HK1087635B - Composition for improving cognition and memory - Google Patents

Description

Composition for improving cognition and memory

Technical Field

The present invention relates to a pharmaceutically active composition and a kit for the treatment of patients with insomnia; and the use of melatonin and related compounds in the manufacture of a medicament for alleviating side effects that occur during nicotine replacement therapy.

Background

Acetylcholine is the major neurotransmitter in the brain and peripheral nervous system, causing a wide variety of physiological and behavioral responses by binding to and activating specific receptors belonging to the receptor families of muscarinic (defined by muscarinic according to their activation) and nicotinic acetylcholine (defined by nicotinic according to their activation).

Neuronal nicotinic acetylcholine receptors (nachrs) belong to a family of ligand-gated ion channels that are widely distributed in the central and peripheral nervous systems. nachrs are the primary mediators of rapid synaptic transmission in the neural center and thus are also the primary molecules in the autonomic nervous system that process neural information. nachrs are also involved in the control of organ systems (e.g., heart, viscera, bladder, etc.). In this respect, it is important to note in particular that Ulcerative Colitis (UC) is a non-smoker-susceptible disease where nicotine has a therapeutic effect. The mode of action is not known, but may be associated with nicotinic acetylcholine receptors (nAChR) on the intestinal wall (Richardson, C.E., J.M.Morgan et al (2003). "Effect of scraping and transduction on a colloidal nicotinic acetylcholine receptor in an intestinal epithelial tissue.Q J Med 96：57-65)。

In the brain, in addition to the effects associated with tobacco use, nAChRs are also associated with a variety of behavioral capabilities, including cognitive capabilities (Araki, H., K.Suemaru et al (2002). "neuronal Nicotinic Receptor and Psychiatric Disorders: Functional and Behavioral effects of Nicotinine"Jpn.J Pharmacol88: 133-138). Both acute and chronic nicotine administration significantly altered the working memory of the rats in the radial arm maze. In humans, nAChR activation can be a beneficial treatment for cognitive disorders such as Alzheimer's Disease, schizophrenia, Attention Deficit and Hyperactivity Disorder (ADHD). Nicotine has been shown to improve attention in all of these conditions. nachrs are involved in the pathogenesis of several types of brain disorders (parkinson's disease, alzheimer's disease, tourette's syndrome, schizophrenia, melancholia, attention deficit disorders). Clinical studies of these diseases have shown that nicotine has beneficial effects, both as a prophylactic and therapeutic agent.

Activation of neuronal Nicotinic acetylcholine Receptors (nAChR) has been shown to maintain cognitive function with the progression of Aging or dementing disorders (Picciotto, M.R. and M.Zol (2002) 'Nicotinic Receptors in Aging and dementia') "J Neurobiol53(4): 641-55). Nicotine and nicotinic agonists have been shown to improve Cognitive performance in elderly or injured subjects (Rezvani, A.H. and E.D.Levin (2001). "Cognitive Effects of Nicotine"Biol Psychiatry49: 258-267). Several epidemiological studies have shown that smoking can prevent neurodegenerative diseases. Both in vivo and in vitro studies in animals have also shown that nicotine has a neuroprotective effect, which supports the aforementioned notion. Thus, nicotinic agonist therapy is useful for slowing the progression of neurodegenerative diseases, and for improving the function of patients suffering from such diseases. Nicotine addiction (primarily through smoking) is a chronic recurring condition that is difficult to treat. DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-fourth edition, American psychiatric Association, Washington D.C.,1994 publication) recorded a nicotine withdrawal syndrome with symptoms of craving for tobacco, irritability, anxiety, restlessness, difficulty concentrating, etc. although some symptoms may appear within 4-6 hours after the last smoking, these symptoms are most often present within the first two weeks of sudden smoking cessation.

Nicotinic acetylcholine receptor pharmacology is becoming increasingly important in clinical symptomology of smoking cessation and neurodegenerative diseases in general, and in particular in cognition and behavior. Cholinesterase inhibitors (cheis) inhibit the degradation of acetylcholine, thereby increasing the concentration of acetylcholine in the brain. ChEI is used to treat dementia by virtue of its ability to increase the concentration of acetylcholine in the brain, which in turn activates nachrs. In addition, the principle of allosteric modulation of nicotinic acetylcholine receptors has become a focus of research in therapeutic agents. In this regard, Galantamine (a recently approved drug for enhancing cognitive performance in patients with Alzheimer's disease) is capable of properly inhibiting acetylcholinesterase and has an allosteric, synergistic ligand effect on Nicotinic receptors (Woodruff-Pak, D.S., C.Lander et al (2002). "Nicotinic Cholinergic Modulation: Galantamine as a type of pathway").CNS Drug Reviews 8(4)：405-426)。

However, it is an interesting fact that different subtypes of neuronal nachrs are also modulated by endogenous substances (such as choline, the tryptophan metabolite kynurenic quinolinic acid, neurosteroids, beta-amyloid peptides) and exogenous hallucinogenic drugs (such as phencyclidine, ketamine) (Pereira, e.f., c.hilmas et al (2002). "Uncoventional vitamins and Modulators of nicotinic receiptors.J Neurobiol53(4): 479-500). Recently, the therapeutic effect of extended release Bupropion (Bupropion SR) in Smoking cessation has been discovered (Jorenby, D. (2002). "Clinical efficacy of Bupropion in the Management of Smoking cessation.") "Drugs 62(2)：25-35)。

When nicotinic cholinergic receptors are present in many areas of the brain, although nicotine is responsible for sleep and daytimeThe role of alertness is well understood, but the importance of this role is not well understood. There is also very little literature concerning the effects of Nicotine on sleep in non-smokers, who are associated with symptoms of sleep discontinuity during the early stages of smoking cessation (Wetter, d.w., m.c. score et al (1995). "tobaco withdrawal and nicontine Replacement influx Objective measurers of sleep.Journal of Consulting and Clinical Psychology 63(4)：658-667)。

It has been found that one of the significant side effects of Nicotine replacement by patches is insomnia (Jorenby, D.E., S.J.Leischow et al (1999). "A Controlled Trial of Sustainated-releaseBupropion, A Nicotine Patch, or Both for eating society"The New England Journal of Medicine340(9): 685-691). In light of the known stimulating effect of nicotine on cortisol secretions, significantly reduced cortisol concentrations are likely to be the result of neuroendocrine processes during smoking cessation. Nicotine replacement therapy can activate the HPA axis and increase cortisol levels. It is speculated that this activation may cause sleep problems, as recent findings indicate that higher cortisol levels are accompanied by poorer sleep quality (Rodenbeck, a., g. huether et al (2002). "Interactions between and not physiological sleep characteristics and sleeping parameters in patients with a social respiratory primary immunity"Neuroscience Letters324: 159-163; and Vgontzas, A.N., E.O.Bixler et al (2001). "Chonic Insomnia Is Associated with Nyctohemameral Activation of the Hypothalamic-Pituitary-Adreanal Axis: clinical indications "J Clin Endocrinol Metab 86(8)：3787-3794)。

Melatonin, a hormone secreted by the pineal gland at night, has the property of promoting sleep when provided during the day (i.e., when melatonin is present at very low levels in the body). Despite hypnotic drugs (benzodiazepine)And non-benzodiazepines) Indeed, like hypnotics, vigilance and behavioral decline are severe one hour after melatonin administration (Wurtman United States Patent 5,641,801 June 24, 1997; graw, P., E.Werth et al (2001). "Early moving media administration animals pseudo horovirland"Behavioural Brain Research121: 167-; dollins, A.B., H.J.Lynch et al (1993) "Effect of pharmacological specimen doses of collagen blood and performance"Psychopharmacology 112：490-496)。

Furthermore, experts in the field may report that melatonin in fact impairs alertness, and indeed we have found that patients experience depression after 1 week of daily oral administration of melatonin (sher, m.a., h.weingartner et al (1985). "Effects of melatonin on testing in patients with a local infection disease") "Neuroscience Letters58: 277-82). Therefore, the pharmacological activity of low doses (0.3-10mg) of melatonin is considered hypnotic. Also, it is not expected that the mental or cognitive ability or the daytime function can be improved in a short period after administration.

Elderly insomnia patients, i.e. those with low melatonin production due to age and disease, and other cases in which melatonin deficiency is clearly involved, demonstrate an induction of sleep by melatonin during the night. For elderly subjects with insomnia, night administration of Melatonin (0.3-2 mg daily for 1-3 weeks) can improve sleep quality compared to placebo (Haimov, I., P.Lavie et al (1995). "Melatonin replacement therapy of electroluminescence insulators).Sleep18(7): 598-; 18: 598-; garfinkel, D., M.Laudon et al (1995). "Improvement of sleep quality in anderlypeople bycontrolled-release melatonin.”The Lancet346: 541-544). However, melatonin produces a poor effect at night in young insomnia patients who apparently are able to produce sufficient amounts of melatonin internally (James, s.p., d.a.sack et al (1990). "melatoninnadministration in insomnia").Neuropsychopharmacology3: 19-23; james, S.P., W.B.Mendelson et al (1987). "The effect of melatonin on normal slide"Neuropsychopharmacology1: 4144). In a recent study, melatonin (0.5mg) was administered either immediate (evening or sub-night) or prolonged (evening) to a group of age-related sleep-sustaining insomnia patients. All three classes of melatonin treatment shorten the latency of permanent sleep, but are not very effective for sustained sleep (Hughes, R.J., R.Sack et al (1998)' role of medicine and cyclic phase in a related sleep-maintence in a clinical trial of medicine replacement.) "Sleep21(1): 52-68). Thus, melatonin is not effective in promoting sleep at night for patients who are able to produce sufficient amounts of hormone internally.

Animal and human in vivo studies have failed to demonstrate the significant effects of nicotine on endogenous melatonin production (Tarquini, B., F. Perfectto et al (1994). "Dayte circulating mediators in smokers"Tumori80: 229-232; "Pineal monomers and woven transceivers in CBA microbial viral nucleic acid administration", Gaddnas, H.K. Pietila et al (2002) "Brain Research957: 76-83). Thus, neither in the form of smoking nor nicotine replacement therapy for abstaining tobacco users can infer that melatonin can alleviate sleep problems associated with nicotine therapy. In one study, the symptoms after sudden withdrawal of nicotine were alleviated by administering exogenous melatonin without nicotine replacement therapy, compared to placebo-treated control subjects, shortly after cessation of smoking (4 hours); the subjects given melatonin (4mg, i.p.) also did not experience a sedating and fatigue sensation(Zhdanova，I.and V.Piotrovskaya(2000).“Melatonin treatment attenuatessymptoms of acute nicotine withdrawal in humans.”Pharmacology， Biochemistry and Behavior67: 131-135) which show that melatonin alone can alleviate the symptoms of smoking cessation, but do not indicate that nicotine replacement therapy can be alleviated at the same time, because, on the one hand, nicotine does not inhibit melatonin production; on the other hand, melatonin is also not effective in improving sleep quality in subjects capable of producing sufficient amounts of hormones; in addition, any hypnotic effect of melatonin may be accompanied by a decrease in cognitive and behavioral abilities, and thus no data is available showing that melatonin may be an effective agent for alleviating insomnia caused by nicotine replacement therapy, or that it may enhance the effect of nicotine on cognitive ability.

In Markus, R.P., J.M.Santos et al (2003), "Melaton non-targeted surgery and nicontine-Induced [3H ]]-GlutamateRelease in Rat Cerebellum Slices.”JPET Fast Forward.45625, it was reported that activation of α 7nAChR causes [ (3) H-]Glutamate overflow is higher during the dark phase (melatonin can be endogenous) and is nicotine-induced [ (3) H-]The increase in glutamate release during the night is affected by the nocturnal jerking of melatonin, since this phenomenon does not occur when the production of melatonin in the pineal gland is inhibited by illuminating the animal for 48 hours, or by injecting propranolol two weeks before the cessation of illumination; it can be concluded that: driven by the endogenous melatonin surge in the pineal gland at night, nicotine in the cerebellum of rats is induced by [ (3) H]Glutamate release occurs with daytime variations.

In Markus, R.P.M., A, W.M.Zago et al (1996). "Melatoninmodulation of presynaptic nicotinic acid receptors in the rat vas deferens".The Journal of Pharmacology and Experimental Therapeutics279: 18-22 reports that, after an increase in endogenous melatonin, the prostate part incubated with exogenous melatonin is in the nighttimeThe higher sensitivity to nicotine in the organs of the killed animals was concluded, possibly due to the appearance of low affinity neuronal nicotine Ach binding sites.

The Markus article appears to suggest that melatonin may enhance the effects of nicotine. The conclusion of Markus, if extrapolated to humans, may explain the beneficial effects of melatonin during smoking cessation when exogenous nicotine administration is absent and has been confirmed by Zhdanova. However, these articles also imply that melatonin can lead to worsening of nicotine-induced insomnia during smoking cessation in subjects treated with nicotine.

Oral administration of nicotine for treatment has been suggested, for example, in US 6,183,775 (see below), WO8803803, WO02076211, and published US patent application 2001029959.

Published U.S. patent applications 20030051728 and 20030062042 disclose methods of delivering physiologically active compounds (e.g., nicotine and melatonin, etc.) in an aerosol form.

US patent 6,183,775 discloses a controlled release lozenge comprising an active substance containing the mentioned nicotine and melatonin.

US patent 6,068,853 describes a transdermal delivery device for the delivery of active agents and mentions various types of active agents and specific examples, such as melatonin and nicotine.

US 5,284,660 describes a device which can be administered to the skin or to the mucosa at predetermined intervals. The deliverable drug may be, for example, nicotine (for daytime administration) or melatonin (for nighttime administration). Neither of this patent nor any other patent documents mentioned therein (patents and published patent applications) describe or suggest the combined administration of nicotine and melatonin.

All patent documents (patents and published patent applications) mentioned herein are incorporated by reference in their entirety.

We have now surprisingly found that exogenous melatonin produces a significant beneficial effect on smoking-habitual insomnia patients, accompanied by nicotine therapy, compared to non-smokers, and that synergistic effects of nicotine and melatonin on Sleep have never been found before, and that it alleviates Sleep problems occurring during these treatments, and has potential utility in clinical interventions involving nAChR activation, particularly nicotine administration, furthermore, concomitant treatment of melatonin and modulation of nicotinic acetylcholine receptors provides greater potential beneficial effects than nicotine activation alone in improving cognition in elderly patients in general, particularly in Alzheimer's patients, because Sleep has a significant effect on memory consolidation (Maquet, P. (2001). "Sleep Roeep. in Learning and memory.Science294: 1048-1052), it is also expected that concomitant treatment with nicotine and melatonin can improve cognitive and memory next day as a result of enhancing sleep-dependent memory consolidation.

Summary of The Invention

The present invention relates generally to the administration (or any other manner of administration) of melatonin and related compounds in a periodic or extended release dosage form for the treatment of insomnia associated with nAChR activation (in smoking cessation and other medical conditions) while simultaneously improving cognitive function and memory.

Thus, in one aspect, the present invention provides a pharmaceutically active composition for treating insomnia patients, comprising: (a) at least one first active ingredient selected from melatonin, other melatonergic agents, melatonin agonists and melatonin antagonists; and (b) at least one second active ingredient selected from nicotine and nicotine receptor agonists. In the pharmaceutically active composition of the present invention, the component (a) and the component (b) may be formulated separately or in a single formulation.

In another aspect, the invention comprises the use of at least one first active ingredient (a) selected from melatonin, other melatonergic agents, melatonin agonists and melatonin antagonists, for the preparation of a first medicament for alleviating at least one of the following side effects in a patient undergoing a nicotine replacement therapy: impairs sleep quality, impairs cognitive ability and impairs memory, wherein the patient can optionally receive simultaneously a second medicament comprising at least one second active ingredient (b) selected from nicotine and a nicotinic receptor agonist.

In another aspect, the invention comprises the use of at least one first active ingredient (a) selected from melatonin, other melatonergic agents, melatonin agonists and melatonin antagonists, for the preparation of a first medicament for alleviating at least one of the following side effects in a patient who has not received a course of nicotine replacement therapy in the presence of a second medicament as described below: impairs sleep quality, impairs cognitive ability and impairs memory, wherein the second medicament comprises at least one second active ingredient (b) selected from nicotine and nicotine receptor agonists.

In another aspect, the present invention also provides a kit for treating a patient with insomnia, comprising:

(A) a first pharmaceutical formulation in unit dosage form comprising: in addition to the at least one diluent, carrier or adjuvant, at least one first active ingredient selected from melatonin, other melatonergic agents, melatonin agonists and melatonin antagonists; and

(B) a second pharmaceutical formulation in unit dosage form comprising: at least one second active ingredient selected from nicotine and nicotine receptor agonists, in addition to at least one diluent, carrier or adjuvant;

wherein the dosage units in (a) and (B) are independently selected from those suitable for oral, rectal, parenteral, sublingual, intrapulmonary or transdermal administration.

Detailed description of the invention

The pharmaceutically active composition of the invention, as well as each drug in the use of the invention, may have at least one of the following characteristics:

(i) which comprises at least one diluent, carrier or adjuvant;

(ii) in the form of dosage units suitable for oral, rectal, parenteral, sublingual, intrapulmonary or transdermal administration;

(iii) it is a controlled release, sustained release or prolonged release formulation;

(iv) which is a depot form that slowly releases the active ingredient in vivo over a preselected period of time;

(v) ingredient (a) is melatonin;

(vi) component (b) is nicotine;

(vii) which comprises at least one melatonin receptor modulator and/or melatonin profile modulator;

(viii) the first active ingredient (a) and the second active ingredient (b) are formulated in a single formulation.

The pharmaceutically active compositions according to the invention, as well as each drug in the uses according to the invention, may be in the form of dosage units, wherein each dosage unit comprises at least one active ingredient in an amount of from 0.025 to 100mg, preferably from 0.25 to 50mg, particularly preferably from 0.5 to 40 mg.

The kit of the invention also preferably has at least one of the following features:

i) at least one of (A) and (B) is a controlled release, sustained release or extended release formulation;

ii) at least one of (A) and (B) is in a depot form that slowly releases the active ingredient in vivo over a preselected period of time;

iii) the at least one first active ingredient comprises melatonin;

iv) the at least one second active ingredient comprises nicotine;

v) (a) further comprises at least one melatonin receptor modulator and/or melatonin profile modulator;

vi) a) (a) further comprises at least one additional active ingredient selected from nicotine and nicotine receptor agonists;

vii) said first and said second active ingredient, and said further active ingredient if present, are present in said dosage unit in an amount of 0.025-100mg, preferably 0.25-50mg, particularly preferably 0.5-40 mg.

Without prejudice to the general concept of this aspect of the invention, it is currently preferred that each of (a) and (B) is a transdermal patch. Such a kit comprising the day patch and the night patch described in the following formulation example (C) will be exemplified below.

In another presently preferred embodiment of the kit of the present invention, (a) may be formulated as an oral controlled release tablet and (B) as a transdermal patch. Such a kit comprising a tablet containing melatonin and a patch containing nicotine will be described below by formulation examples (a) and (B).

According to the present invention, when comparing melatonin levels in smokers and non-smokers, it can be surprisingly found that: after 4 weeks of nightly melatonin (2mg controlled release formulation) administration, the effect on improving sleep quality in smoking patients was significantly greater in patients with insomnia over 55 years of age than in non-smoking patients, and also exceeded the placebo treatment value for the same patients (see example 1).

Furthermore, after 3 weeks of daily melatonin (2mg controlled release formulation) administration, the effect on improving sleep quality in smoking patients was significantly greater for insomnia patients between the ages of 22 and 50 years than in non-smoking patients.

Furthermore, after 3 weeks of daily melatonin (2mg controlled release formulation) administration, the effect on enhancing mental motor skills in smokers was significantly greater in patients with insomnia above 55 years of age than in non-smoking patients (as shown in example 3).

It was even more surprising to find that the improvement in memory of subjects smoking patients or giving up to 6 months of smoking was significantly greater with melatonin (2mg controlled release formulation) administered alone than with non-smokers than with placebo-treated subjects.

The invention is illustrated below with reference to non-limiting examples.

Example 1

The effect of controlled release formulations of melatonin on subjectively assessed sleep quality was studied in 17 elderly insomnia patients (age 66.9(SD 5.4) years) as subjects according to a randomized, double-blind crossover study. Basal secretion of the primary melatonin metabolite 6-sulfooxymetatomin (6-sulfomelatonin) in urine was measured at night (8p.m. -8a.m.), subjects were treated with placebo for 1 week to establish baseline characteristics, and then subjects were subjected to a 2-cycle crossover design (4 weeks with 2mg of melatonin controllably released or placebo) with one washout period (1 week) between the two cycles. The quality of sleep in the first night was asked by drawing the patient on a 140mm visual approximation scale during the baseline period and the last 1 week of the treatment period. The patient is measured with the patient marker at a distance from the left hand side of the scale, with higher values indicating higher quality sleep. The difference between the resting better sleep assessment and placebo values was calculated for smoking and non-smoking patients. In the study population, there was no significant difference in the overnight amounts of 6-oxomelatonin sulfate secreted by smokers and non-smokers (3.5 +1.5vs.6.3+5 μ g of 6-oxomelatonin sulfate, respectively). It was surprisingly found that melatonin improves sleep quality significantly better than placebo for smokers, showing a synergistic effect of melatonin and nicotine (table 1). Smokers and non-smokers did not respond differently to placebo.

Table 1:melatonin in comparison to placebo for smoking and non-smoking insomnia patientsSubjective evaluation of sleep

Parameter(s)	Non-smokers (n ═ 4)	Smoker (n ═ 10)	Significance (t-test)
				Mean change in the subjective perceived quality of sleep (in mm) with melatonin compared to placebo	-2.8	15	P＝0.003
Average night 6-oxomelatonin sulfate secretion (. mu.g/night)	3.5	6.3	P＝0.29

Example 2

The effect of controlled release formulations of melatonin on subjectively assessed sleep quality was studied on a mixed age group of insomnia patients (20-80 years). Subjects were treated for 1 week with placebo to establish baseline characteristics and then with controlled release melatonin (1 mg/night) or placebo for 3 weeks. In the baseline and the last three of the treatment periodsDay, by using The Leeds sleep assessment questionnaire (Parrott, A.C. and I.Hindmarch (1980). "The Leeds sleep evaluation diagnostic in viral physiological information-a review".Psychopharmacology(Berl)71(2): 173-9)) to ask the patient for the quality of sleep in the previous night, the questionnaire comprising two visual approximation measure bars of 100mm relating to the quality of sleep. The distance of the patient mark from the right hand side was measured in mm and the average answer to two questions over 3 consecutive nights was averaged. Responders with mean values over 10mm or more were defined as patients. It was surprisingly found that the proportion of respondents in the smoking group (62%, n-16) was significantly higher than in the non-smoking group (40%, n-43, p-0.002), regardless of age. For placebo, there was no difference in the proportion of respondents in the smoking group (46%, n-13) and non-smoking group (44% n-53, p-0.89, chi-square test).

Example 3

40 patients with senile insomnia (age 60.8(SD 0.8) years) were studied for the effect of controlled release formulations of melatonin on mental activity performance (total response time TRT, mean response time MRT.) subjects were treated with placebo for 2 weeks (baseline) and treated with controlled release melatonin (2 mg/night) for 3 weeks.

Example 4

The effect of melatonin (2mg controlled release formulation) and placebo on memory was studied in 16 elderly volunteers (> 55 years; age 59(SD 3.2) years) (Rivermead story test). In a randomized double-blind crossover study, subjects were given one placebo tablet at night to establish baseline, and then one melatonin or placebo tablet at random for 1 week without treatment in between. At hours 2 and 12.5 after tablet administration, the patient was subjected to the Rivermead test. Surprisingly, the improvement in memory of subjects by melatonin was significantly greater than the values of the placebo's within the first hours after dosing. Memory efficiency was improved for both memories (immediate and delayed) after 2mg controlled release melatonin administration compared to baseline or cross placebo, and the effect was better for patients smoking or quitting smoking within 6 months prior to the study than for non-smokers.

Table 2:average of memory events in a story

And difference in memory performance after 2 hours of inhalation of placebo or melatonin from administration of placebo

Quantitative time after taking medicine	Smoker (n ═ 4)	Non-smokers (n is 12)	Effect (t-test)
				Memory number-melatonin	14.8	9.8	P＝0.056
Memory number-placebo	12.2	12.1	P＝0.33
				Memory differences between melatonin and placebo	3.5	-2.41	P＝0.043

Examples of non-limiting pharmaceutical formulations useful in the present invention are described below.

Formulation examples

(A) Controlled release melatonin

Oral controlled release formulations are obtainable by: the powdered raw materials, i.e. 2mg melatonin (lipopmed co., Switzerland) and acrylic resin carrier (Rohm Pharma), were dry mixed and then pressed in a 7mm cylindrical punch under a pressure of 2.5 tons so that the product contained35.3% of RSPO, 16.7% of lactose, 41.4% of calcium hydrophosphate, 1.3% of mica, 4% of magnesium stearate and 1.3% of melatonin. It may be compressed into tablets containing, for example, 1mg or 2mg of melatonin.

(B) Nicotine-only formulations

In this embodiment, a transdermal patch is made that can contain and deliver sufficient nicotine for up to 24 hours of efficacy. Such patches are typically replaced once a day and may be used for smoking cessation therapy or other situations where systemic nicotine delivery is desired. Melatonin tablets were administered overnight to relieve insomnia caused by nicotine therapy. Melatonin is administered at night, preferably in the form of a controlled release tablet as described in formulation example (a) above, which can contain and deliver sufficient melatonin, e.g., for up to 8 hours at night.

To prepare 1g of a patch adhesive base, acetone (0.21 g), isopropanol (0.23 g), ethanol (0.117 g) were placed in a stirred tank and added in portions with stirringE100(0.422g) until all was dissolved. Dibutyl sebacate (0.19g) was then added and stirring was continued for 20 minutes, followed by succinic acid (0.038 g) with stirring, which was continued for 10 minutes. A viscous solution containing nicotine was prepared by adding 33 wt% liquid nicotine to the viscous base solution and stirring for 30 minutes. A layer of 3M-1005 grade substrate material (100 cm) was laid on the pan²) And then coated with the matrix mixture. The mixture was cast with a blade having a height of 1500 μm. The dish was covered and the matrix was left behind as the solvent evaporated at room temperature. An area of 10cm was cut from the final substrate²The patch of (1). An inert release 3M-1512 pad was applied to the adhesive surface and removed prior to application of the device to the skin. The amount of nicotine on each patch was 33mg, providing potency for up to 24 hours.

(C) Formulations comprising nicotine and melatonin

It is anticipated that the formulation of this embodiment will be used to effectively deliver sufficient amounts of nicotine and melatonin (after replacement) over 8-12 hours during the night, and preferably with a separate patch for daytime delivery over a 12-16 hour period, to accommodate smoking cessation therapy or other therapeutic situations where systemic nicotine delivery is desired, without causing insomnia. The day patch is typically replaced after 12-16 hours and may be prepared as described in example (B) above, except that the nicotine solution concentration is 21 wt% instead of 33 wt%.

To prepare 1g of the nighttime patch adhesive base, acetone (0.21 g), isopropanol (0.23 g), ethanol (0.117 g) were placed in a stirrer and added in portions with stirringE100(0.422g) until all was dissolved. Dibutyl sebacate (0.19g) was then added and stirring was continued for 20 minutes, followed by succinic acid (0.038 g) with stirring, which was continued for 10 minutes. A viscous solution containing nicotine and melatonin was prepared by suspending 23 wt% melatonin in 0.35g of a mixture of acetone/isopropanol/ethanol (9: 1: 5) and adding 12 wt% liquid nicotine, adding the suspension to the viscous base solution, and stirring for 30 minutes. Spreading a layer of grade 3M-1005(100 cm) on the plate²) Then coated with the matrix mixture. The mixture was cast with a blade having a height of 2500 μm. The dish was covered and the matrix was left behind as the solvent evaporated at room temperature. An area of 10cm was cut from the final substrate²The patch of (1). An inert release 3M-1512 pad was applied to the adhesive surface and removed prior to application of the device to the skin. Each patch contains 12mg of nicotine and 23mg of melatonin, and can exert potency for 8-12 hours at night.

Although specific embodiments of the present invention have been described above in considerable detail, it will be appreciated that the invention is not limited thereto. Various changes and modifications may be readily made by those skilled in the art. Such modifications and variations that are not specifically described are considered to be equivalents of the present invention.

Claims (21)

1. A synergistic pharmaceutically active composition for the treatment of insomnia patients, suitable for rectal, parenteral, sublingual, intrapulmonary or transdermal administration, comprising:

(a) at least one first active ingredient selected from melatonin; and

(b) at least one second active ingredient selected from nicotine.

2. The pharmaceutically active composition according to claim 1, having at least one of the following characteristics:

(i) which comprises at least one diluent, carrier or adjuvant;

(ii) in the form of dosage units;

(iii) it is a controlled release, sustained release or prolonged release formulation;

(iv) which is a depot form that slowly releases the active ingredient in vivo over a preselected period of time;

(v) the ingredient (a) is melatonin;

(vi) the ingredient (b) is nicotine;

(vii) which comprises at least one melatonin receptor modulator and/or melatonin profile modulator;

(viii) the first active ingredient (a) and the second active ingredient (b) are formulated in a single formulation.

3. The pharmaceutically active composition according to claim 2, which is in the form of dosage units, wherein each dosage unit comprises 0.025-100mg of active ingredient (a).

4. A pharmaceutically active composition according to claim 3, wherein at least one of the active ingredients (a) and (b) is present in an amount of 0.25-50 mg.

5. The pharmaceutically active composition according to claim 4, wherein the amount is 0.5-40 mg.

6. Use of at least one first active ingredient (a) selected from melatonin in controlled release form for the manufacture of a first medicament for treating a patient undergoing a nicotine replacement therapy procedure to alleviate cognitive impairment and/or memory impairment or synergistically alleviate insomnia in said patient.

7. The use according to claim 6, wherein each of said medicaments has at least one of the following characteristics:

(i) which comprises at least one diluent, carrier or adjuvant;

(ii) in the form of dosage units suitable for oral, rectal, parenteral, sublingual, intrapulmonary or transdermal administration;

(iii) which is a depot form that slowly releases the active ingredient in vivo over a preselected period of time;

(iv) the ingredient (a) is melatonin;

(v) the ingredient (b) is nicotine;

(vi) which comprises at least one melatonin receptor modulator and/or melatonin profile modulator;

(vii) the first active ingredient (a) and the second active ingredient (b) are formulated in a single formulation.

8. The use according to claim 7, wherein said first medicament and said second medicament are each in the form of a said dosage unit, wherein each said dosage unit comprises 0.025-100mg of active ingredient (a).

9. Use according to claim 8, wherein the content of at least one of the active ingredients (a) and (b) is from 0.25 to 50 mg.

10. Use according to claim 9, wherein the content is 0.5-40 mg.

11. Use of at least one first active ingredient (a) selected from melatonin in the manufacture of a first medicament for treating a patient concurrently receiving a second medicament comprising at least one second active ingredient (b) selected from nicotine, for the alleviation of cognitive impairment and/or memory impairment or the synergistic alleviation of insomnia of said patient.

12. The use according to claim 11, wherein each of said medicaments has at least one of the following characteristics:

(i) which comprises at least one diluent, carrier or adjuvant;

(ii) in the form of dosage units suitable for oral, rectal, parenteral, sublingual, intrapulmonary or transdermal administration;

(iii) it is a controlled release, sustained release or prolonged release formulation;

(iv) which is a depot form that slowly releases the active ingredient in vivo over a preselected period of time;

(v) the ingredient (a) is melatonin;

(vi) the ingredient (b) is nicotine;

(vii) which comprises at least one melatonin receptor modulator and/or melatonin profile modulator;

(viii) the first active ingredient (a) and the second active ingredient (b) are formulated in a single formulation.

13. The use according to claim 12, wherein said first medicament and said second medicament are each in the form of a said dosage unit, wherein each said dosage unit comprises 0.025-100mg of active ingredient (a).

14. Use according to claim 13, wherein the content of at least one of the active ingredients (a) and (b) is from 0.25 to 50 mg.

15. Use according to claim 14, wherein the content is 0.5-40 mg.

16. A kit for treating a patient suffering from insomnia comprising a synergistic pharmaceutically active composition defined as:

(A) a first pharmaceutical formulation in unit dosage form comprising: at least one first active ingredient selected from melatonin, in addition to at least one diluent, carrier or adjuvant; and

(B) a second pharmaceutical formulation in unit dosage form comprising: at least one second active ingredient selected from nicotine, in addition to at least one diluent, carrier or adjuvant;

wherein the dosage units in (a) and (B) are independently selected from those suitable for oral, rectal, parenteral, sublingual, intrapulmonary or transdermal administration.

17. The kit of claim 16, further having at least one of the following features:

(α) at least one of (a) and (B) is a controlled release, sustained release or extended release formulation;

(β) at least one of (a) and (B) is a depot form that slowly releases the active ingredient in vivo over a preselected period of time;

(γ) the at least one first active ingredient comprises melatonin;

(δ) the at least one second active ingredient comprises nicotine;

(epsilon) (a) further comprises at least one melatonin receptor modulator and/or melatonin profile modulator;

(ζ) (a) further comprises at least one further active ingredient selected from nicotine;

(. eta.) said first active ingredient, and said further active ingredient if present, are present in said dosage unit in an amount of 0.025-100 mg.

18. The kit according to claim 17, wherein said first and said second active ingredient, and said further active ingredient if present, are present in said dosage unit in an amount of 0.25-50 mg.

19. The kit according to claim 18, wherein said first and said second active ingredient, and said further active ingredient if present, are present in said dosage unit in an amount of 0.5-40 mg.

20. The kit of any one of claims 16-19, wherein each of (a) and (B) is a transdermal patch.

21. The kit according to any one of claims 16 to 19, wherein (a) is an oral controlled release tablet and (B) is a transdermal patch.