OPIOID ANTAGONIST FORMULATIONS
The present disclosure relates to pharmaceutical compositions comprising an opioid antagonist, isotonicity agent, a preservative agent, a stabilizing agent and citric acid. The pharmaceutical compositions are stable under various storage conditions. Methods of using the pharmaceutical compositions are also disclosed including methods of treatment
1 . A formulation comprising:
between about 0.3% (w/v) and about 3.0% (w/v) naloxone or a pharmaceutically acceptable salt thereof,
between about 0.3% (w/v) and about 3% (w/v) NaCl,
between about 0.005% (w/v) and about 0.05% (w/v) BZK,
between about 0.02% (w/v) and about 0.25% (w/v) EDTA, and
between about 0.10% (w/v) and about 1.0% (w/v) citric acid.
2 . The formulation of claim 1 , comprising:
between about 0.7% (w/v) and about 1.5% (w/v) naloxone or a pharmaceutically acceptable salt thereof,
between about 0.5% (w/v) and about 1.5% (w/v) NaCl,
between about 0.005% (w/v) and about 0.03% (w/v) BZK,
between about 0.05% (w/v) and about 0.10% (w/v) EDTA, and
between about 0.20% (w/v) and about 0.50% (w/v) citric acid.
3 . The formulation of claim 2 , wherein the formulation comprises about 1% (w/v) naloxone or a pharmaceutically acceptable salt thereof.
4 . The formulation of any one of claims 1 - 3 , wherein the NaCl is present in a concentration between about 0.7% (w/v) and about 1.4% (w/v).
5 . The formulation of any one of claims 1 - 3 , wherein the NaCl is present in a concentration between about 0.8% (w/v) and about 1.2% (w/v).
6 . The formulation of any one of claims 1 - 3 , wherein the NaCl is present in a concentration about 0.8% (w/v), about 0.9% (w/v), or about 1.0% (w/v).
7 . The formulation of any one of claims 1 - 6 , wherein BZK is present in an amount between about 0.01% (w/v) and about 0.02% (w/v).
8 . The formulation of any one of claims 1 - 6 wherein BZK is present in an amount about 0.008% (w/v), 0.009% (w/v), 0.010% (w/v), about 0.012% (w/v), about 0.014% (w/v), about 0.016% (w/v), about 0.018% (w/v), about 0.02% (w/v), about 0.021% (w/v), or about 0.022% (w/v).
9 . The formulation of any one of claims 1 - 8 , wherein the formulation has an osmolality between about 250 mOsm and 500 mOsm.
10 . The formulation of any one of claims 1 - 9 , wherein the formulation has a pH between about 3 and about 7, between about 3 and about 6, between about 3 and about 5, or between about 3 and about 4.
11 . The formulation of any one of claims 1 - 9 , wherein the formulation has a pH about 3.5.
12 . The formulation of any one of claims 1 - 11 , wherein the EDTA is present about 0.03%, about 0.04%, about 0.05% about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, or about 0.12% (w/v).
13 . The formulation of any one of claims 1 - 12 , wherein the formulation does not comprise a methylparaben, a propylparaben, or combinations thereof.
14 . The formulation of any one of claims 1 - 12 , wherein the formulation does not comprise alkylparabens.
15 . The formulation of any one of claims 1 - 12 , wherein the total amount of an alkylparaben present in the formulation is no greater than about 0.001% (w/v).
16 . An auto-injector device, wherein the device comprises a housing, a medicament container, and a delivery member, wherein the medicament container is disposed within the housing and defines an internal volume containing the formulation of any of claims 1 - 15 .
17 . A method of treating an opioid exposure in a subject in need thereof, the method comprising:
administering the formulation of any one of claims 1 - 15 , to a subject.
18 . The method of claim 17 , wherein the administering comprises injecting the subject with the formulation.
19 . The method of claim 18 , wherein the administration comprises injecting the subject intramuscularly with the formulation.
20 . The method of claim 18 , wherein the administration comprises injecting the subject subcutaneously with the formulation.
21 . The method of claim 18 , wherein the administration is performed with an autoinjector.
22 . A formulation comprising,
a) between about 0.3% (w/v) and about 3.0% (w/v) naloxone or a pharmaceutically acceptable salt thereof;
b) between about 0.3% (w/v) and about 3% (w/v) NaCl;
c) between about 0.005% (w/v) and about 0.05% (w/v) BZK;
d) between about 0.02% (w/v) and about 0.25% (w/v) EDTA; and
e) between about 0.10% (w/v) and about 1.0% (w/v) citric acid;
wherein administration of about 0.15 mg/Kg to about 0.45 mg/Kg to a subject in need of provides
i. an elimination half-life of between about 20 minutes and about 60 minutes;
ii. an AUC in plasma at between about 40 and about 70 hr*ng/mL when the AUC is measured at three times the elimination half-life or greater;
iii. a Cmax from about 30 to about 150 nanograms per milliliter;
iv. a Tmax between about 10 minutes and about 20 minutes; or
v. bioavailability greater than about 90%; or
vi. any combination thereof.
23 . A method of treating an opioid exposure in a subject in need thereof, the method comprising administering to the subject about 0.15 mg/Kg to about 0.45 mg/Kg of naloxone from a formulation comprising:
a) between about 0.3% (w/v) and about 3.0% (w/v) naloxone or a pharmaceutically acceptable salt thereof;
b) between about 0.3% (w/v) and about 3% (w/v) NaCl;
c) between about 0.005% (w/v) and about 0.05% (w/v) BZK;
d) between about 0.02% (w/v) and about 0.25% (w/v) EDTA; and
e) between about 0.10% (w/v) and about 1.0% (w/v) citric acid;
wherein said administration provides:
i. an elimination half-life of between about 20 minutes and about 60 minutes;
ii. an AUC in plasma at between about 40 and about 70 hr*ng/mL when the AUC is measured at three times the elimination half-life or greater;
iii. a Cmax from about 30 to about 150 nanograms per milliliter;
iv. a Tmax between about 10 minutes and about 20 minutes;
v. a bioavailability greater than about 90%; or
vi. a combination thereof.
24 . The method of claim 23 , wherein said administration comprises an auto-injector device comprising a housing, a medicament container, and a delivery member, wherein the medicament container is disposed within the housing and defines an internal volume containing the formulation.
25 . The method of claim 24 , wherein said administration provides an elimination half-life of between about 20 minutes and about 60 minutes; and/or an AUC in plasma at between about 40 and about 70 hr*ng/mL when the AUC is measured at three times the elimination half-life or greater.
26 . The method of claim 23 , wherein said administration provides an elimination half-life of between about 20 minutes and about 60 minutes; and/or a Cmax from about 30 to about 150 nanograms per milliliter.
27 . The method of claim 23 , wherein said administration provides an elimination half-life of between about 20 minutes and about 60 minutes; and/or a Tmax between about 10 minutes and about 20 minutes.
28 . The method of claim 23 , wherein said administration provides an AUC in plasma at between about 40 and about 70 hr*ng/mL when the AUC is measured at three times the elimination half-life or greater; and/or a Cmax from about 30 to about 150 nanograms per milliliter.
29 . The method of claim 23 , wherein said administration provides an AUC in plasma at between about 40 and about 70 hr*ng/mL when the AUC is measured at three times the elimination half-life or greater; and/or a Tmax between about 10 minutes and about 20 minutes.
30 . The method of claim 23 , wherein said administration provides a Cmax from about 30 to about 150 nanograms per milliliter; and/or a Tmax between about 10 minutes and about 20 minutes.
31 . The method of any of claims 23 - 31 , wherein an elimination half-life of between about 20 minutes and about 60 minutes; and/or a bioavailability greater than about 90%.
32 . The method of any of claims 23 - 31 , wherein an AUC in plasma at between about 40 and about 70 hr*ng/mL when the AUC is measured at three times the elimination half-life or greater; and/or a bioavailability greater than about 90%.
33 . The method of any of claims 23 - 31 , wherein a Cmax from about 30 to about 150 nanograms per milliliter; and/or a bioavailability greater than about 90%.
34 . The method of any of claims 23 - 31 , wherein a Tmax between about 10 minutes and about 20 minutes; and/or or a bioavailability greater than about 90%.
35 . The method of any of claims 23 - 34 , wherein the formulation has an osmolality between about 250 mOsm and 500 mOsm.
36 . The method of any of claims 23 - 35 , wherein the formulation has a pH between about 3 and about 7, between about 3 and about 6, between about 3 and about 5, or between about 3 and about 4.
37 . The method of any of claims 23 - 36 , wherein the formulation does not comprise a methylparaben, a propylparaben, or combinations thereof.
38 . The method of any of claims 23 - 37 , wherein the subject is administered a dose between about 8 mg and about 12 mg.
39 . The method of any of claims 23 - 38 , wherein the method comprises administering to the subject about 0.16 mg/Kg of naloxone from a formulation comprising:
a) about 1.0% (w/v) naloxone or a pharmaceutically acceptable salt thereof;
b) about 0.9% (w/v) NaCl;
c) about 0.02% (w/v) BZK;
d) about 0.1% (w/v) EDTA; and
e) about 0.5% (w/v) citric acid.
40 . The method of any of claims 23 - 38 , wherein the method comprises administering to the subject about 0.16 mg/Kg of naloxone from a formulation comprising:
a) about 1.0% (w/v) naloxone or a pharmaceutically acceptable salt thereof;
b) about 0.9% (w/v) NaCl;
c) about 0.01% (w/v) BZK;
d) about 0.1% (w/v) EDTA; and
e) about 0.5% (w/v) citric acid.
41 . The method of any of claims 23 - 40 , wherein the subject is administered about 10 mg naloxone.
42 . The method of any of claims 23 - 41 , wherein the subject is a human.
43 . The method of any of claims 23 - 39 , wherein the method comprises administering to the subject about 0.3 mg/Kg of naloxone from a formulation comprising:
a) about 1.0% (w/v) naloxone or a pharmaceutically acceptable salt thereof;
b) about 0.9% (w/v) NaCl;
c) about 0.02% (w/v) BZK;
d) about 0.1% (w/v) EDTA; and
e) about 0.5% (w/v) citric acid.
44 . The method of any of claims 23 - 38 , wherein the method comprises administering to the subject about 0.3 mg/Kg of naloxone from a formulation comprising:
a) about 1.0% (w/v) naloxone or a pharmaceutically acceptable salt thereof;
b) about 0.9% (w/v) NaCl;
c) about 0.01% (w/v) BZK;
d) about 0.1% (w/v) EDTA; and
e) about 0.5% (w/v) citric acid.
45 . The method of any of claims 43 and 44 , wherein the subject is a canine.