Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Patent
1994-06-13
1996-04-16
Phelan, D. Gabrielle
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
424447, 424449, A61F 1300
Patent
active
055080391
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates the efficacious and safe, controlled transdermal administration of melatonin and related compounds for systemic hypnotic and soporific effects in the treatment of insomnias of several kinds.
BACKGROUND OF THE INVENTION
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland. The exact function of the hormone in adult human beings has not been determined. In healthy young adults, melatonin is secreted as a broad pulse during nighttime sleep in the total amount of approximately 25-30 .mu.g per night, producing peak plasma concentrations of approximately 70 pg/ml, occurring at approximately 0200 h. Melatonin is secreted into the blood stream and possibly also into cerebrospinal fluid (CSF) simultaneously. The CSF/plasma concentration ratio is 1.0 or less. The terminal plasma elimination half-life is approximately 45 minutes; volume of distribution is approximately 40 liters; and the metabolic clearance of melatonin is approximately 1 liter per minute. The melatonin circadian (.about.24 hr) rhythm is thought to be driven by the same central nervous system oscillator that drives the daily rhythms of cortisol, urine volume, and core temperature (Shanahan and Czeisler, 1991), The relationship of the melatonin cycle to the activity/rest (sleep) cycle is not clear, but melatonin may organize the normal sleep pattern.
Melatonin has been administered to human beings orally and intranasally. It is readily absorbed through the gastrointestinal tract. The liver inactivates as much as 99% of the absorbed melatonin on the first-pass. Thus, the oral route of administration is inefficient and erratic.
Oral melatonin has been given to human beings to treat the phenomenon of "jet lag" following airplane trips associated with a change in time zones (Arendt et al. (1987) Ergonomics 30:1379-1393); U.S. Pat. Nos. 4,600,723 and 4,665,086). It has been given to patients with Parkinson's disease (Anton-Tay et al. (1971) Life Sciences 10:841-850), epilepsy (Anton-Tay et al., ibid.), or seasonal affective disorders (Wirz-Justice et al. (1990) J. Psychiat. Res. 24(2):129-137). It has been tried as a sleep-wake organizer in desynchronized blind persons (Arendt et al. (1988) Lancet pp 772-773; Folkard et al. (1990) Neuroscience Lett. 113:193-198; Sack et al., (1987) in, "Temporal Disorder in Human Oscillatory Systems", Eds. L. Rensing et al., Springer-Verlag, Heidelberg, pp 219-224; Sack and Lewy (1988) Am. Psychiatric Assoc. 141 Ann. Meeting, Montreal, Quebec). Improved timing of sleep cycles resulted. Oral melatonin has been given to insomniacs (Waldhouser et al. (1990) Psychopharmacology 100:222-226; Arendt et al. (1991) Lancet 337:1121-1124). Melatonin reduced the time awake before sleep onset and diminished sleep latency and number of awakenings. Overall sleep efficiency was increased, and mood, drive, alertness, and reaction time were improved the next day. Most of the published studies are consistent with the assumption that melatonin has mild sedative and hypnotic properties and may be a natural, sleep-inducing and sleep-organizing signal in humans. In addition, melatonin has been reported to lower intraocular pressure in glaucoma, to inhibit breast cancer (U.S. Pat. No. 4,855,305; Barch et al. (1991) Cancer 67:1681-1684), to be useful in the treatment of premenstrual depression (U.S. Pat. No. 4,945,103; Parry et al. (1990) Arch. Gen. Psychiatry 47:1139-1146; Yen et al. (1990) Arch. Gen. Psych. 47:1139-1146), for effecting contraception in humans (PCT Appln. WO 90/14084), and to prevent sudden infant death syndrome (Wurtman et al. (1990) Forensic Science Interntl. 45:171-180). Melatonin appears to be useful in animal husbandry by, for example, regulating the reproductive behavior of animal seasonal breeders (Reiter (1981) Endocr. Rev. 1:109-131; Nittman et al. (1983) Endocrinology 113:2276-2283; Arendt (1986) Oxford Reviews of Reproductive Biology 8:266-320) and regulating fur coat development in animals with seasonal variation.
Numerous
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Crisologo Nieves M.
Taskovich Lina T.
Yates F. Eugene
Yum Su I.
ALZA Corporation
Mandell Edward L.
Phelan D. Gabrielle
Rafa Michael J.
Stone Steven F.
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