COMPOSITIONS FOR SMALL MOLECULE THERAPEUTIC AGENT COMPOUNDS
A composition comprising an aqueous suspension comprising a small molecule therapeutic agent and an organic acid is described. The small molecule therapeutic agent is a base and has a water solubility at room temperature of less than about 1.0 g/L. The organic acid has a water solubility at room temperature of between 0.1 and 10, has a molar mass of less than 500 grams per mole, and/or maintains a pH of the suspension in its environment of use of between 3.0-6.5. The organic acid enhances the solubility of the small molecule therapeutic agent and when present in stoichiometric excess, the organic acid drives release of the small molecule therapeutic agent into a buffered environment of use for prolonged periods of, for example, six months to one year. Devices comprising the compositions and methods of treatment are also described.
1 . A composition, comprising:
an aqueous suspension comprising
a therapeutic agent that (i) has a water solubility at room temperature of less than 1.0 g/L and (ii) is an organic base, and
an organic acid that (i) has a water solubility at room temperature between 0.1 and 10 g/L, (ii) has a molar mass of less than 500 grams per mole, (iii) is present in a stoichiometric (molar) excess relative to the therapeutic agent, and (iv) maintains a pH of the suspension in its environment of use of between 3.0-6.5 for a period of at least about 30 days.
2 . The composition of claim 1 , wherein a saturated aqueous solution of the organic acid has a pH value approximately equal to or less than the pKa of the protonated therapeutic agent.
3 . The composition of claim 1 , wherein the organic acid is present in an amount approximately equal to or above its saturation concentration at the end of the period.
4 . The composition of claim 1 , wherein the organic acid is present in a stoichiometric excess of 105% to 1000% relative to the therapeutic agent.
5 - 7 . (canceled)
8 . The composition of claim 1 , wherein the therapeutic is risperidone, olanzapine, asenapine, aripiprazole, or brexpiprazole.
9 - 10 . (canceled)
11 . The composition of claim 1 , wherein the organic acid is an aromatic carboxylic acid.
12 - 13 . (canceled)
14 . The composition of claim 11 , wherein the carboxylic acid is one having a carboxylic acid group bound to an unsubstituted benzene or pyridine ring.
15 . The composition of claim 14 , wherein the carboxylic acid is selected from the group consisting of benzoic acid, picolinic acid, nicotinic acid, and isonicotinic acid.
16 . The composition of claim 14 , wherein the carboxylic acid is one having a benzene ring and one electron-donating group with antioxidant properties.
17 . The composition of claim 16 , wherein the carboxylic acid is selected from the group consisting of o-anisic acid, m-anisic acid, p-anisic acid; p-aminobenzoic acid (PABA), o-aminobenzoic acid (anthranilic acid), o-toluic acid, m-toluic acid, p-toluic acid and salicylic acid.
18 - 25 . (canceled)
26 . The composition of claim 14 , wherein the carboxylic acid is one having one or two carboxylic acid groups directly bonded to a biphenyl ring system.
27 . The composition of claim 26 , wherein the carboxylic acid is selected from the group consisting of 2-phenylbenzoic acid, 3-phenylbenzoic acid, 4-phenylbenzoic acid and diphenic acid.
28 . The composition of claim 14 , wherein the carboxylic acid is one having one additional electron donating substituents in addition to hydroxyl group on the carboxylic acid moiety.
29 . The composition of claim 28 , wherein the carboxylic acid is selected from the group consisting of 4′-hydroxy-4-biphenylcarboxylic acid, 4′-hydroxy-2-biphenylcarboxylic acid, 4′-methyl-4-biphenylcarboxylic acid, 4′-methyl-2-biphenylcarboxylic acid, 4′-methoxy-4-biphenylcarboxylic acid, and 4′-methoxy-2-biphenylcarboxylic acid.
30 . The composition of claim 1 , wherein the organic acid is one having a carboxylic acid functional group separated from a benzene, pyridine, naphthalene, or quinoline ring by a chain of 1-4 sp3 hybridized carbons.
31 . The composition of claim 30 , wherein the carboxylic acid is phenylacetic acid or 3-phenylpropionic acid.
32 . The composition of claim 1 , wherein the organic acid is an aliphatic dicarboxylic acid with 4-8 carbon atoms between the carboxylic acid groups.
33 . The composition of claim 32 , wherein the carboxylic acid is selected from the group consisting of adipic acid (CH2)4(COOH)2), pimelic acid (HO2C(CH2)5CO2H), suberic acid (HO2C(CH2)6CO2H), azelaic acid (HO2C(CH2)7CO2H), and sebacic acid (HO2C(CH2)8CO2H).
34 . The composition of claim 1 , wherein the organic acid is an unsaturated or polyunsaturated dicarboxylic acids containing 4-10 carbons.
35 . The composition of claim 34 , wherein the carboxylic acid is selected from the group consisting offumaric acid, trans,trans-muconic acid, cis,trans-muconic acid, and cis,cis-muconic acid.
36 . The composition of claim 1 , wherein the organic acid is a cis-cinnamic acid or a trans-cinnamic acid.
37 . The composition of claim 36 , wherein the carboxylic acid is a trans-cinnamic acid with one or two electron-donating groups selected from hydroxy, methoxy, amino, alkylamino, dialkylamino, or alkyl groups.
38 . The composition of claim 37 , wherein the trans-cinnamic acid is selected from the group consisting o-coumaric acid, m-coumaric acid, p-coumaric acid, o-methylcinnamic acid, m-methylcinnamic acid, p-methylcinnamic acid; o-methoxycinnamic acid, m-methoxycinnamic acid, and p-methoxycinnamic acid, andferulic acid.
39 - 43 . (canceled)
44 . The composition of claim 1 , wherein the organic acid is a hydroxamic acid.
45 . The composition of claim 44 , wherein the hydroxamic acid is an aromatic hydroxamic acid containing one hydroxamic functional group bonded directly to an aromatic ring.
46 . The composition of claim 45 , wherein the aromatic ring is selected from the group consisting of a benzene ring, a pyridine ring, a naphthalene ring, a quinoline ring, and a biphenyl ring.
47 - 49 . (canceled)
50 . The composition of claim 44 , wherein the hydroxamic acid is a dihydroxamic acid containing two or more hydroxamic acid functional groups bonded directly to a benzene ring, a pyridine ring, a naphthalene ring, a quinoline ring, or a biphenyl ring system.
51 - 54 . (canceled)
55 . The composition of claim 1 , wherein the organic acid contains an aromatic ring and a carboxylic acid functional group.
56 . The composition of claim 55 , wherein the carboxylic acid is selected from the group consisting of 3-phenylpropionic acid, cinnamic acid, a hydroxy-derivative of cinnamic acid, a methoxy derivative of cinnamic acid, nicotinic acid, benzoic acid, an amino-derivative of benzoic acid, a methoxy derivative of benzoic acid, and phthalic acid.
57 . The composition of claim 56 , wherein the hydroxy-derivative of cinnamic acid is m-coumaric acid or p-coumaric acid.
58 - 59 . (canceled)
60 . The composition of claim 56 , wherein the amino-derivative of benzoic acid is 2-amino-benzoic acid (anthranilic acid) or 4-aminobenzoic acid (para-aminobenzoic acid; PABA).
61 - 63 . (canceled)
64 . A device, comprising: a composition according to claim 1 , wherein the device is configured for subcutaneous implantation into a mammal.
65 - 72 . (canceled)
73 . A method for sustained, controlled delivery of a small molecule therapeutic agent, comprising:
providing a composition according to claim 1 .
74 - 76 . (canceled)