasally produces a rapid physiological response. Pharmaceutical compositions may also include at least one or more sweeteners, flavoring agents, or masking agents or combinations thereof.

Claims

1. A pharmaceutical composition for intranasal administration comprising:

an effective amount of a benzodiazepine or pharmaceutically acceptable salt thereof;

a nasal carrier; and

at least one or more sweeteners, flavoring agents, or masking agents or combinations thereof.

2. A pharmaceutical composition according to claim 1, wherein the benzodiazepine is alprazolam, brotizolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flurazepam, quazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazapam, oxazepam, prazepam, quazepam, temazepam, triazolam, zolpidem, zaleplon or combinations thereof.

3. A pharmaceutical composition according to claim 2, wherein the benzodiazepine is midazolam.

4. A pharmaceutical composition according to claim 3, wherein the volume of the composition is about 0.1 ml.

5. A pharmaceutical composition according to claim 3, wherein the composition is preservative free.

6. A pharmaceutical composition according to claim 3, wherein the composition contains a buffer.

7. A pharmaceutical composition according to claim 3, wherein the composition is a sterile solution or suspension.

8. A pharmaceutical composition according to claim 3, wherein the composition contains an anesthetic agent.

9. A pharmaceutical composition according to claim 1, wherein the one or more sweeteners, flavoring agents or masking agents is saccharin, sodium saccharin, xylitol, mannitol, sorbitol, sucrose, sucralose, maltodextrin, aspartame, acesulfame potassium, dextrose, glycosides, maltose, sweet orange oil, glycerin, wintergreen oil, peppermint oil, peppermint water, peppermint spirit, menthol, or combinations thereof.

10. A pharmaceutical composition according to claim 1, wherein the composition has a pH of about 5.0.

11. A pharmaceutical composition for intranasal administration to a mammal comprising:

an effective amount of midazolam or pharmaceutically acceptable salt thereof, polyethylene glycol, saccharin powder, and propylene glycol.

12. A pharmaceutical composition according to claim 11, wherein the polyethylene glycol comprises from about 15% to about 25% by volume and the propylene glycol constitutes from about 75% to about 85% by volume of the composition.

13. A pharmaceutical composition according to claim 11, wherein the composition contains a preservative.

14. A pharmaceutical composition according to claim 11, wherein the composition is preservative-free.

15. A pharmaceutical composition according to claim 11, wherein the composition contains an anesthetic agent.

16. A pharmaceutical composition according to claim 11, wherein the composition achieves a time to maximum plasma concentration (T_max) within about 5 minutes to about 20 minutes after intranasal administration.

17. A pharmaceutical composition according to claim 11, wherein the composition achieves a time to maximum plasma concentration (T_max) within about 5 minutes after intranasal administration.

18. A pharmaceutical composition according to claim 11, wherein the composition achieves a maximum plasma concentration (C_max) of about 40 ng/mL from a 2.5 mg dose or about 80 ng/mL from a 5 mg dose after intranasal administration.

19. A pharmaceutical composition according to claim 18, wherein the ratio of the AUC for intranasal midazolam to AUC of for midazolam after an equivalent dose of intravenous midazolam is at least about 1:

1.7.

20. A method of treating a mammal in need of rapid sedation, anxiolysis, amnesia, or induction of anesthesia comprising intranasally administering to the mammal an effective amount of a pharmaceutical composition comprising midazolam or pharmaceutically acceptable salt thereof;

and a nasal carrier;

wherein the rapid sedation, anxiolysis, amnesia, or induction of anesthesia occurs within 5 minutes after intranasal administration.

21. A method of treating a mammal in need of rapid sedation, anxiolysis, amnesia, or induction of anesthesia comprising intranasally administering to the mammal an effective amount of a pharmaceutical composition comprising midazolam or pharmaceutically acceptable salt thereof;

a nasal carrier; and

at least one or more sweeteners, flavoring agents, or masking agents or combinations thereof.

22. A method according to claim 21, wherein the at least one sweetener, flavoring agent or masking agent is saccharin, sodium saccharin, xylitol, mannitol, sorbitol, sucrose, aspartame, acesulfame potassium, dextrose, glycosides, maltose, sweet orange oil, glycerin, wintergreen oil, peppermint oil, peppermint water, peppermint spirit, menthol, or combinations thereof.

23. A method according to claim 21, wherein the rapid sedation, anxiolysis, amnesia, or induction of anesthesia occurs within 5 minutes after intranasal administration.

24. A method according to claim 21, wherein the rapid sedation, anxiolysis, amnesia, or induction of anesthesia occurs at a time to maximum plasma concentration (T_max) of within 5 minutes after intranasal administration.

25. A method according to claim 21, wherein the pharmaceutical composition achieves a 1-hydroxymidazolam plasma level of about 1 to about 8 nanograms/ml after intranasal administration.

26. A method of making a pharmaceutical composition for intranasal administration comprising adding at least one or more sweeteners, flavoring agents, or masking agents or combinations thereof to a pharmaceutical composition comprising midazolam or pharmaceutically acceptable salt thereof, and a nasal carrier so as to make the pharmaceutical composition.