Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Patent
1996-12-12
1999-03-09
Knode, Marian C.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
424484, A61K 900
Patent
active
058797106
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a pharmaceutical dosage formulation enabling products such as melatonin or its derivatives to be administered, by combining a loading dose permitting a rapid action and, in the case of melatonin (or its derivatives), a clear chronobiological signal and one or more doses released gradually, enabling products to be made available rapidly, and in a sustained manner, in the body.
Generally speaking, the present invention relates to any mucoadhesive formulation combining at least two formulations affording controlled released of different rates, ranging from a rapid form to a sustained-release form.
The product is especially advantageous when the formulation is applied to a joint administration via the transmucosal or sublingual route and via the oral route, where the pharmaceutical dosage formulation combines a rapid oral form with a controlled-release oral form and a transmucosal form within a single mucoadhesive buccal tablet.
Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone synthesized by the epiphysis (or pineal gland) and involved, inter alia, in the regulation of the circadian rhythm, in the inhibition of gonadal development and in the regulation of ovulation.
It has the special feature of being released during the night only in mammals, and especially in human being.
In the body, this molecule is catabolized in the liver and kidneys to form, inter alia, 6-hydroxymelatonin.
An important feature of melatonin is its very marked circadian rhythm of secretion; in effect, the plasma levels of this hormone are low during the day (less than 10 pg/ml) and are high during the night (of the order of 70 pg/ml) in human being (1, 2).
The relationship between the melatonin cycle, that is to say its variations in concentration in the plasma, and the sleep cycle is not clear, but melatonin may assist in organizing or reorganizing the circadian cycles.
In the present application, melatonin and its derivatives will be used and described as active principles administered in the heterofunctional mucoadhesive pharmaceutical dosage composition.
It represents an especially significant example precisely as a result of the features of the action of this compound, which must both reach the systemic circulation rapidly and concomitantly afford a gradual release, thus enabling the product to be made available immediately and then in a sustained manner.
Any type of compound, such as melatonin derivatives substituted at position 2 or position 6 with halogens, or alternatively any other derivative as described in Patent Applications WO88/07367 or WO89/04659, or other substances having a pharmacological effect necessitating both a rapid release ranging from a flash type release to a slow and controlled type release, may be advantageously introduced into the pharmaceutical dosage formulation of the invention.
Melatonin and its derivatives, bearing in mind their feature of being a regulatory factor of the circadian system, are usable, for example, during a journey across time zones for treating the phenomenon of jet lag (3). During this period, most people suffer from, among other symptoms, mood disorders, sleep disturbance and a modification of alertness during the daytime; various studies show, in actual fact, an improvement in the symptoms of jet lag after a melatonin-based treatment; more recently, it was shown that subjects who underwent 6- to 12-hour time shifts showed a faster resynchronization of the different circadian rhythms (6-sulfatoxymelatonin, cortisol, temperature, urinary electrolytes, and the like) after a treatment with melatonin (4, 5).
Other applications of the regulation of circadian rhythms conferred by administration of melatonin are, in particular:
shift work:
it has been shown that the intake of melatonin at bedtime by individuals subjected to different types of shift work (7-day shift, gradual changes, and the like) improves the quality and duration of sleep and alertness during the period of activity (6);
blind subjects:
these subjects no longer perceive light
REFERENCES:
patent: 4250163 (1981-02-01), Nagai
patent: 4470846 (1984-09-01), Sandyk
patent: 4740365 (1988-04-01), Yukimatsu et al.
Biotec Centre S.A.
Brumback Brenda G.
Knode Marian C.
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