Soluble pharmaceutical compositions comprising salts of disubstituted 1, 2, 4-triazine compound
Disclosed are pharmaceutical compositions comprising a salt of a compound having the formula: and one or more excipients, wherein the pharmaceutical composition avoids inducing disproportionation of the salt of the compound.
1 . A pharmaceutical composition comprising a halogen anion salt of a compound having the formula:
and one or more excipients, wherein the one or more excipients do not comprise a metal salt, and wherein the pharmaceutical composition avoids inducing disproportionation of the halogen anion salt of the compound.
2 . A pharmaceutical composition comprising a halogen anion salt of a compound having the formula:
and one or more excipients, wherein the one or more excipients do not comprise a metal salt, and wherein the pharmaceutical composition has a dissolution profile such that more than 70% of the compound is dissolved in 15 minutes in an in vitro dissolution test of the pharmaceutical composition using USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water at 37° C.
3 . The pharmaceutical composition of claim 1 , wherein the salt of the compound is an HBr salt.
4 . The pharmaceutical composition of claim 2 , wherein the salt of the compound is an HBr salt.
5 . The pharmaceutical composition of claim 2 , wherein the salt of the compound is in crystalline form.
6 . The pharmaceutical composition of claim 2 , wherein the salt of the compound is in amorphous form.
7 . The pharmaceutical composition of claim 2 , comprising 5 milligrams to 150 milligrams of the compound.
8 . The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition comprises:
a) about 30 wt % to about 60 wt % of lactose, mannitol, or a combination thereof;
b) about 25 wt % to about 50 wt % of microcrystalline cellulose;
c) about 1 wt % to about 10 wt % of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof; and
d) about 1 wt % to about 10 wt % of talc, glyceryl dibehenate, colloidal silicone dioxide, or a combination of two or more thereof.
9 . The pharmaceutical composition of claim 7 , wherein the compound is more soluble in water than the same compound in an equivalent pharmaceutical composition comprising a calcium salt, a sodium salt or magnesium salt, wherein the pharmaceutical composition avoids disproportionation in excess of 10% when stored at 25° C. and 60% relative humidity for 6 months in a closed container.
10 . The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition comprises about 5 milligrams to about 20 milligrams of the compound.
11 . The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition comprises:
a) about 1 wt % to about 8 wt % of the compound;
b) about 50 wt % to about 60 wt % of lactose, mannitol, or a combination thereof;
c) about 25 wt % to about 40 wt % of microcrystalline cellulose;
d) about 1 wt % to about 10 wt % of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof; and
e) about 1 wt % to about 10 wt % of talc, glyceryl dibehenate, colloidal silicone dioxide, or a combination of two or more thereof.
12 . The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition comprises about 15 milligrams to about 35 milligrams of the compound.
13 . The pharmaceutical composition of claim 12 wherein the pharmaceutical composition comprises:
a) about 5 wt % to about 15 wt % of the compound;
b) about 30 wt % to about 50 wt % of mannitol;
c) about 30 wt % to about 50 wt % of microcrystalline cellulose;
d) about 1 wt % to about 10 wt % of pregelatinized starch; and
e) about 1 wt % to about 5 wt % of glyceryl dibehenate, colloidal silicone dioxide, or a combination thereof.
14 . The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition comprises about 80 milligrams to about 120 grams of the compound.
15 . The pharmaceutical composition of claim 14 ,
wherein the pharmaceutical composition comprises:
a) about 30 wt % to about 40 wt % of the compound;
b) about 20 wt % to about 30 wt % of mannitol;
c) about 20 wt % to about 40 wt % of microcrystalline cellulose;
d) about 1 wt % to about 10 wt % of pregelatinized starch;
e) about 1 wt % to about 5 wt % of glyceryl dibehenate, colloidal silicone dioxide, or a combination thereof.
16 . The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is a tablet.
17 . A process for making a pharmaceutical composition comprising a halogen anion salt of a compound having the formula:
and one or more excipients, wherein the one or more excipients do not comprise a metal salt, wherein the pharmaceutical composition avoids inducing disproportionation of the halogen anion salt of the compound and/or the pharmaceutical composition has a dissolution profile such that more than 70% of the compound is dissolved in 15 minutes in an in vitro dissolution test of the pharmaceutical composition using USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water at 37° C., comprising:
a) obtaining a halogen anion salt of a compound having the formula:
and
b) mixing the salt with the one or more excipients to thereby produce the pharmaceutical composition.
18 . The process of claim 17 , wherein step b) comprises:
i) blending the salt with one or more excipients; and
ii) roller compaction of the product of step i); and
iii) milling the product of step ii);
wherein the one more excipients of step i) comprises stearic acid; and wherein step b) further comprises a step of blending the product of step iii) with one or more additional excipients, wherein the one or more additional excipients comprise stearic acid.
19 . The process of claim 17 , wherein the one or more excipients are selected from the group consisting of microcrystalline cellulose, lactose, mannitol, polyvinylpyrrolidone, colloidal silicone dioxide, pregelatinized starch, low-substituted hydroxypropyl cellulose, talc, glyceryl dibehenate, and stearic acid.
20 . A method of treating hypertension and/or reducing blood pressure in a hypertensive subject, the method comprising administering to the hypertensive subject the composition of claim 2 .
21 . A method of inhibiting CYP11β2 beta hydroxylase in a subject, the method comprising administering to the subject the composition of claim 2 .