SOLID MICRONIZED MELATONIN COMPOSITION
A melatonin composition has a dry granulation including a melatonin powder with a median melatonin particle size of 5 μm to 40 μm, a carboxylic acid powder, and a powder of a hydrogel-forming polymer. The dry granulation is combined with pharmaceutical excipients in a dry orally ingestible pharmaceutical dosage form adapted to absorb water upon ingestion and form a hydrogel including soluble melatonin and soluble carboxylic acid in the hydrogel, the carboxylic acid being in an amount sufficient to impart a pH of 4.4 or less to the hydrogel after ingestion.
1 . A method of making a melatonin dosage form, the method comprising:
forming granules by dry granulating a melatonin powder having a median melatonin particle size of 5 μm to 40 μm, a carboxylic acid powder, and a powder of a hydrogel-forming polymer to form a dry granulation having a substantially uniform distribution of melatonin powder, carboxylic acid powder, and powder of the hydrogel-forming polymer; and
placing the granules into a dry orally ingestible pharmaceutical dosage form, the dosage form being adapted to absorb water upon ingestion and form a hydrogel including soluble melatonin and soluble carboxylic acid in the hydrogel, the carboxylic acid being in an amount sufficient to impart a pH of 4.4 or less to the hydrogel after ingestion.
2 . The method of claim 1 , wherein dry granulating is performed without including a liquid solvent.
3 . The method of claim 1 , wherein the dosage form is selected from the group consisting of a tablet, capsule, caplet, and multiparticulate.
4 . The method of claim 1 , wherein the carboxylic acid is citric acid.
5 . The method of claim 1 , wherein a particle size of the carboxylic acid is greater than the particle size of the melatonin.
6 . The method of claim 1 , further comprising compacting the granules by roller compaction and/or slugging after the forming step and prior to the placing step.
7 . The method of claim 1 , wherein the dosage form comprises 0.4% w/w to 8% w/w melatonin, 12% w/w to 40% w/w carboxylic acid, and 8% w/w to 48% w/w hydrogel-forming polymer.
8 . The method of claim 1 , wherein the dosage form comprises 0.4% w/w to 8% w/w melatonin, 24% w/w to 30% w/w carboxylic acid, and 16% w/w to 24% w/w hydrogel-forming polymer.
9 . The method of claim 1 , wherein the dosage form provides a sustained release of melatonin after ingestion for 3-10 hours regardless of the pH environment the dry orally ingestible pharmaceutical dosage form passes through.
10 . The method of claim 1 , wherein the melatonin powder and carboxylic acid powder are in direct physical contact in the granules.
11 . A melatonin composition comprising:
a dry granulation including a melatonin powder with a median melatonin particle size of 5 μm to 40 μm, a carboxylic acid powder, and a powder of a hydrogel-forming polymer; and
the dry granulation being combined with pharmaceutical excipients in a dry orally ingestible pharmaceutical dosage form, the dosage form being adapted to absorb water upon ingestion and form a hydrogel including soluble melatonin and soluble carboxylic acid in the hydrogel, the carboxylic acid being in an amount sufficient to impart a pH of 4.4 or less to the hydrogel after ingestion.
12 . The composition of claim 11 , wherein the dosage form is selected from the group consisting of a tablet, capsule, and multiparticulate.
13 . The composition of claim 11 , wherein the carboxylic acid is citric acid.
14 . The composition of claim 11 , wherein a particle size of the carboxylic acid is greater than the particle size of the melatonin.
15 . The composition of claim 11 , wherein the dosage form comprises 0.4% w/w to 8% w/w melatonin, 12% w/w to 40% w/w carboxylic acid, and 8% w/w to 48% w/w hydrogel-forming polymer.
16 . The composition of claim 11 , wherein the dosage form comprises 0.4% w/w to 8% w/w melatonin, 24% w/w to 30% w/w carboxylic acid, and 16% w/w to 24% w/w hydrogel-forming polymer.
17 . The composition of claim 11 , wherein the dosage form provides a sustained release of melatonin after ingestion for 3-10 hours regardless of the pH environment the dosage form passes through.
18 . The composition of claim 1 , wherein the melatonin powder and carboxylic acid powder are in direct physical contact in the dry granulation.
19 . A method of treatment comprising:
administering to a patient in need of melatonin therapy a therapeutically effective amount of a dry orally ingestible pharmaceutical dosage form having therein a dry granulation including a melatonin powder with a median melatonin particle size of 5 μm to 40 μm, a carboxylic acid powder, and a powder of a hydrogel-forming polymer;
the dry granulation being combined with pharmaceutical excipients in the dosage form, the dosage form being adapted to absorb water upon ingestion and form a hydrogel including soluble melatonin and soluble carboxylic acid in the hydrogel, the carboxylic acid being in an amount sufficient to impart a pH of 4.4 or less to the hydrogel after ingestion.
20 - 22 . (canceled)
23 . The method of claim 19 , wherein the dosage form comprises 0.4% w/w to 8% w/w melatonin, 12% w/w to 40% w/w carboxylic acid, and 8% w/w to 48% w/w hydrogel-forming polymer.
24 - 26 . (canceled)