SOLID PHARMACEUTICAL COMPOSITIONS COMPRISING BIOPTERIN DERIVATIVES AND USES OF SUCH COMPOSITIONS

1 . A method of treating a disease in a subject, comprising the step of administering to a subject in need thereof a solution of a solid pharmaceutical composition containing a compound of formula (I), formula (II) or formula (III), wherein the disease is selected from the group consisting of traumatic brain injury, non-traumatic brain injury, elevated cranial pressure, and secondary brain injury, and wherein the solution comprising the compound of formula (I), formula (II) or formula (III) is prepared by a process comprising (A), (B) or (C)

(A):

(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

(B):

(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

(C):

(a) a compound having the formula (I):

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

 and

(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; or

(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;

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 method of claim 1 , wherein the fifth solution is administered by infusion or injection.

3 . The method of claim 1 , wherein the non-traumatic brain injury is stroke or meningitis.

4 . The method of claim 1 , wherein the compound having the formula (I) or formula (II) is administered at a maximal daily dose selected from the group consisting of about 10 mg/kg body weight, about 8.5 mg/kg body weight, about 7.5 mg/kg body weight, about 5.0 mg/kg body weight, and about 2.5 mg/kg body weight.

5 . The method of claim 1 , wherein the compound (I) is (6R)-4-Amino-5, 6, 7, 8-tetrahydro-L-biopterin.

6 . The method of claim 1 , wherein the compound (I) is (6S)-4-Amino-5, 6, 7, 8-tetrahydro-L-biopterin.