WO1995003043A1 - Compositions administrees par voie orale, de type retard, contenant de la melatonine - Google Patents

Compositions administrees par voie orale, de type retard, contenant de la melatonine Download PDF

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Publication number
WO1995003043A1
WO1995003043A1 PCT/US1994/008365 US9408365W WO9503043A1 WO 1995003043 A1 WO1995003043 A1 WO 1995003043A1 US 9408365 W US9408365 W US 9408365W WO 9503043 A1 WO9503043 A1 WO 9503043A1
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Prior art keywords
melatonin
dosage form
time
hours
patient
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PCT/US1994/008365
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English (en)
Inventor
Alfred J. Lewy
Robert L. Sack
Keith A. Parrott
James W. Ayres
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State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education On Behalf Of The Oregon Health Sciences University
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Priority to AU75509/94A priority Critical patent/AU7550994A/en
Publication of WO1995003043A1 publication Critical patent/WO1995003043A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the field of the invention disclosed in this application relates to the regulation of circadian rhythms in humans, and to the synchronization of circadian rhythms with the external environment. Specifically, this invention describes a method to achieve a chronobiologic effect in humans. In particular, this invention relates to the reestablishment of synchrony between a human's endogenous biological circadian rhythm and the external environment (including the sleep- wake cycle) after its disruption in any of a number of ways.
  • this invention relates to methods and compositions to achieve normal melatonin patterns in humans having melatonin deficiency syndrome.
  • circadian rhythms are periodic fluctuations in biologic properties over time; these include circadian as well as seasonal variations.
  • Circadian, or approximately 24-hour, rhythms include the production of biological molecules such as hormones, the regulation of body temperature, and behaviors such as wakefulness, sleep and periods of activity.
  • circadian rhythms are closely tied to environmental cues that impose a 24-hour pattern on many of these fluctuations.
  • An example of longer patterns that also involve the effect of hormones includes the menstrual cycle.
  • Experimental inquiry has established that when environmental cues are absent, most apparent 24-hour circadian rhythms have a periodicity of approximately 25 hours.
  • Circadian rhythms that are not regulated by environmental cues are said to be free-running.
  • the regulation of circadian rhythms by signals from the environment is said to involve entrainment of the circadian rhythms.
  • the environmental signals that effect entrainment have been termed zeitgebers, an example of which is the light-dark cycle.
  • SCN superchiasmatic nuclei
  • SCN superchiasmatic nuclei
  • Melatonin an indoleamine, N-acetyl-5-methoxytryptamine, is a neurohormone secreted primarily by the pineal gland in a circadian rhythm. This neurohormone is believed to be a physiological zeitgeber in some species.
  • the former is commonly associated with jet lag and the latter with aging.
  • melatonin As with all hormones, a disruption of a normal hormonal pattern cam result in a variety of physiological changes and in many apparently unrelated outcomes. These outcomes can be improved by modifying, restoring, or mimicking the normal hormonal pattern.
  • definitive human physiological function of melatonin remains unknown, it has been suggested to have a role in, for example, sleep, appetite, reproduction, contraception, thyroid function, wool or hair production in animals, breeding, aging, depression, schizophrenia, sudden infant death or crib death syndrome, migraine headache, jet lag, seasonal affective disorder, shift worker syndrome, melatonin deficiency syndrome, pre-menstrual syndrome, mammalian breast and other carcinomas, and to have immunostimulant and immunomodulatory effects.
  • U.S. Patents Nos. 4,665,086 and 4,600,723 teach the use of melatonin to alleviate the symptoms of jet lag. These patents teach the use of 1-10 mg of melatonin, taken at destination bedtime, and again upon premature awakening in the middle of the night. A number of examples are disclosed in these patents, all involve travelers who take these doses of melatonin at destination bedtime and report the alleviation of the symptoms of jet lag. It is known that melatonin in high pharmacological doses increase tiredness and the tendency to sleep in some people (see Arendt et a Neurosci. Lett. 45: 317-325, 1984; Arendt et a CIBA Found. Symp. 117:266-283, 1986).
  • Hormonal patterns are described by the timing (including onset time, offset time, and duration time) and amplitude of concentrations in the body or blood.
  • hormonal treatment may include increasing the amplitude by administering exogenous hormone if the quantity produced internally is too small, increasing the duration if it is too short, or changing the onset or offset time.
  • hormones require relatively uniform bioavailability since normal ranges of hormone concentrations in the body are relatively narrow and reproducible within their circadian or normal rhythm patterns. Hormones are part of complicated feedback physiological activity loops, often resulting in a variety of outcomes depending on the stability of hormonal concentrations and phasic patterns. Products that result in large variations in availability of these agents are unacceptable in medical practice. Some estrogen hormonal products, for example, have been removed from the market because of unacceptable variations in blood concentrations and bioavailability.
  • melatonin production by the pineal gland is essentially non-existent during the daytime. Sometime after dusk (often about 9 P.M.), melatonin levels increase 10- to 50-fold; the levels then decrease several hours later, either because of an endogenous mechanism or because of exposure to light in the morning, whichever happens first.
  • Van Coevorden et ah Am. J. Physiol., 260 (Endocrinol. Metab. 23): E651-E661 (1991), demonstrated that melatonin concentrations in normal young subjects ranged from about 58 to 92 pg/ml during the night with an average of 70 pg/ml while in the elderly the range was about 23-46 pg/ml with an average of about 37 pg/ml (data converted from reported concentrations originally presented in pM/1).
  • This pattern known as the daily rhythm of melatonin, is repeated every day with the onset time and offset (shut-off) time changing very little each day depending on the time of daylight and dusk. Lane and Moss, J. Clin.
  • Intravenous and oral administration of melatonin has usually involved pharmacological doses, so-called because they produce concentrations of melatonin that are up to several hundred times normal. After administration of a pharmacological dose, the drug is cleared from the body in a short time (not sustained so as to mimic a normal pattern).
  • melatonin in the range of 2 mg to 2,500 mg are considered pharmacological and not physiological. Melatonin is also remarkably non-toxic in large doses. Nevertheless, smaller doses are preferred over such pharmacological doses.
  • Fifty milligram oral immediate release melatonin tablets for example, produce average plasma melatonin concentrations of about 80,000 pg/ml, i.e. , about 1600 times normal. This melatonin dosage form does not produce a sustained pattern of release: the concentration drops to about 1/4 of the peak concentration in only about 3 hours.
  • the bioavailability from oral doses containing at least 2.5 mg of melatonin is normally about 3% to 9%. However, bioavailability has been reported to be as high as 23% or 76% from an 80 mg dose. Similar decreases in bioavailability have been associated with reduced dosages of drugs such as melatonin that undergo extensive first pass metabolism.
  • fraction of the orally ingested dose absorbed was reported to vary by 25-fold among study subjects by F. Waldhauser et a , in The Pineal Gland, Russell Reiter, editor, Raven Press, New York, 1984, p. 359. They also noted that peak concentrations varied about 40-fold.
  • the results were highly variable and plasma melatonin patterns were unlike normal melatonin patterns in both amplitude and duration.
  • the maximum plasma concentrations for example, were about 900 pg/ml in some cases while peaks occurred at either 2, 3, 4, 5, or 7 hours following the dose. In other cases the melatonin concentration was so low as to produce essentially no melatonin pattern over 4 or even 7 hours. In two of five cases the melatonin concentrations were about 9-fold normal and for some the concentrations were less than one-fifth of normal.
  • Aldhous et a further teach that the nutritional state of the individual greatly influences the melatonin pattern produced and that careful control of nutrition is necessary to control peak concentrations and the pattern of melatonin. Still, the best results from non-fasting subjects indicate that oral slow release melatonin cannot be used to mimic normal melatonin patterns.
  • Bioavailability from the 2 mg sustained release formulation is not reported. However, Aldhous' results appear to indicate that the sustained release formulation provides no more than about 15 % of the bioavailability expected from the 2 mg immediate release tablet (about 3% to 6% as taught by Lane and Moss). Thus, the prior art teaches that there is less than 1 % bioavailability from oral sustained release melatonin.
  • European Patent Application No. 0 518 468 Al provides a method for correcting a melatonin deficiency syndrome comprising administering to a patient having the syndrome, over a predetermined time period including at least part of the nocturnal period, an amount of melatonin in controlled-release form, such that the melatonin is released according to a profile which, taking into account the existing profile, simulates the profile in plasma of a human being having a normal endogenous nighttime melatonin profile.
  • Entrainment and regulation of the melatonin circadian rhythm has thus been demonstrated in a number of animal species.
  • the present inventors are the first to disclose a PRC for melatonin in a human.
  • the ability to effect an actual change in phase of the circadian rhythm would be useful for the alleviation of a number of circadian rhythm related disorders, as will be further discussed in the embodiments below.
  • This application discloses a method to advance or delay the onset of the production of endogenous melatonin, and hence actually affect the regulation of an endogenous circadian rhythm in man.
  • This invention relates to a method for achieving a chronobiologic effect in a human.
  • This effect is achieved by regulation of a human's circadian rhythm.
  • the circadian phase-shifting effect is achieved by the administration of exogenous melatonin, which naturally occurs in the human only during the night.
  • the timing of the nighttime onset of melatonin production in a particular individual will vary from person to person.
  • the circadian rhythm of melatonin production in a human is entrained principally by the (bright) light-dark cycle and reflects a variety of other biological properties which vary with a circadian rhythm.
  • the method of the invention entails the phase-shifting of the circadian rhythm by administration of exogenous melatonin.
  • the method of the invention involves the administration of a particular dosage of melatonin to the human.
  • the particular dosage is lower than dosages taught by others, and is designed to achieve melatonin levels which are substantially equal to physiological levels in the human.
  • the method of the invention relates to the timing of the administration of the dosage of melatonin to the human.
  • the timing of this dosage in the human is described to specifically phase-shift the circadian rhythm of endogenous melatonin production.
  • the method described in the invention can be used to advance or delay the phase of the circadian rhythm of melatonin production in the human. In this way, the present invention is able to alleviate jet lag and other circadian rhythm disorders of both the phase-delay and the phase-advance types.
  • time of administration of exogenous melatonin relative to the time of endogenous melatonin onset is critical to the production of the appropriate phase-shifting effect.
  • the time of administration of exogenous melatonin must be carefully set relative to the time of endogenous melatonin onset, preferably from more than 4 hours to about 8 hours before endogenous melatonin onset when a phase advance is desired, and about 9 hours to about 17 hours before endogenous melatonin onset when a phase-delay is desired.
  • exogenous melatonin should be preferably administered from more than 6 hours to about 10 hours prior to the commencement of the patient's normal sleep phase when a phase-advance is desired, and about 11 hours to about 19 hours prior to the commencement of the patient's normal sleep phase when a phase-delay is desired.
  • the preferred time of administration of exogenous melatonin for a particular individual human will be unique, depending on the individual's time of endogenous melatonin onset, which can vary markedly from individual to individual (between 7 PM to 11 PM for most individuals).
  • This invention also provides methods to mimic a normal melatonin pattern when the melatonin pattern is diminished because of a melatonin deficiency.
  • This aspect of the invention contemplates administration of a sustained release melatonin formulation to a patient suffering from a deficiency of melatonin where the formulation comprises (a) a sugar-based core comprising less than about 1 mg of melatonin where the melatonin is about 0.05 to 2% by weight of the core; and (b) about 5 to 25% by weight of ethylcellulose coating comprising ethylcellulose and a plasticizer.
  • Figure 1 discloses the experimental results of part 1 of Example 3, i.e.. the effect of immediate release melatonin administration on endogenous melatonin onset.
  • Figure 2 is a graph of time in hours post-administration of a formulation comprising sustained and immediate release melatonin versus plasma melatonin concentrations for 0.8 mg (circles), 0.4 mg (squares), and 0.2 mg (triangles) in elderly (filled symbols) and young (open symbols) individuals.
  • Figure 3 discloses the experimental results of Example 5, and shows the relationship between the degree of phase shift obtained and the interval time of administration of exogenous melatonin and the endogenous dim light melatonin onset (DLMO).
  • DLMO dim light melatonin onset
  • Figures 4 and 5 disclose the experimental results of part 1 of Example 6.
  • Figures 6 and 7 disclose the results of part 2 of Example 6 and are graphs of the time of melatonin administration versus phase shift in hours.
  • Figure 8 is a graph of melatonin onset versus day of study for a patient administered 0.4 mg sustained release melatonin at 9 P.M.
  • physiological levels or patterns By physiological levels or patterns is meant melatonin concentrations in the blood that mimic or are similar to normal concentrations in terms of timing, amplitude and duration.
  • melatonin amplitude is meant a specific concentration of melatonin in the blood.
  • melatonin duration is meant the length of time that a specific concentration of melatonin is present in the blood.
  • onset time is meant the time [clock time or circadian time (defined below)] that a specific concentration of melatonin is reached in the blood.
  • circadian time is meant the time some internal pysiological event that occurs at some predictable time relative to the endogenous circadian pacemaker. For example, the onset of melatonin production occurs at circadian time (14 in most individuals).
  • offset time is meant the time (clock time or circadian time) that a specific concentration of melatonin is no longer present in the blood.
  • melatonin levels ranges of melatonin such as those taught by Van Coevorden et ah, and Strassman et a
  • a deficiency of melatonin is meant a melatonin concentration below the average normal concentration present in an individual at the time sleep is desired.
  • Such melatonin deficiencies may be present when the individual is unable to produce a normal nighttime melatonin concentration.
  • Low melatonin concentrations are common in the elderly and frequently have a low quality of sleep usually in combination with a decreased duration of sleep.
  • a deficiency of melatonin at "bed time" typically exists in an individual suffering from jet lag. When such low nighttime or bedtime concentrations of melatonin are present, the individual's melatonin or circadian rhythm is dispersed or shifted out of phase.
  • the present invention encompasses the administration at the time sleep is desired of a sustained release melatonin composition that yields improved amounts of bioavailable melatonin and unexpectedly provides adequate melatonin levels in individuals suffering from a deficiency of melatonin.
  • sustained release melatonin or immediate release melatonin formulations corrects melatonin or circadian rhythms that are dispersed or shifted out of phase.
  • the administration of a sustained release formulation sets the individual's phase, i.e. , the formulation provides a phase shift.
  • administration of either sustained or immediate release melatonin at a specific, critical time effects a phase shift.
  • the amount of immediate release melatonin administered to the human patient should be sufficient to achieve the desired circadian phase-shifting effect.
  • a dosage of about 0.25 mg to about 75 mg, preferably about 0.75 mg, and most preferably about 0.50 mg, of exogenous immediate release melatonin is used to effect the desired change in phase of the circadian rhythm of endogenous melatonin production.
  • the total dose of immediate release melatonin is given in two or more smaller portions to the human patient over an interval of about two hours if the person is awake. One dose time is preferred if the person is asleep.
  • Pharmaceutical quality melatonin is commercially available.
  • the dosage of melatonin may be administered orally, by injection, via a transdermal patch or by implantation of a reservoir designed to release a steady dosage of melatonin over time.
  • melatonin is administered orally.
  • a phase advance in the circadian rhythm of endogenous melatonin production is effected by the administration of an amount of exogenous melatonin sufficient to achieve the phase advance from more than 6 hours to about 10 hours, preferably from about 7 to about 10 hours, most preferably about 8 hours, before the human's normal sleep phase should begin. This is typically from about 4 hours to about 8 hours, most preferably about 6 hours, before the patient's endogenous melatonin onset.
  • a phase delay in the circadian rhythm of endogenous melatonin production is effected by the administration of an amount of exogenous melatonin sufficient to achieve the phase delay from about 11 to about 19 hours, most preferably from about 12 to about 16 hours, prior to when the human's normal sleep phase should begin. This is typically from about 9 hours to about 17 hours, most preferably from about 10 to about 14 hours, before the patient's endogenous melatonin onset.
  • the amount of melatonin administered in the sustained release formulation to the human patient suffering from a melatonin deficiency should be sufficient to produce a normal nighttime melatonin amplitude, i.e. , a plasma concentration approximating those in normal individuals at night.
  • a dosage of about 0.025 mg to about 1 mg, more preferably from about 0.05 to 0.75 mg, and most preferably about 0.1 mg to about 0.4 mg, of sustained release melatonin is used to treat the patient and, thus, to mimic a normal melatonin pattern in the human during the time sleep is needed.
  • Sustained release formulations containing higher amounts of melatonin will provide longer durations of release and, in addition, higher melatonin amplitudes in the patient.
  • an oral sustained release melatonin formulation provides a sustained plasma concentration of melatonin over a period of at least three hours, and the dose required to achieve this concentration is substantially less than 1 mg.
  • the sustained release melatonin formulation of the invention comprises (a) a core comprising 0.05 to 2% by weight of melatonin; and (b) about 5 to 25 % by weight of ethylcellulose coating comprising ethylcellulose and a plasticizer. This formulation releases melatonin over time such that a normal nighttime amplitude of melatonin in the body is mimicked.
  • the sustained release melantonin composition surprisingly provides at least about 5% bioavailable melatonin. In more preferred embodiments, the composition provides at least about 50% bioavailable melatonin, and more preferably at least about 10% bioavailable melatonin.
  • the plasticizer is an alkyl sebacate or a trialkyl citrate, where each alkyl is the same or different and represents straight or branched chain alkyl groups having 1-6 carbon atoms.
  • a particularly preferred plasticizer is a mixture of dibutyl sebacate and triethyl citrate at a ratio of about 1:1 by weight.
  • compositions containing the sustained release melatonin formulation may also contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may be prepared to contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby modify the sustained release of melatonin.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Gelatin capsules may be prepared wherein the melatonin formulation is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • particulate beads of the sustained release formulation were loaded into a gelatin capsule.
  • Administration of the sustained release formulation of the invention produces a melatonin amplitude that closely mimics the average nighttime pattern in terms of amplitude.
  • This formulation produces less than a five-fold variation in the peak concentrations generated relative to normal; sustained patterns are over a period of about 3 to 10 hours where the average melatonin concentrations vary by less than five-fold.
  • Preferred formulations according to the invention produce bioavailability of at least about 5%.
  • Mimicked (exogenously produced) normal melatonin patterns are defined as melatonin patterns in which the average melatonin concentration is between about one-fifth and five times normal and a sustained average concentration over a period of at least three hours where the plasma concentration does not fluctuate more than about five-fold.
  • the oral compositions produce a minimum concentration of at least one-third normal and no more than three times normal for a peak, with a sustained concentration over at least three hours where the concentrations fluctuate no more than three fold.
  • Preferred oral doses of sustained release melatonin produce initial melatonin concentrations of from about 25 to 300 pg/ml, average melatonin concentrations of about 70 to 80 pg/ml over a three-hour period, and no more than three-fold variation in average concentrations over the three hours.
  • Such products may be capsules or tablets or liquids so long as they provide a relatively sustained release over a time period of about 3 to 12 hours and usefully supplement or replace normal melatonin patterns.
  • a useful dosage form can be produced using only controlled release melatonin without immediate release hormone.
  • Oral sustained release melatonin is useful to replace or supplement melatonin hormone in a truly physiologic pattern.
  • This formulation can aid Alzheimer's patients and other elderly individuals.
  • the present invention may be used in, but is not limited to, the following situations to achieve chronobiologic effects, alleviate circadian rhythm disorders, and/or achieve normal concentrations of melatonin when initiation of sleep is desired via mimicking of normal melatonin patterns: astronauts in orbit around the earth, on missions in space to the Earth's moon or to the planets or out of the known solar system, or in training for such missions; submariners, or persons confined for research, exploration or industrial purposes below the seas; miners, explorers, spelunkers, researchers or those confined below the earth; psychiatric patients; insomniacs; the comatose, or those who need to be maintained in a state of unconsciousness for medical, psychiatric or other reasons; medical residents, nurses, firemen, policemen or all those whose duties require alertness and
  • North or Antarctica or all those who live in a climate or climates that possess abnormal amounts of light or darkness; the aged, Alzheimer's patients, the sick, or all those who require dosages of medication at appropriate times in the circadian cycle; animal breeders, for use in controlling circadian time; in pathological conditions, such as depression, schizophrenia, sudden infant death or crib death syndrome, migraine headache, seasonal affective disorder, shift worker syndrome, melatonin deficiency syndrome, pre-menstrual syndrome, and breast and other carcinomas in mammals; to acheive immunostimulant and immunomodulatory effects, wool or hair production in animals, breeding affects, aging effects, contraception, appetite affects, reproduction, thyroid function, sleep, or to overcome the effects of jet lag.
  • pathological conditions such as depression, schizophrenia, sudden infant death or crib death syndrome, migraine headache, seasonal affective disorder, shift worker syndrome, melatonin deficiency syndrome, pre-menstrual syndrome, and breast and other carcinomas in mammals
  • to acheive immunostimulant and immunomodulatory effects wool or hair production in
  • this product was then spray coated with ethylcellulose (Aquacoat*, FMC Corp.) containing 15% of solids weight of dibutyl sebacate and 15 % of solids weight of triethyl citrate to a total calculated solids coating on the melatonin and sugar seeds of 20% by weight. Although some coating is lost during the spraying process, the final coat is at least about 10% by weight of the melatonin sustained release formulation and generally greater than 15% by weight, but less than 20%.
  • Sustained release melatonin beads were prepared essentially as described in part 1 of this example except that 18-20 mesh non-pareil sugar seeds were used.
  • Sustained release melatonin beads were prepared essentially as described in part 1 of this example except that the ethylcellulose coating was applied at about 5 % by weight of the formulation.
  • sustained release melatonin using 8-10 mesh sugar seeds and 10% ethylcellulose coating
  • Sustained release melatonin beads were prepared essentially as described in part 1 of this example except that the ethylcellulose coating was applied at about 10% by weight of the formulation.
  • melatonin composition containing sustained and immediate release melatonin was spray layered on 8-10 mesh non-pareil sugar seeds to a concentration of 3.0 mg melatonin per gram of beads using polyvinylpyrrolidone (0.2%) and hydroxypropylcellulose (0.1 %) with melatonin (0.6%) in 95% alcohol, in a spray coater.
  • a 0.80 mg melatonin formulation was prepared in a similar manner to contain 0.08 mg immediate release melatonin and 0.72 mg of sustained release melatonin. 6. Preparation of melatonin composition containing sustained release melatonin
  • Capsules were loaded to contain either 0.80 mg, 0.40 mg or 0.20 mg of the sustained release melatonin beads prepared in part 1 of this example were loaded into a gelatin capsule to result in formulations containing 0.80 mg, 0.40 mg or 0.20 mg total melatonin respectively.
  • An intravenous line or heparin lock is inserted in a forearm vein and 5 ml of blood drawn at specified time periods such as every 30 minutes between 7PM and
  • the dried extract containing melatonin and the added chromatographic control is dissolved in 0.4 ml of anhydrous acetonitrile.
  • the melatonin and the chromatographic control are then derivatized by the addition of 25 mcl of pentafluropropionic acid anhydride and 0.5 ml of a solution of 5% trimethylamine in anhydrous benzene and reacted at 100 degrees C for 10 minutes.
  • the reaction products are washed sequentially with 1 ml water and 1 ml 5% ammonium hydroxide.
  • the mixture is centrifuged briefly at 13,000 g and the organic phase withdrawn and evaporated to dryness under nitrogen.
  • the dried extract is partitioned between 0.5 ml acetonitrile and 1 ml hexane by vigorous mixing followed by centrifugation. The hexane layer is removed and the acetonitrile evaporated to dryness under nitrogen. This partitioning step is performed two times for each sample.
  • the dried extract is re-partitioned for storage.
  • the derivatives are stable and can be stored at -20 degrees C for several weeks.
  • the amount of melatonin present in each sample is determined by analysis using a gas chromatograph-mass spectrometer (GC-MS). Before injection onto the GC column, the dried derivatives are dissolved in 15 mcl of ethyl acetate.
  • a blind subject whose circadian rhythms were free-running was placed on a three-week regimen to phase shift his circadian rhythms using administration of exogenous melatonin.
  • the subject was given 0.25 mg of melatonin orally at 1900 and 2100 hours (clock time) every day for three weeks.
  • the effect of exogenous immediate release melatonin administration on the time of endogenous melatonin onset is shown in Figure 1.
  • the cumulative phase advance seen in this subject is equivalent to the phase advance obtained when a much higher dose (5 mg) was used.
  • Example 1 to a blind patient who was also taking atenolol (100 mg) at 5 AM resulted in a circadian rhythm phase shift.
  • the results shown in Figure 8 demonstrate that a low dose of melatonin formulated to be partially immediate release and partially sustained release composition effects a phase advance in a human.
  • Figure 2 indicate that a 0.8 mg dose of melatonin combining 0.08 mg immediate release and 0.72 mg sustained release melatonin produced plasma concentrations above about 100 mg/ml for at leaset 12 hours in both elderly and young individuals.
  • Figure 2 shows that a 0.4 mg dose of melatonin formulated as only 0.04 mg immediate release and 0.36 mg sustained release produced plasma melatonin concentrations above 100 pg/ml for about 6 hours in the young subjects and for about 7 hours in the elderly subjects.
  • the average peak concentrations relative to the average minimum concentrations during the sustained concentration time interval are only about 2:1 for the young and ⁇ 3:1 for the elderly.
  • Figure 2 shows that 0.2 mg of melatonin with 20 ⁇ g of immediate release melatonin produces truly physiological plasma concentrations of melatonin, especially in the elderly. Because some elderly patients naturally produce some melatonin at night about one-third the melatonin of young subjects, the dose can be even further reduced in that segment of the population to about 0.15 mg or even 0.1 mg or less total melatonin, if desired to supplement normal production, in a manner that will allow plasma melatonin concentrations to mimic normal in terms of amplitude and duration.
  • Example 2 During the second week, subjects were given placebo at 1700 and 1900 hours for two days, and then immediate release melatonin was administered orally in two doses of 0.25 mg at 1700 and 1900 hours for 4 days and the subject's DLMO determined. Seventeen trials were conducted on the eight subjects. The results of this study are shown in Figure 3.
  • the Figure shows the relationship between the degree of phase shift obtained and the interval between the time of administration of exogenous melatonin and the endogenous DLMO. This interval is also known as the phase angle difference or phase angle.
  • the subjects were administered a second dose of the same composition at about 10 PM to midnight bedtime in France (corresponding to about 1 to 3 PM Pacific time) on the arrival night and a third dose on the second night following the arrival at about 10 PM or midnight each night depending on the subject, that was about 1 PM or 3 PM Pacific Time. This was predicted to be about 6 hours before the normal DLMO.
  • a standard 16 channel montage was used: four EEG (C 3 A 2 , O,A 2 ⁇ ⁇ A A,, O 2 A ⁇ ), four EMG (two for chin, one each for right and left lower extremity), one nasal air flow, two ocular movements, two for respiratory muscle movement, one for oximetry, one for body position and one for EKG. Subsequent recordings omitted the airflow and leg EMG channels. Sleep recordings were done in the subjects' own homes using portable Telediagnostics R polysomnograph, in order to minimize effects from the unfamiliar sleep laboratory environment.
  • LDSR low-dose, slow-release
  • the subject was assigned randomly to treatment sequence No. 2. Placebo was administered each night at bedtime for two weeks, followed by a two-week wash-out period, followed by two weeks of 0.2 mg slow-release melatonin capsules (prepared according to part 6 of Example 1) administered each night at bedtime. Ten PSG studies were done; two at baseline and two at both the start and end of each treatment sequence.
  • the diagnostic (baseline) sleep studied demonstrated a lack of sleep pathology.
  • the data from the four nights of placebo treatment were averaged and compared to the average of the four nights of the active treatment. The results are shown in the following table.
  • the wake after sleep onset was decreased by 35.7 minutes.
  • Melatonin increased the time spent in Stage 2, 3 and 4 sleep, considered the deeper stages of sleep, and decreased the time spent in
  • Stage 1 sleep considered light sleep.
  • Total non-REM and total slow wave sleep were increased.
  • Both the number of movement arousals and transient arousals from sleep were decreased with melatonin treatment.
  • melatonin treatment improved the quality of sleep.
  • Input absorption rates and cumulative amounts of melatonin absorbed were estimated using an interactive computer deconvolution program and pharmacokinetic parameters similar to those reported by Iguchi et ah In this case the program was PCDCON, version 1.0, created at the College of Pharmacy, University of Texas. Exact bioavailability was not determined in this study since an intravenous dose was not administered as a reference standard. This method estimates the bioavailability to be at least 5% from 0.2 mg, 0.4 mg and 0.8 mg formulations of the invention.
  • Alzheimer's disease One of the most common and distressing symptoms of Alzheimer's disease
  • AD is the deterioration of the sleep/wake cycle and sleep onset and duration disturbances related thereto. Accordingly, melatonin replacement therapy using the sustained release melatonin formulations disclosed herein were used to alleviate disrupted sleep patterns in AD patients.
  • melatonin may be increasing sleep in the responders by increasing sleep duration by a chronobiologic mechanism, i.e. , by inducing a corrective phase advance in the patients' endogenous melatonin phase response curve.
  • the two responding patients were sleeping for a significant amount of time during the day, consistent with having a phase delay in their circadian rhythms.
  • Melatonin administered at 2000 hrs would be expected to have a phase-advancing effect on these patients' endogenous melatonin circadian rhythm, which would be expected to correct their phase delay.
  • the results obtained were consistent with these expectations based on the patients' circadian phase response curves.

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Abstract

L'invention concerne le traitement des troubles du rythme circadien et des troubles du sommeil. Ce procédé comporte l'administration orale d'une composition retard de mélatonine pour rétablir un pattern normal de la mélatonine lorsque le pattern normal a été rompu ou est absent.
PCT/US1994/008365 1993-07-26 1994-07-25 Compositions administrees par voie orale, de type retard, contenant de la melatonine WO1995003043A1 (fr)

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0719555A2 (fr) * 1994-12-05 1996-07-03 JENAPHARM GmbH Utilisation de la mélatonine pour l'obtention des formes pharmaceutiques pulsatoires à l'administration orale
US5688520A (en) * 1995-03-29 1997-11-18 Minnesota Mining And Manufacturing Company Transmucosal delivery of melatonin for prevention of migraine
US6638963B1 (en) 1990-12-04 2003-10-28 Oregon Health And Science University Methods for treating circadian rhythm disorders
EP1441702A2 (fr) 2001-08-14 2004-08-04 Neurim Pharmaceuticals (1991) Limited Methode de traitement de l'insomnie primaire
EP1656939A1 (fr) * 2004-11-10 2006-05-17 Pooger Properties Limited Utilisation de la mélatonine pour la préparation d'un médicament anticancéreux
GB2434099A (en) * 2006-01-12 2007-07-18 Roger Coghill Very low dosage melatonin compositions and their use in the treatment of the adverse effects of exposure to electromagnetic fields and radiation
EP3056220A1 (fr) 2007-04-11 2016-08-17 John A. Mccarty Comprimé d'une hormone et procédés de préparation et d'utilisation
EP3127536A1 (fr) 2015-08-05 2017-02-08 Versailles B.V. Formulations de mélatonine et procédés de préparation et d'utilisation
US20170128419A1 (en) * 2011-01-28 2017-05-11 Physician's Seal, LLC Controlled-Release Melatonin Compositions and Related Methods
WO2018078429A1 (fr) * 2016-10-31 2018-05-03 Neurim Pharmaceuticals Ltd. Mini-comprimés de mélatonine et leur procédé de fabrication
US10143654B2 (en) 2011-01-28 2018-12-04 Physician's Seal, LLC Controlled-release compositions of melatonin combined with sedative and/or analgesic ingredients
WO2019038586A1 (fr) 2017-08-19 2019-02-28 Ftf Pharma Private Limited Composition pharmaceutique de mélatonine
US10849856B2 (en) 2016-10-31 2020-12-01 Neurim Pharmaceuticals Ltd. Melatonin mini-tablets and method of manufacturing the same
WO2021144403A1 (fr) * 2020-01-17 2021-07-22 Société des Produits Nestlé S.A. Forme posologique à comprimés de mélatonine à libération prolongée
CN114555057A (zh) * 2019-12-10 2022-05-27 耐贝医药株式会社 含有褪黑素的颗粒剂
WO2022152863A1 (fr) 2021-01-15 2022-07-21 Galventa Gmbh Formulation de caféine à libération pulsatile
CN114845712A (zh) * 2020-03-18 2022-08-02 耐贝医药株式会社 新型颗粒剂及其制造方法

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Publication number Priority date Publication date Assignee Title
EP0126630A1 (fr) * 1983-05-18 1984-11-28 Monash University Utilisation de melatonine pour la fabrication d'un medicament
WO1985003227A1 (fr) * 1984-01-26 1985-08-01 Gene Link Australia Limited Implants veterinaires
EP0246910A2 (fr) * 1986-05-23 1987-11-25 Hoechst Veterinär GmbH Implants vétérinaires enrobés
US4945103A (en) * 1989-01-17 1990-07-31 Michael Cohen Method of treating pre-menstrual syndrome
EP0518468A1 (fr) * 1991-05-09 1992-12-16 Neurim Pharmaceuticals (1991) Limited Compositions à base de mélatonine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0126630A1 (fr) * 1983-05-18 1984-11-28 Monash University Utilisation de melatonine pour la fabrication d'un medicament
WO1985003227A1 (fr) * 1984-01-26 1985-08-01 Gene Link Australia Limited Implants veterinaires
EP0246910A2 (fr) * 1986-05-23 1987-11-25 Hoechst Veterinär GmbH Implants vétérinaires enrobés
US4945103A (en) * 1989-01-17 1990-07-31 Michael Cohen Method of treating pre-menstrual syndrome
EP0518468A1 (fr) * 1991-05-09 1992-12-16 Neurim Pharmaceuticals (1991) Limited Compositions à base de mélatonine

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6638963B1 (en) 1990-12-04 2003-10-28 Oregon Health And Science University Methods for treating circadian rhythm disorders
EP0719555A3 (fr) * 1994-12-05 1997-02-26 Jenapharm Gmbh Utilisation de la mélatonine pour l'obtention des formes pharmaceutiques pulsatoires à l'administration orale
US6214377B1 (en) 1994-12-05 2001-04-10 Jenapharm Gmbh Melatonin for the production of a peroral pulsatile form of medication
EP0719555A2 (fr) * 1994-12-05 1996-07-03 JENAPHARM GmbH Utilisation de la mélatonine pour l'obtention des formes pharmaceutiques pulsatoires à l'administration orale
US5688520A (en) * 1995-03-29 1997-11-18 Minnesota Mining And Manufacturing Company Transmucosal delivery of melatonin for prevention of migraine
US8962024B2 (en) 2001-08-14 2015-02-24 Neurim Pharmaceuticals (1991) Ltd Method for treating primary insomnia
EP1441702A2 (fr) 2001-08-14 2004-08-04 Neurim Pharmaceuticals (1991) Limited Methode de traitement de l'insomnie primaire
EP1656939A1 (fr) * 2004-11-10 2006-05-17 Pooger Properties Limited Utilisation de la mélatonine pour la préparation d'un médicament anticancéreux
GB2434099A (en) * 2006-01-12 2007-07-18 Roger Coghill Very low dosage melatonin compositions and their use in the treatment of the adverse effects of exposure to electromagnetic fields and radiation
EP3056220A1 (fr) 2007-04-11 2016-08-17 John A. Mccarty Comprimé d'une hormone et procédés de préparation et d'utilisation
US20170128419A1 (en) * 2011-01-28 2017-05-11 Physician's Seal, LLC Controlled-Release Melatonin Compositions and Related Methods
US10226447B2 (en) * 2011-01-28 2019-03-12 Physician's Seal, LLC Controlled-release melatonin compositions and related methods
US10143654B2 (en) 2011-01-28 2018-12-04 Physician's Seal, LLC Controlled-release compositions of melatonin combined with sedative and/or analgesic ingredients
US11389428B2 (en) 2011-01-28 2022-07-19 Société des Produits Nestlé S.A. Controlled-release melatonin compositions and related methods
EP3127536A1 (fr) 2015-08-05 2017-02-08 Versailles B.V. Formulations de mélatonine et procédés de préparation et d'utilisation
WO2018078429A1 (fr) * 2016-10-31 2018-05-03 Neurim Pharmaceuticals Ltd. Mini-comprimés de mélatonine et leur procédé de fabrication
US10722494B2 (en) 2016-10-31 2020-07-28 Neurim Pharmaceuticals Ltd. Melatonin mini-tablets and method of manufacturing the same
US10849856B2 (en) 2016-10-31 2020-12-01 Neurim Pharmaceuticals Ltd. Melatonin mini-tablets and method of manufacturing the same
US10869857B2 (en) 2016-10-31 2020-12-22 Neurim Pharmaceuticals Ltd. Melatonin mini-tablets and method of manufacturing the same
EP3777842A1 (fr) * 2016-10-31 2021-02-17 Neurim Pharmaceuticals Ltd. Mini-comprimés de mélatonine et leur procédé de fabrication
WO2019038586A1 (fr) 2017-08-19 2019-02-28 Ftf Pharma Private Limited Composition pharmaceutique de mélatonine
CN114555057A (zh) * 2019-12-10 2022-05-27 耐贝医药株式会社 含有褪黑素的颗粒剂
WO2021144403A1 (fr) * 2020-01-17 2021-07-22 Société des Produits Nestlé S.A. Forme posologique à comprimés de mélatonine à libération prolongée
US11723862B2 (en) 2020-01-17 2023-08-15 Societe Des Produits Nestle S.A. Dosage form with sustained release melatonin pellets
CN114845712A (zh) * 2020-03-18 2022-08-02 耐贝医药株式会社 新型颗粒剂及其制造方法
WO2022152863A1 (fr) 2021-01-15 2022-07-21 Galventa Gmbh Formulation de caféine à libération pulsatile

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