Process for preparation of liquid dosage form containing sodium 4-phenylbutyrate
A process for preparing a stable aqueous dosage form of sodium 4-phenylbutyrate, including such dosage forms in a highly concentrated solution, as well as methods for making 4-phenylbutyrate and 4-phenylbutyric acid, and for using 4-phenylbutyrate. The stable aqueous dosage forms do not freeze at 0° C.
1 . A pharmaceutical liquid composition, comprising: a solution of sodium 4-phenylbutyrate in an aqueous medium at a concentration of at least about 300 mg/mL.
2 . The composition of claim 1 , further comprising a preservative.
3 . The composition of claim 1 , further comprising a flavoring agent.
4 . The composition of claim 1 , further comprising a preservative and a flavor.
5 . The composition of claim 3 , wherein the flavoring agent is a sweetening agent.
6 . The composition of claim 4 , wherein the flavoring agent is a sweetening agent.
7 . The composition of claim 1 , further comprising at least two flavoring agents, at least one of said flavoring agents being a sweetening agent, and a preservative.
8 . The composition of claim 1 , wherein the concentration of sodium 4-phenylbutyrate ranges from about 300 mg/mL to about 700 mg/mL.
9 . The composition of claim 8 , wherein the concentration of sodium 4-phenylbutyrate is in the range from about 400 mg/mL to about 600 mg/mL.
10 . The composition of claim 9 , wherein the concentration is about 500 mg/mL.
11 - 15 . (canceled)
16 . The composition of claim 1 , further comprising a base.
17 - 20 . (canceled)
21 . The composition of claim 1 , wherein the weight fraction of water is less than the weight fraction of sodium 4-phenylbutyrate.
22 . A process for preparing an aqueous solution of 4?phenylbutyrate, comprising the steps of: adding water to sodium 4-phenylbutyrate powder; and dissolving the powder in the water by agitation at temperature ranging from about 25° C. to about 80° C. to obtain a solution having a concentration of at least about 300 g/mL of 4-phenylbutyrate.
23 . (canceled)
24 . A process for making of sodium 4-phenylbutyrate, comprising the steps of:
(A) dissolving 4-phenylbutyric acid in a first organic solvent medium;
(B) treating the solution of step (A) with a inorganic alkali;
(C) heating the treated solution of step (B) to a predetermined temperature;
(D) adding a second solvent to the heated mixture effective to precipitate sodium 4-phenylbutyrate therefrom; and
(E) isolating the precipitate product by filtration and drying under vacuum at a predetermined temperature.
25 - 32 . (canceled)
33 . A process for making 4-phenylbutyric acid, comprising:
(i) treating an organic ester of the formula Ph-CH2-CH2-CH—(COOR) 2 , wherein each R is independently an alkyl containing up to four carbon atoms, an aryl group, or an aralkyl group wherein the alkyl portion has up to four carbon atoms, with a mineral acid in a water miscible organic solvent at a predetermined temperature; and
(ii) precipitating 4-phenylbutyric acid using a non-polar solvent.
34 - 41 . (canceled)
42 . A method of treating a patient suffering from a urea cycle deficiencies, sickle-cell anemia, cancer, or potential cerebral ischemic injury, comprising providing an oral aqueous solution of 4-phenylbutyrate having a concentration of at least about 300 mg/mL and orally administering said solution to a patient in need thereof.
43 . The method of claim 40 , wherein the solution further comprises a preservative, a flavoring agent, a fragrance, or a mixture thereof.
44 . The method of claim 41 , wherein the solution further comprises a preservative and a flavoring agent.
45 . The method of claim 42 , wherein the solution further comprises a fragrance and a sweetener as the flavoring agent.
46 . The composition of claim 1 , wherein the solution does not freeze at 0° C.
47 . The process of claim 20 , wherein the solution does not freeze at 0° C.