Intranasal naloxone compositions and methods of making and using same

• US 9,192,570 B2
• Filed: 12/19/2014
• Issued: 11/24/2015
• Est. Priority Date: 12/20/2013
• Status: Active Grant

• Current Assignee: Indivior UK Limited (Indivior Plc)
• Original Assignee: AntiOp, Inc.
• Inventors: Wyse, Joseph, DeHart, Michael Paul
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US14/576,357
• Publication Number:
  US 20150174061A1
• Time in Patent Office: 340 Days
• Field of Search: 514/23
• US Class Current: 1/1
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• 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 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

Disclosed herein are compositions containing an opioid antagonist such as naloxone and one or more pharmaceutically acceptable excipients. The compositions may be used for intranasal delivery of Naloxone for the treatment of, for example, opioid overdose in an individual in need thereof. Also disclosed are methods of making compositions containing Naloxone, and devices for nasal delivery of naloxone compositions.

Claims

1. A nasal spray composition comprising

a. from about 5 mg/mL to about 50 mg/mL of naloxone;

b. from about 5 mM to about 50 mM citric acid;

c. from about 2 to about 20 mM disodium ethylene diamine tetraacetic acid (EDTA);

d. from about 0.1 to about 2 weight % benzyl alcohol; and

e. a carrier.

2. The nasal spray composition of claim 1, wherein administration of said composition intranasally results in a parameter selected from a T_max of about 0.1 hours to about 0.5 hours in a subject;

a peak plasma concentration of from about 1.0 to about 4.0 ng/mL at a time period of from about 5 to about 30 minutes after administration; and

combinations thereof.

3. The nasal spray composition of claim 1, wherein administration of about 200 μ

L of said composition administers about 2 mg of naloxone intranasally, and results in an AUC_0-inf of from about 2.5 to about 4.5 ng-hr/mL, or about 2.5 to about 2.7 ng-hr/mL, or about 2.6 ng-hr/mL.

4. The nasal spray composition of claim 1, wherein administration of about 200 μ

L of said composition administers about 2 mg of naloxone intranasally, and results in a Cmax of from about 1 to about 3 or about 1.5 to about 2.5 or about 1.8 ng/mL.

5. The nasal spray composition of claim 1, wherein said composition has an osmolality of from about 300 to about 500 mOsm.

6. The nasal spray composition of claim 1, wherein said composition has a pH of about 4.

7. The nasal spray composition of claim 1, wherein said composition is substantially free of a material selected from a viscoelastic polymer, hydroxypropyl methylcellulose (hypromellose), glycerine, propylene glycol, sorbitol, ascorbic acid, a paraben preservative, or a combination thereof.

8. The nasal spray composition of claim 1, wherein said composition is substantially free of a paraben preservative selected from methylparaben, ethylparaben, propylparaben, butylparaben, heptylparaben, isobutyparaben, isopropylparaben, benzylparaben, sodium salts thereof, and combinations thereof, preferably methyl paraben, propylparaben, and combinations thereof.

9. The nasal spray composition of claim 1, wherein said composition comprises less than 0.1% of any individual Naloxone Related Substance.

10. The nasal spray composition of claim 1, wherein said composition is stable at room temperature for at least 6 months.

11. The nasal spray composition of claim 1 comprising

a. about 10 mg/mL naloxone HCl dihydrate;

b. about 25 mM citric acid;

c. about 10 mM EDTA;

d. about 0.5 weight % benzyl alcohol; and

e. a pharmaceutically acceptable carrier;

wherein intransal administration of about 200 μ

L of said composition achieves one or more parameters selected from a plasma concentration of about 1 ng/mL within about 5 to 15 minutes after intranasal administration;

a T_max of about 0.1 hours to about 0.5 hours, or about 0.3 hours;

an AUC_0-inf of from about 2.5 to about 4.5 ng-hr/mL, or about 2.5 to about 2.7 ng-hr/mL, or about 2.6 ng-hr/mL; and

a Cmax of from about 1 to about 3 or about 1.5 to about 2.5 or about 1.8 ng/mL.

12. The nasal spray composition according to claim 1, wherein said composition is a nasal spray comprising:

(i) about 7 mg/mL to about 11 mg/mL naloxone;

(ii) about 20 mM to about 30 mM citric acid;

(iii) about 5 mM to about 15 mM ethylenediaminetetraacetic acid; and

(iv) about 0.2% to about 1.0 weight % benzyl alcohol;

wherein the nasal spray has a pH of about 4.25±

0.1.

13. The nasal spray composition of claim 12, wherein the naloxone is naloxone hydrochloride dihydrate.

14. The nasal spray composition of claim 13, which comprises:

(i) about 10 mg/mL naloxone hydrochloride dihydrate;

(ii) about 25 mM citric acid;

(iii) about 10 mM ethylenediaminetetraacetic acid; and

(iv) about 0.5 weight % benzyl alcohol;

wherein the nasal spray has a pH of about 4.25±

0.1.

15. A nasal spray composition comprising

a. from about 5 mg/mL to about 50 mg/mL of naloxone;

b. from about 5 mM to about 50 mM citric acid;

c. from about 2 to about 20 mM disodium ethylene diamine tetraacetic acid (EDTA);

d. from about 0.1 to about 2 weight % benzyl alcohol; and

e. a carrier;

wherein said composition has a pH of about 4; and

wherein said composition has an osmolality of from about 300 to about 500 mOsm.