Process for preparing solutions comprising biopterin derivatives
Disclosed is a method of preparing a solution adapted for administration by infusion, comprising a) a compound having the formula (I): and/or a compound having the formula (II): and b) two different sodium phosphate salts, wherein the two different sodium phosphate salts are NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O, and wherein the quantity of the NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O present in the composition is chosen such that the molar ratio of both NaH 2 PO 4 ·H 2 O and Na 2 HPO 4 ·2H 2 O to compound (I) or compound (II) ranges from 0.02 to 0.5 and optionally NaCl. Also disclosed is a method of treating a disease in a subject, comprising the step of administering to a subject in need thereof a reconstituted solution as disclosed.
1 . A process for preparing a solution comprising (I), (II), or (III):
(I):
(a) a compound having the formula (I):
(b) NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O; and optionally
(c) NaCl;
wherein the quantity of the NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O present in the solution is chosen such that:
(i) the molar ratio of NaH 2 PO 4 ·2H 2 O to compound (I) is in the range of from 0.02 to 0.50; and
(ii) the molar ratio of Na 2 HPO 4 ·2H 2 O to compound (I) is in the range of from 0.02 to 0.50; and
wherein the solution is adapted for administration by infusion or injection; or
(II):
(a) a compound having the formula (II):
(b) NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O; and optionally
(c) NaCl;
wherein the quantity of the NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O present in the solution is chosen such that:
(i) the molar ratio of NaH 2 PO 4 ·2H 2 O to compound (II) is in the range of from 0.02 to 0.50; and
(ii) the molar ratio of Na 2 HPO 4 ·2H 2 O to compound (II) is in the range of from 0.02 to 0.50; and
wherein the solution is adapted for administration by infusion or injection; or
(III):
(a) a compound having the formula (I):
(b) a compound having the formula (II):
(c) NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O; and optionally
(d) NaCl;
wherein the quantity of the NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O present in the solution is chosen such that:
(i) the molar ratio of NaH 2 PO 4 ·2H 2 O to compound (I) is in the range of from 0.02 to 0.50; and
(ii) the molar ratio of Na 2 HPO 4 ·2H 2 O to compound (I) is in the range of from 0.02 to 0.50; and
wherein the solution is adapted for administration by infusion or injection;
wherein the process comprises the following steps:
(1) preparing a buffer comprising NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O by:
(a) dissolving NaH 2 PO 4 ·2H 2 O in water, to form a first solution;
(b) dissolving Na 2 HPO 4 ·2H 2 O in water, to form a second solution;
(c) adding the first NaH 2 PO 4 ·2H 2 O solution formed in step (a) above to the second Na 2 HPO 4 ·2H 2 O solution formed in step (b) above, to form a third sodium phosphate solution having a pH of 7.4; and
(d) adding the third sodium phosphate solution formed in step (c) above to a 5N NaOH solution, to form the buffer comprising NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O;
(2) dissolving a compound of formula (II):
in the buffer comprising NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O prepared in step (1) above, to form a fourth solution; or
(2) dissolving a compound of formula (III):
in the buffer comprising NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O prepared in step (1) above, to form a fourth solution; or
(2) dissolving a compound of formula (II):
and a compound of formula (III):
in the buffer comprising NaH 2 PO 4 ·2H 2 O and Na 2 HPO 4 ·2H 2 O prepared in step (1) above, to form a fourth solution;
(3) lyophilizing the fourth solution formed in step (2) above, to form a lyophilisate;
(4) filling the lyophilisate formed in step (3) above into a vial; and
(5) reconstituting the lyophilisate of step (4) above in a pharmaceutically acceptable fluid, to prepare a fifth solution comprising (I), (II), or (III) above that is adapted for administration by infusion or injection.
2 . The process of claim 1 , wherein:
(a) the process is adapted for administration by injection; and
(b) the buffer formed in step (1) comprises 12-16% (w/w) 5N NaOH, 8-12% (w/w) sodium hydrogen phosphate buffer, and 74-78% (w/w) water.
3 . The process of claim 1 , wherein the buffer formed in step (1) is degassed.
4 . The process of claim 3 , wherein the buffer is degassed with nitrogen until the oxygen content is less than 1.0 ppm.
5 . The process of claim 1 , wherein the solution formed in step (2) is sterile filtered.
6 . The process of claim 5 , wherein the filter is a 0.22 μm filter.
7 . The process of claim 1 , wherein the lyophilization of step (3) is performed in a period less than two hours after the completion of step (2).
8 . The process of claim 1 , wherein the lyophilisate formed in step (3) is filled into a 50 mL vial.
9 . The process of claim 8 , wherein:
(a) the amount of lyophilizate is in the range of from about 0.9 g to 1.4 g; or
(b) the amount of lyophilizate is in the range of from about 1.0 g to 1.5 g.
10 . The process of claim 9 , wherein:
(a) the amount of lyophilizate is about 1.15 g in a solid formulation; or
(b) the amount of lyophilizate is about 1.25 g in a solid formulation.
11 . The process of claim 9 , wherein:
(a) the process is adapted for administration by injection; and
(b) the buffer formed in step (1) comprises 12-16% (w/w) 5N NaOH, 8-12% (w/w) sodium hydrogen phosphate buffer, and 74-78% (w/w) water for injection.