FIELD

This relates to the field of orally dissolving pharmaceutical dosage forms and, more particularly, to those containing melatonin.

BACKGROUND

Melatonin is a naturally produced hormone that helps regulate the body's sleep/wake cycles. The amount of melatonin the body produces depends on the time of day. Endogenous melatonin levels start increasing in the evening, peak during the late night hours, and gradually start decreasing in the early morning.

Melatonin is known to have many therapeutic benefits, especially associated with sleep. It has been used to treat sleep problems such as insomnia and jet lag. It has also been used to help patients re-program their circadian clocks to account for changes in light/dark cycles due to time changes. It has also been proposed to act as an antioxidant.

Conventional oral melatonin treatments present several problems. Oral dosage forms have shown low and variable bioavailability. It can take a long time for absorption into the plasma when administered via the gastrointestinal tract. This is partly due to the fact that melatonin must first release from the dosage form, then permeate the walls of gastrointestinal tract before entering the bloodstream.

Orally-dissolving oral dosage forms also exist, but suffer from their own drawbacks. They often provide an unreliably measurable dose of melatonin to the patient. The dose a patient absorbs can vary even when the same product is administered to the same patient or different patients.

BRIEF SUMMARY

The melatonin compositions described here are formulated to deliver melatonin to the mouth where it is absorbed by the body through the oral mucosa. To overcome the high pH of the saliva and tongue, the composition includes an acidifying agent that lowers the pH inside the mouth, which enhances the oral solubility of melatonin. By being more soluble in the mouth, melatonin may more readily pass through the oral mucosa and into the bloodstream. This may make the melatonin dose in the plasma more predictable when compared to convention orally-dissolving melatonin dosage forms.

A first example of the composition includes a pharmaceutical dosage form configured to disintegrate in saliva and maintain a pH of 4 or less within the saliva during the time the dosage form is dissolving therein. The dosage form may include a therapeutically effective amount of melatonin in a carrier matrix, a disintegrant, and a sufficient amount of acid to impart the pH to the saliva. The amount of disintegrant is sufficient to cause the dosage form to completely disintegrate in the saliva within ten minutes from contacting the saliva.

The dosage form of this first example may be at least one of a sublingual tablet, a buccal tablet, and a polymer strip.

When the dosage form of this first example is a buccal or sublingual tablet, it may be at least 20% w/w of the acid.

When the dosage form of this first example is a polymer strip, it may be at least 5% w/w of the acid.

When the dosage form of this first example is a buccal tablet, it may be at least 6% w/w disintegrant.

When the dosage form of this first example is a sublingual tablet, it may be at least 15% w/w disintegrant.

The therapeutically effective amount of melatonin in this first example may be 0.2 mg to 20 mg.

The dosage form of this first example may be a tablet and the carrier matrix includes microcrystalline cellulose as at least 45% w/w of the dosage form, the acid as at least 20% w/w of the dosage form, and the disintegrant as at least 6% w/w of the dosage form.

The acid in this first example may be a carboxylic acid such as citric acid.

In the dosage form of this first example, the amount of disintegrant may be sufficient to cause the dosage form to completely disintegrate in the saliva within 2 minutes from contacting the saliva.

In the dosage form of this first example, the amount of disintegrant may be sufficient to cause the dosage form to completely disintegrate in the saliva within 1 minute from contacting the saliva.

A second example of the composition includes a pharmaceutical dosage form configured to disintegrate in saliva and maintain a pH of 4 or less within the saliva during the time the dosage form is dissolving therein. The dosage form includes 0.2% w/w to 20% w/w melatonin in therapeutically effective amount; a carrier matrix including 45% w/w to 68% w/w filler, and 6% w/w to 20% w/w disintegrant. The amount of disintegrant is sufficient to cause the dosage form to completely disintegrate in the saliva within ten minutes from contacting the saliva. The dosage form also includes 20% w/w to 30% w/w acid. The amount of acid is effective to impart the pH to the saliva.

The dosage form of this second example may be at least one of a sublingual or buccal tablet.

In the dosage form of this second example, the disintegrant may include crospovidone, the filler may include microcrystalline cellulose, and the acid may include citric acid.

When the dosage form of this second example is a sublingual tablet, the disintegrant may be at least 15% w/w of the dosage form.

The therapeutically effective amount of melatonin in this second example may be 0.2 mg to 20 mg.

The acid in this second example may be a carboxylic acid such as citric acid.

In the dosage form of this second example, the amount of disintegrant may be sufficient to cause the dosage form to completely disintegrate in the saliva within 2 minutes from contacting the saliva.

In the dosage form of this second example, the amount of disintegrant may be sufficient to cause the dosage form to completely disintegrate in the saliva within 1 minutes from contacting the saliva.

A third example of the composition includes an oral strip pharmaceutical dosage form configured to disintegrate in saliva and maintain a pH of 4 or less within the saliva during the time the strip is dissolving therein. The dosage form includes 0.2% w/w to 20% w/w melatonin in therapeutically effective amount; a carrier matrix including 45% w/w to 90% w/w water soluble polymer, 1% w/w to 20% w/w plasticizer; and 5% w/w to 20% w/w acid. The amount of acid is effective to impart the pH to the saliva.

In the composition of this third example, the strip has a thickness of 1 mm or less.

In the composition of this third example, dosage form may further include 20% w/w to 30 w/w surfactant.

In the composition of this third example, the water soluble polymer may be 50% w/w to 70% w/w of the dosage form.

In the composition of this third example, the acid may be 8% w/w to 12% w/w of the dosage form.

In the composition of this third example, the acid may be a carboxylic acid such as citric acid.

Any of the first second and third examples of the composition described above may be used in a method of treatment. An example of such a method includes administering a composition comprising a pharmaceutical dosage form to a subject in need thereof. The pharmaceutical dosage form disintegrates in the subject's saliva while maintaining a pH of 4 or less within the saliva during the time the dosage form is dissolving. The dosage form includes a therapeutically effective amount of melatonin in a carrier matrix, a disintegrant, and a sufficient amount of acid to impart the pH to the saliva. The amount of disintegrant is sufficient to cause the dosage form to completely disintegrate in the saliva within ten minutes from contacting the saliva.

The dosage from in this method may be at least one of a sublingual tablet, a buccal tablet, and a polymer strip.

The dosage form in this method may be a buccal or sublingual tablet, which is at least 20% w/w of the acid.

The dosage form in this method may be is a polymer strip, which is at least 5% w/w of the acid.

The dosage form in this method may be a buccal tablet, which is at least 6% w/w disintegrant.

The dosage form in this method may be a sublingual tablet, which is at least 15% w/w disintegrant.

In this method, the therapeutically effective amount of melatonin may be 0.2 mg to 20 mg.

The dosage form in this method may be a tablet and the carrier matrix may include microcrystalline cellulose as at least 45% w/w of the dosage form, the acid as at least 20% w/w of the dosage form, and the disintegrant as at least 6% w/w of the dosage form.

In this method, administering may occur within 30 minutes of the time the subject desires to fall asleep.

In this method, administering may occur at night after the subject has awoken from sleep and desires to fall back asleep.

In this method, the acid may be a carboxylic acid such as citric acid.

In this method, the amount of disintegrant may be sufficient to cause the dosage form to completely disintegrate in the saliva within 2 minutes from contacting the saliva.

In this method, the amount of disintegrant may be sufficient to cause the dosage form to completely disintegrate in the saliva within 1 minute from contacting the saliva.

