LOW-SORBING GLYBURIDE FORMULATION AND METHODS
Methods and formulations for minimizing or avoiding the sorption of glyburide to surfaces of delivery tubing, filters, bags, and other containers and materials, thereby storing and delivering a more stable product, delivering a predictable and accurate dose of glyburide, while minimizing impurities, avoiding drug waste, reducing cost, and significantly reducing the amount of dosing solution that must be infused into the patient.
1 . A formulation comprising:
a) glyburide or a pharmaceutically acceptable salt thereof;
b) a buffering agent;
c) a base; and
d) a sugar alcohol,
wherein the formulation has a pH outside of the buffering capacity of the buffering agent when reconstituted in water for injection (WFI), and
wherein the formulation is free of cyclodextrins.
2 . The formulation of claim 1 , wherein the pharmaceutically acceptable salt thereof is a sodium addition salt.
3 . The formulation of claim 1 , wherein the glyburide or pharmaceutically acceptable salt thereof is about 2 to 3.5%, 2.5 to 3.3%, 2.7 to 3.1%, 2.8 to 2.98%, 2.9 to 2.97%, or 2.94 to 2.96% (w/w) of the formulation.
4 . The formulation of claim 1 , wherein the sugar alcohol is about 70 to 93%, 75 to 92%, 80 to 91%, 84 to 90%, 86 to 89%, or 87 to 89% w/w of the formulation.
5 . The formulation of claim 1 , comprising the sugar alcohol and the glyburide or pharmaceutically acceptable salt thereof in a weight ratio of 25 to 50:1, 26 to 45:1, 27 to 40:1, 28 to 35:1, 29 to 33:1, 30:1, 31:1, or 32:1.
6 . The formulation of claim 1 , wherein, upon storage for 12 months at 25° C./60% relative humidity (RH), has a pH when reconstituted in WFI that is within about 0.2 pH unit of the formulation prior to storage.
7 . The formulation of claim 1 , wherein, upon storage for 6 months at 40° C./75% RH, has a pH when reconstituted in WFI that is within about 0.2 pH unit of the formulation prior to storage.
8 . The formulation of claim 1 , wherein, upon storage for 4 weeks at 70° C./75% RH, has a pH when reconstituted in WFI that is within about 0.2 pH unit of the formulation prior to storage.
9 . The formulation of claim 1 , wherein the buffering agent is a buffer having a pH of 7.8 to 9, 7.9 to 8.9, 8 to 8.8, 8.1 to 8.7, 8.2 to 8.6, 8.3 to 8.5, 8.4 to 8.6, or 8.5.
10 . The formulation of claim 1 , comprising the base and the glyburide or pharmaceutically acceptable salt thereof in a ratio so the formulation has a pH of 9.8 to 11.2, 9.9 to 11.1, 10.0 to 11.0, 10.1 to 10.9, 10.2 to 10.8, 10.3 to 10.7, or 10.4 to 10.6 when reconstituted in water for injection (WFI).
11 . The formulation of claim 1 , comprising the sugar alcohol and the buffering agent in a weight ratio of 5 to 15:1, 6 to 14:1, 7 to 13:1, 8 to 12:1, 9 to 11:1, 9.5:1, 10:1, or 10.5:1.
12 . The formulation of claim 1 , comprising 26 to 34 mg/ml of the sugar alcohol.
13 . The formulation of claim 1 , wherein the base and the glyburide or pharmaceutically acceptable salt thereof have a molar ratio of 5.0 to 6.7:1, 5.1 to 6.6:1, 5.2 to 6.5:1, 5.3 to 6.4:1, 5.4 to 6.3:1, 5.5 to 6.2:1, 5.6 to 6.1:1, 5.7 to 6.0:1, or 5.2:1, 5.3:1, 5.4:1, 5.5:1, or 5.6:1.
14 . The formulation of claim 1 , comprising the base and the glyburide or pharmaceutically acceptable salt thereof in a ratio so the formulation has a pH of 9.8 to 11.2, 9.9 to 11.1, 10.0 to 11.0, 10.1 to 10.9, 10.2 to 10.8, 10.3 to 10.7, or 10.4 to 10.6 when reconstituted in WFI.
15 . The formulation of claim 1 , comprising about 5 to 15%, 6 to 14%, 7 to 13%, 8 to 12%, 9 to 13%, or 10 to 12% (w/w) of the buffering agent.
16 . The formulation of claim 1 , wherein the buffering agent has a pKa of 7.7 to 9.2.
17 . The formulation of claim 1 , in the form of a reconstituted solution having a pH greater than 9.0.
18 . The formulation of claim 1 , in the form of a reconstituted solution having a pH of 9.3 to 11.
19 . The formulation of claim 1 , wherein the base has a pKb of 0.1 to 1.5.
20 . The formulation of claim 1 , wherein the base is NaOH, CaOH, KOH, or a combination thereof.
21 . The formulation of claim 1 , wherein the buffering agent is a Tris, a lysine, an arginine, an ethylenediamine, an imidazole, a 4-(2-Hydroxyethyl)morpholine, a triethanolamine, a glucamine, a deanol (dimethylaminoethanol), or a combination thereof.
22 . The formulation of claim 1 , wherein the buffering agent is a combination of Tris-HCl and Tris-base.
23 . The formulation of claim 22 , having a weight ratio between Tris-HCl and Tris-base of 7:4.
24 . The formulation of claim 22 , having a weight ratio between Tris-HCl and Tris-base of 6.2:5.0.
25 . The formulation of claim 1 , wherein the sugar alcohol is mannitol, sorbitol, xylitol, or a combination thereof.
26 . A saline infusion solution comprising the formulation of claim 1 , and having a pH of 7.8 to 9, 7.9. 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, or 8.9.
27 . The formulation of claim 1 , having a pH of 10 to 11 in 20 mL WFI.
28 . The formulation of claim 1 , further comprising
or a combination thereof.
29 . A kit comprising a first container containing a lyophilized formulation comprising:
a) glyburide or a pharmaceutically acceptable salt thereof;
b) a base;
c) a sugar alcohol; and
d) a buffering agent,
and an admixture device configured to reconstitute and transfer the lyophilized formulation between the first container and a second container, wherein the lyophilized formulation is free of cyclodextrins.
30 . The kit of claim 29 , wherein the lyophilized formulation comprises:
0.2 to 10.8 wt % of the glyburide or a pharmaceutically acceptable salt thereof;
4.4 to 8.8 wt % of the buffering agent; and
80.1 to 94 wt % of the sugar alcohol.