HK1075616B - Pharmaceutical formulation comprising melatonin - Google Patents

Description

Pharmaceutical formulations comprising melatonin

Technical Field

The present invention relates to the use of melatonin for the preparation of a medicament for short-term potentiation of certain hypnotics and to pharmaceutical formulations comprising melatonin and such hypnotics.

Background

Gamma-aminobutyric acid (GABA), which acts through GABA-a receptors, is the main inhibitory neurotransmitter system of the brain and plays an important role in regulating brain excitability. The GABA-a receptor comprises five subunits. The different protein subunits that make up the receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) have been identified and constitute the alpha, beta, gamma and delta families, with several subtypes existing in each group. The subunit composition of the receptor, and in particular its alpha-subunit content, determines its pharmacological properties. Many drugs and GABA-A receptorsThe binding sites of the different subunits of the body interact and these drugs include modern hypnotic drugs (i.e., benzodiazepines)Compounds of the class, and newer non-barbiturates and non-benzodiazepinesSuch as imidazopyridines and cyclopyrones), as well as anticonvulsants, anesthetics, and neurosteroids (e.g., pregnalone, a progesterone metabolite).

Receptor subtype specificity of hypnotics has been explained by differences in affinity for receptors containing different alpha subunits expressed in different regions of the brain. Thus, receptors comprising the alpha 1 subunit have type (I) pharmacology and high affinity to non-barbiturates and non-benzodiazepinesThe substances zolpidem and zaleplon bind, while receptors with alpha 2, alpha 3 or alpha 5 subunits have type (II) pharmacology and bind to these drugs with low affinity. (I) Both form (I) and form (II) bind diazepam and other benzodiazepinesA substance. In contrast, receptors containing both α 4 and α 6 subunits are insensitive to diazepam. The ligand selectivity of the receptor subunit contributes to its properties. Site-directed mutagenesis has been shown to benzodiazepinesThe species bind to the cleavage at the GABA-a receptor surface at the interface between the alpha and gamma subunits. Other drugs (flumazenil, zopiclone, zolpidem) also bind to the alpha subunit, but bind to benzodiazepinesAmino acids in different binding regions to which the species binds interact.

Using immunochemical and ligand binding techniques, it has been shown that the subunit composition of GABA-A exhibits a degree of brain site specificity. The major GABA-a receptor component found in the brain is α 1 β 2 γ 2, which is encoded on human chromosome 5. Disruption of the target gene provides clues to the physiological functions provided by GABA-a receptors comprising different subunits. While the gamma 2-containing receptor has been shown to play an important role in maintaining appropriate central inhibition, the beta 3-containing receptor is also an important determinant of excitability in certain brain regions, these techniques have not yet established a clear role for the alpha 5-, alpha 6-, and gamma 3-containing receptors.

GABA-A receptors are of great interest in several clinical conditions including insomnia, epilepsy, anxiety and alcoholism; common benzodiazepinesThe class of substances to treat anxiety and studies have shown benzodiazepinesAntagonists and inverse agonists (which induce an opposite effect on the receptor than the agonist) are useful in the rehabilitation of alcohol withdrawal.

GABA-A receptor modulators (benzodiazepines)Class of substances and non-benzodiazepinesHypnotics) is the most predominant use for treating insomnia, which is defined as at least three evenings/weeks with simultaneous distress or impairment during the day when initiating and/or maintaining sleep is problematic. Intractable insomnia is associated with a range of individual and social consequences, including higher medical and psychiatric morbidity, life-threatening accidents, decreased quality of life, impaired performanceAnd spacious work. Insomnia is related to the health-related quality of life, the negative consequences of daytime well-being, and is also of economic significance. The cost of insomnia is estimated to be $770 to $920 billion per year in the sense of lost productivity and accidents.

BenzodiazepineThe analogs are very effective in inducing sleep (shortening sleep latency) and maintaining sleep (increasing total sleep time). However, these drugs have a detrimental effect on next morning waking from sleep (hangover effect) and daytime alertness (psychomotor function). Newer non-barbiturates and non-benzodiazepines have been available since the late 80 s of the 20 th centuryHypnotics (e.g., imidazopyridines and cycloproprolones) and have been proposed as an alternative strategy. These drugs shorten sleep latency and do not produce the major "hangover" effect the next day. Possible side effects of these sleep aids include sedation and psychomotor impairment, daytime anxiety, progressive amnesia and cognitive impairment, insomnia rebound, drug tolerance and dependence. Because patients may experience daytime sleepiness, work may be compromised and the risk of accidents, particularly traffic accidents, is increased. All benzodiazepinesThe classmates all have a detrimental effect on cognition by destroying both short-term and long-term memory. Semantics and image memory are occasionally compromised. Previously used benzodiazepinesThe class is associated with a significant increase in the risk of dementia in elderly people (65 and over 65 years). The degree of memory loss is related to the particular substance and dosage. Thus, it is reduced while maintaining its hypnotic effectDosages of these substances may be beneficial to avoid these damages.

The development of dependence on these drugs is also a concern. The molecular mechanisms of hypnotic dependence have been explored and appear to involve down-regulation of the transcription of the normally prevalent α 1, β 2 and γ 2 subunits, and conversely up-regulation of the expression of the less frequent subunits. Zolpidem is an imidazopyridine substance indicated as useful for short-term (up to 4 weeks) treatment of insomnia, with recommended doses of 10 mg/day for adults and 5 or 10 mg/day for elderly or patients with liver damage. Long-term treatment with hypnotics such as zopiclone and zolpidem produces more limited changes in GABA-a receptor subunit expression. The hypnotic efficacy of zolpidem in treating elderly and adult patients with insomnia has been shown to be comparable to benzodiazepinesThe classes of flunitrazepam, fluzepam, nitrazepam, temazepam and triazolam, and non-barbiturates and non-benzodiazepinesThe efficacy of hypnotics such as zopiclone and trazodone are comparable.

Zaleplon is N- [3- (3-cyanopyrazolo [1, 5-a ] pyrimidin-7-yl) phenyl ] -N-ethylacetamide; zolpidem is N, N, 6-trimethyl-2-p-tolyl (toyl) -imidazo [1, 2, -a ] pyridine-3-acetamide L- (+) -tartrate (2: 1); zopiclone is 6- (5-chloropyridin-2-yl) -5- (4-methylpiperazin-1-yl) carbonyloxy-7-oxo-6, 7-dihydro-5H-pyrrolo [3, 4-b ] pyrazine; trazodone is 2- [3- {4- (m-chlorophenyl) -1-piperazinyl } propyl ] -triazolo [4, 3-a ] pyridin-3 (2H) -one monohydrochloride.

For example, zolpidem has gained worldwide acceptance because of its efficacy and its side effects, compared to benzodiazepines used to treat insomniaThe quasi-substance and barbiturates are milder andless problematic than these substances. When the drug is used as recommended (10 mg/day, < 1 month) or over a longer period, there is little evidence of insomnia rebound or withdrawal symptoms after the drug is discontinued. Initially, there were no reports of the development of tolerance to the hypnotic effect of zolpidem in a number of studies of duration up to 6 months. Nevertheless, side effects (delirium, hallucinations) often occur with zolpidem and it may have significant dependence. International regulation of zolpidem is recommended in a recent report by WHO Expert Committee, responsible for commenting on drug information that produces dependency to assess its international regulatory needs. Thus, reducing the risk of developing dependency is a public health issue.

The daily cycle in physiology and behavior is obviously a common property of living organisms. The internal biological clock remaining in the suprachiasmatic nucleus (SCN) regulates a complex series of rhythms including sleep-insomnia. Cycles of the endogenous clock are slower or faster than the 24-h day/night cycles of the sun (which are typically > 24h in humans) and are normally generated by 24-h light-dark cycles to match the ambient rhythm. Light is a ubiquitous signal that resets the time of the clock. An important output signal produced by SCN is the induction of the synthesis of the pineal hormone melatonin (N-acetyl-5-methoxytryptamine) at night. Melatonin is directly regulated by SCN and is therefore a marker of the circadian clock phase; it also delivers calendar information (dark signals) for organs including the SCN itself. The dephasing effects of melatonin are essentially opposite to those of light. Therefore, in the evening, administration of melatonin a few hours before its endogenous peak can effectively advance the sleep time of a patient with the phase delay syndrome and can blindly adjust the sleep wake cycle to 24 hours, in which case phototherapy is not applicable. When properly timed (i.e., using melatonin at the subjective night and using melatonin during the subjective day at an internal clock), melatonin and light can also relieve jetlag and sleep of night shift workers attempting to sleep during the day.

Melatonin in the induction and regulation of sleepPlays an important role. Melatonin activity in promoting sleep in humans is best demonstrated during the day when melatonin is not endogenously produced, or in the case of patients with abnormal melatonin production due to aging conditions or the use of certain drugs, such as beta adrenergic receptor blockers. Melatonin and benzodiazepines have been reportedThere are many pharmacodynamic interactions between mediated behavioral effects. It has been found that benzodiazepinesThe treatment suppresses the increase of plasma melatonin plasma concentration at night and changes the day-night rhythmicity thereof; this inhibition may interfere with the normal sleep-wake rhythmicity and additional melatonin supplementation may help maintain the benzodiazepinesSimilar to hypnotic effect. Thus, the 23-bit long-term use of benzodiazepines compared to placebo wasThe use of slow-release melatonin (2mg) in elderly insomnia patients produced significant changes in the maintenance of sleep and total sleep time.

In addition to re-supplementation of endogenous melatonin levels, it has also been reported that melatonin can maintain its hypnotic activity while simultaneously converting benzodiazepinesThe therapeutic dose of the pseudodrug triazolam was reduced by 50%. These results can be attributed to sleep-inducing melatonin and benzodiazepinesAddition of species. More importantly, the sleep-inducing, anxiolytic and anticonvulsant properties of melatonin are notFrom benzodiazepinesReceptor-mediated by the class of substances resulting from the concomitant use of flumazenil, a benzodiazepineAntagonists do not block the action of melatonin.

Melatonin is used to help withdrawal from mammals including benzodiazepinesThe drug addiction including the substance class is also very helpful. Strong evidence that melatonin has efficacy in withdrawal from addictive drugs has been found when it is used in withdrawal nicotine, which is usually accompanied by negative mood and behavior. In addition, to the p-benzodiazepineMelatonin administration in addicted 43-year-old women for rapid cessation of benzodiazepinesAnd (6) treating. 34 of the long-term benzodiazepines were used in comparison with placeboAdult insomnia volunteers of the species (40-90 years old) stopped benzodiazepine on concurrent use of sustained release melatonin (2 mg/day)The promoting effect of (b) was evaluated. The results show that the sustained release of melatonin in the tapering phase while maintaining good sleep quality is effective in promoting benzodiazepines(iii) terminating; at the end of the decrement period, use14 of 18 subjects with melatonin terminated by benzodiazepinesAnd only 4 of 16 patients in the placebo group discontinued the use of the drug (p ═ 0.006). The sleep quality score in the sustained release melatonin group was significantly higher (p ═ 0.04). No serious adverse events were observed. The use of melatonin for terminating drug dependence has been described, for example, in EP 0724878B 1.

Suhner et al, in aviat. 638(2001) reported that zolpidem 10mg co-administered with normally released melatonin 5mg was less potent than zolpidem alone and less tolerable than melatonin for jetlag. This co-administration can cause side effects such as nausea, vomiting, amnesia and inability to sleep to an extent, suggesting that co-administration of zolpidem and melatonin may not be suitable for practical therapeutic applications in treating conditions involving circadian rhythms such as insomnia.

However, applicants have unexpectedly discovered that melatonin potentiates non-barbiturates and non-benzodiazepinesHypnotics such as zolpidem have effects on sedation and psychomotor skills. This interaction is not additive and it is not due to pharmacokinetic changes in the blood concentration of zolpidem or melatonin. More importantly, the pharmacodynamic interaction is transient and disappears within 2 hours, while the concentrations of both drugs in the blood are still high.

Disclosure of Invention

Thus, in one aspect, the invention provides melatonin for use in a method for producing an effective short-term potentiation of at least one drug selected from the group consisting of non-barbiturates and non-benzodiazepinesUse of hypnotic compounds for hypnotic effect.

In another aspect, the present invention provides a pharmaceutical formulation comprising, in addition to at least one carrier, diluent, coating or adjuvant: at least one drug selected from the group consisting of non-barbiturates and non-benzodiazepinesA hypnotic-like compound, and melatonin in an amount and in a form effective to potentiate the hypnotic effect of said at least one compound for a short period of time.

The drug or drug formulation is more preferably characterized by at least one of the following characteristics:

(a) the hypnotic is a GABA-A receptor modulator;

(b) the hypnotic is a compound comprising a fused ring system containing a ring nitrogen;

(c) the medicament or pharmaceutical formulation comprises at least one carrier, diluent, coating or adjuvant;

(d) the medicament or pharmaceutical preparation is in unit dosage form;

(e) the medicament or pharmaceutical preparation comprises at least one non-barbiturate drug and a non-benzodiazepineHypnotic-like compounds;

(f) the at least one compound is present in said medicament or pharmaceutical formulation in an amount that would be sub-therapeutic if administered in the absence of melatonin;

(g) the medicament or pharmaceutical formulation is suitable for sustained release of melatonin.

Definition of

The term "short term potentiation" refers to potentiation over a period of no more than about 4 hours, preferably no more than about 2 hours and particularly preferably about 1 hour ± 25%.

Detailed description of the invention

The present invention focuses on melatonin and therapeutic or sub-therapeutic amounts of non-barbiturates and non-benzodiazepinesHypnotics are used in combination to effectively promote the onset of sleep in patients with difficulty falling asleep while reducing the concept of memory impairment, psychomotor accidents, and subsequent risks of tolerance and dependence.

The medicament or pharmaceutical formulation preferably comprises at least one acrylic resin and is for sustained release of melatonin; ideally, it is also used for the conventional release of said at least one compound.

In this context, sustained release can be achieved, for example, by at least one of the following features:

(a) altering the particle size of melatonin;

(b) using at least two different coating materials that dissolve at different rates in the human body; and/or

(c) The thickness of the coating material is varied to coat the melatonin particles with different thicknesses of coating material(s) that can dissolve at different rates in the human body.

At least one drug selected from the group consisting of non-barbiturates and non-benzodiazepinesHypnotic-like compounds preferably comprise a fused bicyclic ring system, e.g. a system comprising at least two ring nitrogen atoms.

Examples of such ring systems are:

pyrazolo [1, 5-a ] pyrimidine skeleton, e.g. the hypnotic zaleplon;

imidazo [1, 2-a ] pyridine skeletons, such as the hypnotic zolpidem;

pyrrolo [3, 4-b ] pyrazine backbones, such as the hypnotic zopiclone; and

triazolo [4, 3-a ] pyridine skeleton, for example mepiquat chloride.

The invention will now be illustrated by the following non-limiting examples.

Example 1

MethodPharmacokinetics of melatonin (2mg sustained release formulation), zolpidem (10mg) and combinations thereof were evaluated with 16 volunteers (12 men and 4 women). The mean age of the enrolled individuals was 59.4 years (SD 3.2) and the mean body mass index was 25.5kg/m²(SD 2.3), average body weight 75.8kg (SD 11.8) and average height 171.8cm (SD 7.7). In a randomized double-blind crossover study, they were given a placebo tablet in the evening to establish baseline, and then were given melatonin, zolpidem, or a combination dose or placebo tablet in a randomized fashion in the evening (one night only), with a one-week washout period between these treatments.

Blood samples were drawn from these individuals at preselected intervals after administration of the tablets.

ResultsPharmacokinetic parameters for both drugs when administered alone and in combination are listed in table 1:

table 1: pharmacokinetic parameters of melatonin (2mg sustained release) and zolpidem (10mg) when administered alone and in combination

ConclusionThe absorption of melatonin after co-administration of the sustained release melatonin and zolpidem is similar to that obtained after administration of only the sustained release melatonin. After zolpidem 10mg alone, plasma concentration values of zolpidem can be compared to those after co-administration of zolpidem and slow-release melatonin. There should be no difference in the efficacy of zolpidem when given concurrently with melatonin, based on the absence of pharmacokinetic interactions.

Example 2

MethodPsychomotor skills and driving behavior were evaluated with 16 volunteers (12 men and 4 women) on melatonin (2mg sustained release formulation), zolpidem (10mg), combinations thereof and placebo. The mean age of the enrolled individuals was 59.4 years (SD 3.2) and the mean body mass index was 25.5kg/m²(SD 2.3), average body weight 75.8kg (SD 11.8) and average height 171.8cm (SD 7.7).

In a randomized double-blind crossover study, subjects were given a placebo tablet in the evening to establish baseline and then a tablet of melatonin, zolpidem, a combination thereof, or placebo in the evening in a randomized fashion with a one week period of no treatment between treatments. A set of behavioral tests and driving skill tests are performed on the patient at preselected intervals after administration of the tablet. These tests include psychomotor work, alertness and coordination for reaction tests: ARCI 49, groovedpigboard, rivermedia store, photographic description, simple reaction time, task of sleeplessness number, choice of reaction time, delayed picture recognition, visual tracking, driving simulator: road driving and waking-EEG.

And (6) obtaining the result.

Research experiment for understanding medicine: sustained release melatonin administered alone is believed to have no recognized side effects or adverse effects to the contrary. Compared to placebo, some acute injury was seen with zolpidem, which was resolved 12.5 hours after dosing. The effects found with zolpidem alone can be seen in the measurement of attention, episodic secondary memory and motor coordination. When sustained release melatonin and zolpidem were co-administered, lesions were seen in all measurements taken at 1 hour in the placebo comparison, some of these lesions lasted up to 4 hours. 1 hour after administration, the lesions produced by co-administration were significantly higher than those produced by zolpidem alone, and therefore synergy had to be considered. At 4 hours, the lesions seen with co-administration were similar to the effect of zolpidem alone at this time. At 12.5 and 15 hours post-administration, there was no evidence of any effect of the co-administered two compounds.

ARCI49: a decrease in euphoria (MBG score) was observed for all groups at 1 hour post-dose. This effect was more pronounced in the three treatment groups compared to placebo at 4 hours post-dose. An increase in dullness or mental retardation (LSD score) was observed during the 4 hour period after dosing for the three treatment groups compared to placebo. In the zolpidem 10mg and slow release melatonin 2mg + zolpidem groups, a very significant sedative effect (increased PCAG score) was noted during the first 4 hours after administration, compared to placebo. In the combination group, this effect peaked at about 1 hour after administration, whereas in the zolpidem group, the effect gradually increased and reached the same maximum only about 4 hours after administration. For the group of sustained release melatonin 2mg, a slight increase in the effect was also observed 4 hours after the administration, but the effect was not significant as compared with the control. Finally, a similar reduction in empirical stimulation (BG score) was also noted in the zolpidem 10mg and sustained release melatonin 2mg + zolpidem 10mg groups compared to placebo. This effect confirms the observed sedative effect. All these effects are completely passed the next morning (12 hours 30 minutes to 15 hours after administration).

Rivermead story: zolpidem 10mg and slow release melatonin 2mg + zolpidem 10mg reduced memory efficiency for both memories (immediate and delayed) compared to control and slow release melatonin 2 mg. Zolpidem 10mg + melatonin release 2mg interfering with immediate recovery was higher than zolpidem 10mg alone, whereas in both treatment groups the impairment of delayed memory (amnesic effect) was comparable. The amnestic effect observed in both treatment groups was mainly associated with zolpidem. Indeed, the sustained release of melatonin at 2mg for transient memory appears to potentiate the effect of zolpidem 10mg on behavior in transient memory rather than delayed memory.

Grooved Pegboard: the results observed in the ground Pegboard test indicate that although fine manual coordination is not disturbed, the execution of the task by both hands is slowed down. In fact, for both cases (ipsi and conttra lateral), a significant increase in duration was observed at 1 and 4 hours after administration in the zolpidem 10mg group and in the sustained melatonin 2mg + zolpidem 10mg group compared to the baseline and the other two treatment groups (placebo and sustained melatonin 2 mg). This increase was more pronounced in the combination treatment group, indicating that a sustained release of melatonin at 2mg promoted the action of zolpidem at 10 mg. The major slowing effect occurred 1 hour after administration and then the effect decreased with the passage of time.

Driving simulator: no significant differences were observed in the mean values of the studied parameters (absolute speed, deviation of the speed limit and deviation of the ideal route). However, significant differences were noted for the standard deviation and number of impacts for these parameters. In fact, the standard deviation of the absolute velocity, of the velocity limits and of the deviation of the ideal path increases 2 hours after administration with zolpidem 10mg and zolpidem 10mg + melatonin 2mg in sustained release. This effect was more pronounced in the combination treatment group for the absolute rate parameter. These increased standard deviations indicate irregular driving, with fluctuations not only in speed, but also in road control. Compared with the zolpidem 10mg group, the ideal routeThe observed changes in the line parameters were consistent with an increase in the number of hits counted at 2 hours after administration of zolpidem 10mg and slow release melatonin 2 mg. By the next morning, this driving irregularity disappeared, and the number of hits was similar to those in the placebo group and the slow release melatonin 2mg treatment group. Neither drug interfered with drivability at 13 hours post-dose.

Wake EEG: in the resting situation, no major difference in alpha activity has been observed compared to placebo. The reduction in alpha seen with zolpidem alone or with zolpidem + sustained release melatonin is consistent with the sedative potential of zolpidem. In the driving situation, the alpha activity was significantly increased in the case of zolpidem or zolpidem + sustained release melatonin compared to melatonin alone (not placebo). Zolpidem has an increased theta rhythm on the front leader (front lead) compared to placebo, which is interpreted as another signal of sleep induction.

On day 2, with the eyes closed, there were still some effects that showed a decrease in alertness, possibly due to rest. In effect, these effects are eliminated in the active state when driving or behavior awareness testing is conducted.

The most common therapeutic adverse event that occurred in this study was drowsiness. Zolpidem and zolpidem + melatonin were shown to have similar incidence of drowsiness, but an increase in the amount of melatonin and placebo, respectively, was evident. The concomitant administration of sustained release melatonin appears to potentiate the central effects of zolpidem, since adverse events are more intense when the combination is administered than zolpidem alone; however, only sustained release melatonin may be well tolerated.

ConclusionThe effects on behaviour, memory and sedation of treatment with sustained release melatonin 2mg can be compared with most parameters of these effects observed with placebo. This study clearly demonstrates a short-lived pharmacodynamic interaction between sustained release melatonin and zolpidem,in particular, there was an interaction at 1 hour after co-administration. This effect was greatly reduced at 4 hours, although the concentrations of both drugs in plasma were still high and completely disappeared at 12.5 and 15 hours.

When used in combination with a sustained release of 2mg of melatonin, the observed impairment of mood, skills and cognition with zolpidem is enhanced, particularly 1 hour after administration. It should be noted that these interactions may be clinically important as they allow for short term potentiation of the effect of the sub-clinical dose of zolpidem, particularly during the first hour after administration when it is favourable for sleep induction, and also may reduce the risk of additional damage caused by zolpidem due to subsequent non-potentiation.

Zolpidem treatment significantly worsened driving skills and memory work during the first hour after its administration, while the effects of melatonin were not different from those of placebo treatment. These studies indicate that the improvement in sleep quality reported by patients (as in the case of zolpidem) does not necessarily indicate a contribution to enhancing sleep recovery if daytime vigilance is not improved.

It should be noted that sustained release melatonin formulations are of particular interest in one respect, as they have been shown to improve the quality of sleep in insomnia patients aged 55 and above 55, and at the same time improve the alertness of the following day. However, the patient did not consider the improvement in sleep onset to be due to melatonin and considered that this aspect was well provided by zolpidem. These facts are important for new hypnotic treatments involving better safety/efficacy.

The present invention contemplates co-administration of melatonin and the identified hypnotic (e.g., zolpidem). The present invention aims to improve clinical results, and the term "co-administration" may be carried out by administering separate dosage forms of melatonin and hypnotic, or may be carried out by administering a combined dosage form. One illustrative example of preparing a combination dosage form is as follows. It will be appreciated, however, that the combination dosage forms may be prepared by other known methods, for example, as described in US 6,174,873B1, the entire contents of which are incorporated herein by reference.

Example 3

In this example, a bi-layer tablet was prepared that was sustained release for melatonin (inner core) but regular release for hypnotics (e.g. zolpidem) (outer layer). The properties of the zolpidem produced will be similar to those given in example 1, since the outer layer is directly dissolved in the intestinal system, and the properties of the melatonin produced in the blood will also be similar to those of example 1, since the core will gradually dissolve.

A method.The sustained release melatonin core was first prepared by mixing melatonin (2 mg/tablet) in a weight ratio of about 2: 1: 2.5, Eudragit RSPO acrylic resin carrier (Rohm Pharma), lactose and calcium hydrogen phosphate and compressing the mixture in a 7mm punch using a force of 2.5 tons.

An aqueous coating spray suspension was then prepared by suspending acrylic resin (Eudragit RD 100), polysorbate 80 and talc in a weight ratio of about 10: 2: 5, and zolpidem tartrate (5 mg/tablet) in 6ml of water per 1 gram of solid. The tablet cores are then sprayed with the suspension to obtain a dry coating thickness of 2mm, thus forming a coated tablet.

Although administration should be conducted according to the directions of a doctor, it is currently considered appropriate to take 2 such tablets 2 hours before bedtime.

Sustained release melatonin itself has an effect on sleep. This is demonstrated by the improvement of restorative sleep (improvement of subjective sleep quality and subsequent improvement of daytime alertness) as recently described by the applicant in patents on melatonin improvement, and which are given here in the form of examples 4, 5, the cortisol peak was found to be delayed by hours towards the morning with slow release formulations, whereas this was not found with conventional release formulations (example 6). This effect may be responsible for the improved restorative sleep.

Example 4

MethodIn a randomized, double-blind, two parallel group study, the effect of sustained release formulations of melatonin on the amount and quality of sleep in 40 elderly patients with primary insomnia (age 76) (SD 8) was studied. These patients were treated with melatonin (2mg sustained release formulation) or placebo every night for 3 weeks. The number of sleeps was measured by recording with a multifunctional sleep recorder all night on the last two days of treatment. In the laboratory, after each morning wake-up, all patients underwent a panel of psychomotor tests to assess daytime alertness. In addition, the patient daily recorded his daily diary as to the quality of sleep in the night before he thought.

ResultsThe results show that melatonin has a beneficial effect on the onset of sleep, similar to the effect of hypnotics. In contrast to this apparent hypnotic effect, the psychomotor skills of the melatonin group were significantly higher than those of the group treated with placebo: significant therapeutic effects were observed at the end of treatment for the Critical Flicker fusion test (Critical Flicker fusion test) and the total response time of melatonin to placebo.

ConclusionTherefore, these results show for the first time that the hypnotic effect of melatonin (shortening of sleep latency) is associated with an increase in daytime alertness in patients with primary insomnia, which indicates an increase in the sleep recovery values in these patients. When hypnotics are used, the reduction of sleep latency and the improvement of sleep quality is accompanied by an impaired, or at best not significantly worse, morning psychomotor skills. No hypnotics appear to increase daytime alertness. Surprisingly, in their diary, patients were not evaluated for easier sleep with melatonin than placebo. In fact, the patient judges whether his sleep quality is altered by melatonin and not by placebo treatment. Thus, the recovery value of sleep may be related to the perceived improvement in sleep quality.

Example 5

MethodIn a randomized, double-blind, two parallel group study, the effect of sustained release formulations of melatonin on sleep quality and daytime alertness was assessed in a subjective assessment of 170 patients with senile primary insomnia (68.5 years old) (SD 8.3). These individuals were treated with placebo for 2 weeks to establish baseline characteristics and then with melatonin (2mg per night sustained release formulation) or placebo for 3 weeks. On the last three days of the baseline and treatment periods, patients were asked to assess their previous night's sleep quality and their perception in the morning. A question about sleep quality is "how do you feel using a drug compared to not (you are usual)? "the patient marks his perceived quality of sleep on a 100mm, non-opening horizontal line with two endpoints. The left endpoint is labeled "less than usual rest" and the right endpoint is labeled "better than usual rest". A question about the state of waking up is "how do you feel now? "the patient marks the level of his cognitive wake status on a 100mm, no-opening horizontal line with two endpoints. The left endpoint is labeled "tired" and the right endpoint is labeled "alert". The patient's mark is measured in mm from the right end point. (thus, a decrease in value indicates a better or less tiring state of sleep). The average distance over three nights was calculated.

It was found that both the quality of sleep and daytime alertness were significantly improved with sustained release melatonin compared to placebo (table 2), indicating a link between improvement in resting sleep and less tiredness felt in the morning.

Table 2: the effect of sustained release melatonin and placebo on the quality of sleep and daytime alertness of subjective assessments by patients with primary insomnia.

Reaction of	Melatonin, change in mm mean (SE)	Placebo, change in mm mean (SE)
			Changes in perceived sleep quality	-24.3(2.6)	-17.6(2.1)
Changes in perceived daytime alertness	-16.8(2.7)	-6.6(2.0)

^＊The difference with placebo group is significant (p < 0.05)

ConclusionThese results indicate that melatonin enhances the recovery of sleep in these primary insomnia patients.

Example 6

MethodThe following experiments were performed in a double-blind, placebo-controlled crossover manner. Three tablets (placebo, regular release and sustained release) were used for each patient, but the order was randomized and unknown to the patient or staff.

ResultsMelatonin (2mg) in the form of a sustained release formulation (SR-Mf) was administered once a day at 10PM to 8 healthy elderly suffering from insomnia, resulting in a significant increase in their sleepEfficiency but without increasing sleep latency. (sleep efficiency is the amount of time taken to sleep from the total time spent in bed; sleep latency is the time taken from the first light-off to sleep). On the other hand, treatment of the same individuals with melatonin in the form of a conventional release formulation (RM) did not improve sleep efficiency but shortened sleep latency compared to placebo treatment of the same individuals. These results can be explained by the short half-life of melatonin in blood. That is, the sustained-release preparation produces a low level of blood hormone over a long period of time, and thus, its onset may be slow, but it may last for a considerable period of time in the evening.

Cortisol levels in these patients were assessed by monitoring urinary excretion of hormones at 2 hour intervals over a 24 hour period. In the placebo-treated group, patients exhibited a cortisol rhythm that reached its peak at 8:36AM, and then the cortisol declined, as is known to be exhibited by patients over 40 years of age. In the control group, the 24-hour average excretion rate/hour (which is close to the blood concentration) of cortisol in urine was 3.2 micrograms/hour. The amplitude of this rhythm (i.e., the maximum deviation of the 24h mean from the maximum or minimum rate of excretion) was 1.8 mg/hour.

After 1 week of treatment with regular release melatonin, the total amount of cortisol excreted is reduced. The 24 hour average excretion rate decreased to 2.5 mg/hour and the amplitude decreased to 1.0 mg/hour. In addition, the time to peak shifts slightly later, which occurs at 8:27 AM. The expectation of cortisol rhythm after use of conventional released melatonin compared to Terzolo et al, j. 113 and 124. However, Terzolo did not observe a 24 hour mean level and a decrease in cortisol rhythmic amplitude.

After 1 week of treatment with slow release melatonin, it was found that cortisol secretion (24 hours mean rate of 2.5 mg/hour) and amplitude 1.2 mg/hour (as with regular release) decreased similar to conventional melatonin, but that the peak on that day appeared at 12:06PM after being significantly extrapolated. Thus, instead of being the same or slightly advanced, the peak is delayed by the use of sustained release melatonin. The same cortisol properties were also found in these patients after 1 month of treatment with the sustained release formulation (24 hours mean excretion of 2.5 mg/hour, amplitude of 1.0 mg/hour, peak time of 12:08 hours).

ConclusionThese results indicate that the body's response to melatonin is not significant: the body reading melatonin is not just the true response that it has been in existence over a period of time. Interestingly, for people under the age of 40, the cortisol rhythm is also known to be delayed compared to older individuals. Thus, the cortisol profile produced in the elderly after treatment with sustained release melatonin is similar to that of younger people.

Discussion of the related ArtIt has been demonstrated that there is an inverse relationship between cortisol and sleep quality in humans, i.e. cortisol levels of the adrenal hormone increase as the quality and quantity of sleep decreases. It is noted that cortisol is a stress hormone, and its high levels in the evening can prevent the recovery of sleep. This experiment shows that the use of normally released melatonin can reduce cortisol production, but the use of slow release melatonin can both reduce cortisol levels and delay their peaks, and therefore, it can improve sleep during dawn hours.

In the case of the use of established hypnotics (e.g., zolpidem) for the purposes of the present invention, it is important that the drug elimination will be very rapid and that there will be no drug residue in the morning. Since the drug only acts on the onset of sleep, it is useful to increase its effect within the first hour to obtain maximum efficacy with a lower dose and avoid its deleterious effects at some later time in the evening. The intrinsic effects of melatonin can be maintained when co-administered with, for example, zolpidem. Thus, the combination of melatonin and zolpidem will improve the sleep latency of the individual (which is not felt when using melatonin alone) while avoiding the adverse effects (on memory and coordination) of zolpidem at some time later in the night.

Example 7

MethodThe effect of melatonin slow release formulations on subjectively assessed sleep quality and daytime alertness was studied in 5 patients with primary insomnia who were 55 years or over 55 years of age, who had taken 10mg zolpidem late daily. These individuals were treated with placebo for 2 weeks to establish baseline characteristics, and then with melatonin (2mg per night in a slow release formulation) for 3 weeks. On the last three days of the baseline and treatment periods, the patient was asked to assess the quality of sleep in the night before. A question about sleep quality is "how do you feel using a drug compared to not (you are usual)? "the patient marks his perceived quality of sleep on a 100mm, non-opening horizontal line with two endpoints. The left endpoint is labeled "less than usual rest" and the right endpoint is labeled "better than usual rest". The patient's mark is measured in mm from the right end point. (thus, a decrease in value indicates a better or less tiring state of sleep). The average distance over three nights was calculated. The response was defined as an average improvement of 10mm on a 100mm visual analog scale over 3 nights.

Results3 of 5 patients taking zolpidem were found to respond (60%) to co-treatment with melatonin. This value is consistent with the results from a parallel study conducted with patients who did not take zolpidem at the same time.

ConclusionThe improvement in sleep quality when co-treated with melatonin may be due to melatonin instead of zolpidem, since some patients have taken zolpidem on baseline. Furthermore, the synergy of the two drugs was particularly evident the first hour after administration and did not affect the quality of sleep throughout the night. In addition, these data also indicate that the clinical efficacy of melatonin (efficacy after the synergy period) is maintained when given concurrently with zolpidem.

Discussion of the related ArtBecause zolpidem is known not to alter the properties of endogenous melatonin, and melatonin does not react with benzodiazepinesReceptor binding, the potentiation (or synergy) of the present invention is apparently due neither to the deficiency of zolpidem in supplementing melatonin, nor to the binding of both substances to the same receptor.

While particular embodiments of the present invention have been described above, it will be understood that the scope of the invention is not limited thereto but may be subject to numerous changes and modifications by those skilled in the art. Such variations and modifications which are not specifically described herein are to be considered obvious equivalents of the present invention. For example, structural analogs of melatonin that can serve substantially as their function in humans are considered to be apparently chemical equivalents of melatonin. The basic concept, spirit and scope of the invention will be better understood from the following claims.

Claims (16)

1. Melatonin is produced for short-term potentiation of at least one non-benzodiazepine selected from the group consisting ofUse of hypnotic compounds in the manufacture of a medicament for the hypnotic effect of humans, wherein said non-benzodiazepineHypnotics contain a ring nitrogen-containing fused ring system in their structure and are GABA-A receptor modulatorsAnd (3) preparing.

2. The use according to claim 1, further characterized by at least one of the following features:

(a) said medicament comprises at least one carrier, diluent, coating or adjuvant;

(b) the medicament is in unit dosage form;

(c) the drug comprises at least one compound selected from the group consisting of non-benzodiazepinesHypnotic-like compounds;

(d) said at least one compound being present in said medicament and in an amount which would be a sub-therapeutic amount if administered in the absence of melatonin;

(e) said medicament is suitable for the sustained release of melatonin.

3. Use according to claim 2, wherein the medicament comprises at least one acrylic resin and is adapted for sustained release of melatonin.

4. Use according to claim 3, wherein the medicament is also suitable for the regular release of the at least one compound.

5. Use according to any one of claims 1 to 4, wherein said at least one compound comprises a fused bicyclic ring system.

6. Use according to claim 5, wherein said fused bicyclic ring system comprises at least two ring nitrogen atoms.

7. Use according to claim 6, wherein the bicyclic ring system comprises a pyrazolo [1, 5-a ] pyrimidine, imidazo [1, 2-a ] pyridine, pyrrolo [3, 4-b ] pyrazine or triazolo [4, 3-a ] pyridine skeleton.

8. Use according to claim 7, wherein the at least one compound is selected from zaleplon, zolpidem, zopiclone and trazodone.

9. A pharmaceutical formulation comprising, in addition to at least one carrier, diluent, coating or adjuvant, only the following active ingredients:

at least one non-benzodiazepine selected from the group defined in claim 1A hypnotic-like compound, and melatonin in an amount and in a form effective to potentiate, for a short period, the hypnotic effect of said at least one compound.

10. The pharmaceutical formulation of claim 9, further characterized by at least one of the following features:

(a) said formulation is in unit dosage form;

(b) said at least one compound is present in said formulation in an amount which would be a sub-therapeutic amount if administered in the absence of melatonin;

(c) said formulation is suitable for sustained release of melatonin.

11. The pharmaceutical formulation of claim 10, comprising at least one acrylic resin and adapted for sustained release of melatonin.

12. The pharmaceutical formulation of claim 11, further adapted for conventional release of the at least one compound.

13. A pharmaceutical formulation according to any one of claims 9 to 12 wherein the non-benzodiazepine isHypnotics include compounds wherein said fused ring system is a bicyclic system.

14. A pharmaceutical formulation according to claim 13, wherein said bicyclic ring system comprises at least two ring nitrogen atoms.

15. A pharmaceutical formulation according to claim 14, wherein the bicyclic ring system comprises a pyrazolo [1, 5-a ] pyrimidine, imidazo [1, 2-a ] pyridine, pyrrolo [3, 4-b ] pyrazine or triazolo [4, 3-a ] pyridine skeleton.

16. A pharmaceutical formulation according to claim 15, wherein the at least one hypnotic is selected from the group consisting of zaleplon, zolpidem, zopiclone, and trazodone.