Room Temperature Stable, Lyophilized Natriuretic Peptide Formulations
Lyophilized pharmaceutical compositions comprise a natriuretic peptide, a buffer and a bulking agent that are stable at room temperature. Preferably, for a fill volume of 1 mL (pre-lyophilization), the total cake mass, post-lyophilization, is 30-175 mg. Preferably, the natriuretic peptide is ularitide or a pharmaceutically acceptable salt thereof. Various embodiments of the compositions may further comprise at least one of an acid and a base. In some embodiments, the pH of the compositions is between 4.0 and 6.0. In addition, various embodiments of the compositions may further comprise a stabilizing agent. In some embodiments, the compositions are isotonic. Preferably, the compositions are used for the treatment of cardiac conditions. The invention also relates to methods for preparing such compositions.
1 . A lyophilized pharmaceutical composition comprising:
(a) a natriuretic peptide;
(b) a bulking agent; and
(c) a buffer.
2 . The composition of claim 1 wherein the natriuretic peptide is selected from the group consisting of atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide, dendroaspis natriuretic peptide and ularitide.
3 . The composition of claim 2 wherein the natriuretic peptide is ularitide.
4 . The composition of claim 1 wherein the bulking agent is selected from the group consisting of mannitol and glycine.
5 . The composition of claim 1 wherein the buffer is histidine.
6 . The composition of claim 1 wherein the composition further comprises a stabilizing agent.
7 . The composition of claim 6 wherein the stabilizing agent is selected from the group consisting of sucrose and trehalose.
8 . The composition of claim 1 wherein the composition further comprises at least one of an acid and a base.
9 . The composition of claim 8 wherein the acid is hydrochloric acid.
10 . The composition of claim 8 wherein the base is sodium hydroxide.
11 . The composition of claim 1 wherein the pH of the composition is 4.0-6.0.
12 . The composition of claim 1 wherein the lyophilized composition has a post-lyophilization total cake mass of 30-175 mg for a fill volume of 1 mL (pre-lyophilization).
13 . The composition of claim 1 comprising:
(a) 0.1-10 mg/mL natriuretic peptide;
(b) 1-10% bulking agent; and
(c) 1-25 mM buffer.
14 . The composition of claim 1 comprising:
(a) 0.1-10 mg/mL ularitide;
(b) 1-10% bulking agent; and
(c) 1-25mM buffer.
15 . The composition of claim 1 comprising:
(a) 0.1-10 mg/mL ularitide;
(b) 1-10% bulking agent; and
(c) 1-25 mM buffer;
wherein the pH of the composition is 4.0-6.0.
16 . The composition of claim 1 comprising:
(a) 0.1-10 mg/mL ularitide;
(b) 1-10% bulking agent;
(c) 1-25 mM buffer; and
(d) 1-10% stabilizing agent.
17 . The composition of claim 1 comprising:
(a) 0.1-10 mg/mL ularitide;
(b) 1-10% bulking agent;
(c) 1-25 mM buffer; and
(d) 1-10% stabilizing agent;
wherein the pH of the composition is 4.0-6.0.
18 . The composition of claim 15 comprising:
(a) 2 mg/mL ularitide;
(b) 5% mannitol; and
(c) 10 mM histidine;
wherein the pH of the composition is 5.5.
19 . The composition of claim 17 comprising:
(a) 2 mg/mL ularitide;
(b) 5% mannitol;
(c) 10 mM histidine; and
(d) 1% sucrose;
wherein the pH of the composition is 5.5.
20 . The composition of claim 15 comprising:
(a) 2 mg/mL ularitide;
(b) 6% glycine; and
(c) 10 mM histidine;
wherein the pH of the composition is 5.5.
21 . The composition of claim 17 comprising:
(a) 2 mg/mL ularitide;
(b) 6% glycine;
(c) 10 mM histidine; and
(d) 1% sucrose,
wherein the pH of the composition is 5.5.
22 . The composition of claim 15 comprising:
(a) 1-3 mg/mL ularitide;
(b) 3-7% mannitol; and
(c) 8-12 mM histidine;
wherein the pH of the composition is 5.0-6.0.
23 . The composition of claim 17 comprising:
(a) 1-3 mg/mL ularitide;
(b) 3-7% mannitol;
(c) 8-12 mM histidine; and
(d) 0.25-2% sucrose;
wherein the pH of the composition is 5.0-6.0.
24 . The composition of claim 15 comprising:
(a) 1-3 mg/mL ularitide;
(b) 4-8% glycine; and
(c) 8-12 mM histidine;
wherein the pH of the composition is 5.0-6.0.
25 . The composition of claim 17 comprising:
(a) 1-3 mg/mL ularitide;
(b) 4-6% glycine;
(c) 8-12 mM histidine; and
(d) 0.25-2% sucrose,
wherein the pH of the composition is 5.0-6.0.