US 12,458,644 B2
Process for preparing solutions comprising biopterin derivatives
Peter Scheurer, Randersacker (DE); Frank Tegtmeier, Bielefeld (DE); and Reinhard Schinzel, Gerbrunn (DE)
Assigned to VASOPHARM GMBH, Wuerzburg (DE)
Filed by VASOPHARM GMBH, Wuerzburg (DE)
Filed on Jul. 20, 2023, as Appl. No. 18/224,515.
Application 18/224,515 is a continuation of application No. 17/153,749, filed on Jan. 20, 2021, granted, now 11,717,522.
Application 17/153,749 is a continuation of application No. 16/659,401, filed on Oct. 21, 2019, granted, now 10,925,877, issued on Feb. 23, 2021.
Application 16/659,401 is a continuation of application No. 16/003,374, filed on Jun. 8, 2018, granted, now 10,493,075, issued on Dec. 3, 2019.
Application 16/003,374 is a continuation of application No. 15/584,890, filed on May 2, 2017, granted, now 10,016,431, issued on Jul. 10, 2018.
Application 15/584,890 is a continuation of application No. 14/913,665, granted, now 9,895,372, issued on Feb. 20, 2018, previously published as PCT/EP2015/056824, filed on Mar. 30, 2015.
Claims priority of application No. 14162727 (EP), filed on Mar. 31, 2014.
Prior Publication US 2023/0355630 A1, Nov. 9, 2023
Int. Cl. A61K 31/519 (2006.01); A61K 9/00 (2006.01); A61K 9/19 (2006.01); A61K 31/4985 (2006.01); A61K 47/02 (2006.01); C07D 487/04 (2006.01)
CPC A61K 31/519 (2013.01) [A61K 9/0019 (2013.01); A61K 9/19 (2013.01); A61K 31/4985 (2013.01); A61K 47/02 (2013.01)] 11 Claims
 
1. A process for preparing a solution comprising (I), (II), or (III):
(I):
(a) a compound having the formula (I):

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(b) NaH2PO4·2H2O and Na2HPO4·2H2O; and optionally
(c) NaCl;
wherein the quantity of the NaH2PO4·2H2O and Na2HPO4·2H2O present in the solution is chosen such that:
(i) the molar ratio of NaH2PO4·2H2O to compound (I) is in the range of from 0.02 to 0.50; and
(ii) the molar ratio of Na2HPO4·2H2O 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):

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(b) NaH2PO4·2H2O and Na2HPO4·2H2O; and optionally
(c) NaCl;
wherein the quantity of the NaH2PO4·2H2O and Na2HPO4·2H2O present in the solution is chosen such that:
(i) the molar ratio of NaH2PO4·2H2O to compound (II) is in the range of from 0.02 to 0.50; and
(ii) the molar ratio of Na2HPO4·2H2O 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):

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(b) a compound having the formula (II):

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(c) NaH2PO4·2H2O and Na2HPO4·2H2O; and optionally
(d) NaCl;
wherein the quantity of the NaH2PO4·2H2O and Na2HPO4·2H2O present in the solution is chosen such that:
(i) the molar ratio of NaH2PO4·2H2O to compound (I) is in the range of from 0.02 to 0.50; and
(ii) the molar ratio of Na2HPO4·2H2O 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 NaH2PO4·2H2O and Na2HPO4·2H2O by:
(a) dissolving NaH2PO4·2H2O in water, to form a first solution;
(b) dissolving Na2HPO4·2H2O in water, to form a second solution;
(c) adding the first NaH2PO4·2H2O solution formed in step (a) above to the second Na2HPO4·2H2O 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 NaH2PO4·2H2O and Na2HPO4·2H2O;
(2) dissolving a compound of formula (II):

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in the buffer comprising NaH2PO4·2H2O and Na2HPO4·2H2O prepared in step (1) above, to form a fourth solution; or
(2) dissolving a compound of formula (III):

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in the buffer comprising NaH2PO4·2H2O and Na2HPO4·2H2O prepared in step (1) above, to form a fourth solution; or
(2) dissolving a compound of formula (II):

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and a compound of formula (III):

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in the buffer comprising NaH2PO4·2H2O and Na2HPO4·2H2O 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.