Boronic acid salts useful in parenteral formulations
First Claim
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1. A parenteral pharmaceutical formulation comprising a therapeutically effective amount of a pharmaceutically acceptable base addition salt of a boronic acid of formula (I):
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Abstract
Salts of a peptide boronic acid drug, for example of Cbz—(R)—Phe—(S)—Pro—(R)—Mpg—B(OH)2. The counter-ion to the boronate may be an alkali metal or derived from a strongly basic organic nitrogen-containing compound.
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Citations
29 Claims
- 1. A parenteral pharmaceutical formulation comprising a therapeutically effective amount of a pharmaceutically acceptable base addition salt of a boronic acid of formula (I):
- 15. A formulation in parenteral dosage form comprising a therapeutically effective amount of a pharmaceutically acceptable base addition salt of a boronic acid of formula (II):
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23. A pharmaceutical product comprising a sealed container containing in the form of a finely divided solid, ready for reconstitution to form a liquid parenteral formulation, a therapeutically effective amount of a boronate salt which consists essentially of a single pharmaceutically acceptable base addition salt of a boronic acid formula (II):
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24. A pharmaceutical formulation adapted for parenteral administration, whether directly or after combining with a liquid, and comprising
a) a first species selected from a boronic acid of formula (I), and boronate ions of said boronic acid and equilibrium forms of said boronic acid and said boronate ions: -
wherein Y comprises a hydrophobic moiety which, together with the aminoboronic acid residue —
NHCH(R9)—
B(OH)2, has affinity for the substrate binding site of thrombin; and
R9 is a straight chain alkyl group interrupted by one or more ether linkages and in which the total number of oxygen and carbon atoms is 3, 4, 5 or 6 or R9 is —
(CH2)m—
W where m is from 2, 3, 4 or 5 and W is —
OH or halogen; and
(b) a second species selected from pharmaceutically acceptable metal ions, said metal ions having a valency of n, lysine, arginine and aminosugars, wherein the formulation has an observed stoichiometry of first to second species essentially consistent with a notional stoichiometry of 1;
1 when the second species is a metal ion with a valency of 1 or is lysine, arginine or an aminosugar, or an observed stoichiometry of n;
1 when the second species is a metal ion with a valency of greater than 1.
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28. A medicament adapted for parenteral administration and comprising a therapeutically effective amount of a pharmaceutically acceptable base addition salt of a boronic acid which is a selective thrombin inhibitor and has a neutral aminoboronic acid residue capable of binding to the thrombin S1 subsite linked through a peptide linkage to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites, the salt comprising a cation having a valency n and having an observed stoichiometry consistent with a notional stoichiometry (boronic acid:
- cation) of n;
1. - View Dependent Claims (29)
- cation) of n;
Specification