FI116037B - New therapeutic use of leptin, or obese protein - Google Patents

Description

, 116037

New therapeutic use of leptin, or obeseprotein.

The present invention relates to a novel therapeutic use of leptin, or obeseprotein, as defined in the preamble of claim 1.

5

BACKGROUND OF THE INVENTION

According to Rubens Reimao, a Brazilian sleep researcher, insomnia is estimated to affect 35 percent of the world's population. Deborah Suchecki, a researcher at the Sleep Research Center in Sao Paulo, Brazil, says: "If people knew what was going on in their 10 bodies suffering from sleep deprivation, they would think for a moment before saying that sleep is a waste of time and just lazy."

THE CONSEQUENCES OF DREAM

SHORT-TERM CONSEQUENCES LONG-TERM CONSEQUENCES 15 - Sleepiness - Obesity - Mood swings - Premature aging - Decreased risk of - Fatigue - Creativity, planning, and - Infectious diseases, :: -Chronic Memory Impairment • t · '' The Drawback of Conventional Sleep Drugs; · · * Many sleep medications, such as benzodiazepines, at least to some extent, confuse so-called.

25 the natural variation of REM sleep (rapid eye movement) and NREM sleep (non-REM), whereby the quality of sleep and its refreshment and regeneration suffer.

, Then the patient may actually suffer from at least some of the long-

t I I

“.E or short-term discomfort, even if he sleeps adequately over time. Therefore, it would be advantageous for E to use the body's own substances having said ';;; There are no side effects in the treatment of insomnia.

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Pharmaceutical use of hormones

Hormones regulate many functions of the body, acting as chemical message carriers between different organs. It is known that hormones are used as a medicament or for pharmaceutical use. The best known example of this is the various hormones used to control birth control, such as estrogen and also antiprogesterone, both of which are administered orally or transdermally, or further by depot administration according to a particular regimen, known from, for example, FI 953926. microcapsules as described in FI 96278. 10 a dosage form of the microcapsules can be used for injection, transitions, as well as those that are absorbed through the rectum, or endometrium. The medical use of the hormone melatonin is known at least from US 2002/0156121 A1, ZISAPEL October 24, 2002 That disclosure discloses melatonin as the specification further advances for use orally in the treatment of persons who have been dependent on at least one benzodiazepine for their sleep.

Obese gene and obese protein

For example, the Diabetes and Doctor magazine's archive at ... 20 http://www.diabetes.fi/lehdet/diablaak/juttuarkisto/001eptiini.htm, contains summarized information about leptin, as well as scientific studies around leptin.

• · ·, ·; ·. Leptin has been looking for a solution eg. for the treatment of obesity. These pages are clear. mm. that the obese gene positional cloning of the obesity gene 1994: ·. . (Zhang Y, Poenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional Cloning · ". 25 of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432.) Confirmed the above theory, which the fat tissue would be able to regulate its size by a hormonal signal. (Kennedy GC. The role of depot fat in the,: hypothalamic control of food intake in the rat. Nature 1994; 372: 425-432.).

,. The discovery of said obesity gene and its receptor (leptin, or obese protein) confirmed these hypotheses. (Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X,]. Ellis SJ, et al. Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene db / dp mice. Cell 1996 ; 84: 491-495.), And "" (Friedman JM, Halaas JL. Leptin and Regulation of Body Weight in Mammals.

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Nature 1998; 395: 763-770). However, leptin is not known to be used to treat sleep problems.

Preferred embodiments of the invention are set forth in the dependent claims 2 to 5 11.

References to drawings:

The invention will now be explained in more detail by means of preferred embodiments with reference to the accompanying drawings, in which:

Scheme C in Figure 1 shows the amount of 6-sulfamelatonin in the urine before and during treatment with melatonin, in one known case.

SUMMARY OF THE INVENTION It is an object of the present invention to use a hormone called leptin, i.e., the obese protein alone, or with another sleep aiding or sedative agent, preferably in combination with the hormone melatonin, to help the patient to fall asleep and stay asleep. and that a solution is found e.g. many of the problems mentioned above, above all, so that the above-mentioned side effects do not occur or can be minimized. Natural sleep can thus be; achieved by the more natural physiological effect produced by: hormone therapy, as compared to e.g. the lending or narcotic effect, which is: · · ·: with most conventional hypnotics such as benzodiazepines.

It is also generally known that during sleep, said leptin, a hormone secreted by fat cells, normally produces a feeling of satiety (Awakening 22 March 2003). 5, published by Jehovah's Witnesses Religious Community). When we exercise longer than we should, the body produces less leptin and: 30 we feel we need more carbohydrates. Thus, sleep deprivation can cause a person to consume more carbohydrates than usual, which in turn can lead to obesity, although the role of leptin in the actual treatment of human obesity; · · · Is still open. Researchers have recently discovered a protein called hypocretin, or 4 116037 orexin, which is formed in the brain and which keeps us awake (Rev. 22 Mar 2003, p. 6, published by Jehovah's Witnesses Religious Society). When we eat, the body produces leptin, which causes a feeling of satiety. Leptin, in turn, inhibits the production of hypocretin. As a result, the more leptin in the brain, 5 the less hypocretin it is and the more lean you feel (Wake Up Magazine March 22, 2003, p. 5, published by Jehovah's Witnesses Religious Society). Nonetheless, leptin is not known to be used to treat sleep problems.

Leptin, a hormone secreted by fat cells and weight loss in experimental animals 10 Leptin is thus a hormone secreted predominantly by fat cells, also known as obeseprotein. This obese protein (protein) contains 167 amino acids. The Obese protein was produced by a recombinant technique and experimentally treated, for genetic or nutritional reasons, obese rodents, which, according to the following studies, were able to lose weight. (Campfield LA, 15 Smith FJ, Guisez Y, Devos R Bum P. Recombinant murine OB protein: Evidence for peripheral signal linkage and central neural networks. Sciene 1995; 269: 543-546.), And (Halaas JL, Gajiwala KS). , Maffei M, Cohen SL, Chait BT, Rabinovits D, et al., Weight-Reducing Effects of Plasma Protein Encoded by Obese Gene, Science 1995; 269: 540-543.), And (Pelleyrmounter MA, Cullen MJ, Baker MB). , Hect R, Winters 20 D, Boone T, Collins F: Effects of obese gene product on body weigt regulation in, ob / ob mice Science 1995; 269: 540-543). Because of its slimming effect, the obese protein was baptized into leptin, a name derived from the Greek word for "leptos", Leptos. However, leptin has not been proposed to be used alone or in combination with any other preparation as a sleeping pill, or as a sleep aid, such as, for example, as part of some combination of other sleep or depression aids. Instead, the following; · The effect of leptin on the breathing of experimental animals during sleep is known from the publication.

• * ... Sleep apnea and leptin 30 Leptin at least helps to reduce breathing difficulties during sleep in mice, both males and females suffering from sleep apnea. This »<* [(i. It can be deduced from the results obtained in experimental animals. In American

Journal of Respiratory and Critical Care Medicine, vol. 164, 8 Part 1, Oct. 15 2001, p.

116037 5 1470-1475, Polotsky et al., "Female Gender Exacerbates Respiratory Dispersion in Leptin-Deficient Obesity", obese, leptin-free mice with respiratory distress were dosed with leptin to correct the respiratory distress. Perhaps the most important benefit of the study was that obese females had a higher serum leptin content of 5 body weight, which probably protected them from respiratory distress, as these females also experienced respiratory distress as serum leptin levels decreased. Thus, animal studies suggest that leptin may be useful in sleep apnea. However, sleep apnea and the treatment of respiratory failure is different from insomnia, or the treatment of insomnia or malaise according to the present invention e.g. with leptin.

Slight sleep causes a decrease in leptin levels

It is admittedly known from the following description that the amount of leptin in sleep deprivation is still reduced. In studies published in the Journal of sleep research, Vol. Supplement 1, June 2002, pp. 65-66, Everson, "Suppression by sleep disruption and sleep deprivation in rats", was consistent with the assumption that low sleep causes a reduction in leptin levels. In this study, rats were kept awake, resulting in this reduction in leptin and the overall deterioration in the health of said experimental animals. Although lack of sleep and. ·: ·. The linkage of 20 leptin deficiencies has been found in this latter study, here. despite the effects of leptin administration on alertness and sleep improvement. *: *. reportedly measured. Although low sleep caused leptin deficiency, it does not yet prove that giving leptin in turn would help with insomnia, and this study was not based on improving insomnia but on sleep deprivation: '': 25 changes in the body of experimental animals. However, in the light of the present invention, the low level of leptin in sleep deprivation in general may explain, for example, to many ': * a personal experience that sleep does not want to come when for some reason:., T: overtired.

t * *:; 30 Neural signals, autonomic nervous system activity and sleep / wake; · 'Fatty tissue triglycerides are the main form of energy storage in the body.

• »»

The size of adipose tissue depends on the difference between energy intake and consumption, which is regulated by endocrine (including leptin and insulin) neural signals in adipose tissue, endocrine, nervous system, and gastrointestinal tract 116037 6. The nuclei in the hypothalamus integrate these various signals that regulate energy balance and the activity of the hypothalamic pituitary and autonomic nervous system. These arrangements tend to keep the body weight stable. It is clear that since these signals 5 regulate the activity of the autonomic nervous system, said signals also have their own significance in terms of sleep / wakefulness.

Energy balance and leptin

Simplifying the energy balance system itself works as follows: When 10 energy balances are negative, serum leptin levels decrease, hunger and food intake increase, and metabolic pathways for energy storage are activated. When energy is positive, leptin secretion increases. This decreases food intake and activates the metabolic pathways. As a result, the growth of adipose tissue slows down. (Rosenbaum M, Leibel RL, Hirch J

15 Obesity. N Engl J Med 1997; 337: 396-407)

Leptin in the treatment of obesity However, it seems that leptin will not be used extensively in the treatment of obesity in humans, although much research has been done, for example. This:. 20 is due to e.g. the fact that human obesity is almost always characterized by:; ; hyperleptinemia, excessive secretion of leptin, so in several obese individuals who: ':'; most needed care, leptin levels are already high. Considering:: low efficacy of leptin treatment alone for obesity, cost of treatment, and: 'side effects associated with injection site injection with high dose subcutaneous injection, the hopes for an easy-to-use diet for obesity seem to be diminishing.

'... leptin and feeling of drowsiness; :; At best, leptin produces a feeling of satiety and awakens us: a reduction in the amount of hypocretin, orexin, which holds the brain, which causes \ '. drowsiness. In addition, melatonin helps lower body heat, reduce blood ·; · I volume in the brain, and gradually reduce muscle tension, and relax the muscles.

116037 7

In addition, leptin, or a similar molecule, is also likely to increase insulin sensitivity in skeletal muscle, being useful in the treatment of type 2 diabetes.

SUMMARY OF THE INVENTION A person benefiting from such a hormone increase is provided with an effective amount of melatonin hormone in an active pathway, and a so-called "leptin". obesity, a certain amount of obese protein. Alternatively, worse, the leptin is administered alone or in combination with another substance. Leptin is best administered in an amount that results in a rise in serum leptin levels to about 1 / 2-1 lAh after 10 meals without treatment with leptin when a normal healthy person is eating properly. This achieves e.g. a feeling of satiety and drowsiness, without a solid evening meal. Leptin, or preferably a combination of leptin and melatonin, can be used to treat, for example, insomnia, and / or, for example, to reduce the use of other hypnotics, or to discontinue the actual hypnotics. The compound can restore a good sleep pattern and good quality of sleep, for example, when starting from a degree of insomnia, or to some degree of unnatural sleep through sleep medication such as benzodiazepines. Treatment is also likely to have a positive effect on some other conditions, such as cardiovascular disease, at least if the patient's serum leptin levels are below normal when untreated. This is because leptin extensively regulates body functions, e.g. vascular growth and on the other hand::; for example, the need for excessive night-time eating with treatment is reduced. In this case, for example, in the long term: otherwise, the gain will not happen. Thus, weight control:: control can be achieved in persons without hyperleptinemia, i.e.: ': excessive secretion of leptin. Treatment with leptin with leptin, or a similar molecule: lit 'is also likely to increase insulin sensitivity in skeletal muscle, thus being useful in the treatment of type 2 diabetes.

'···' Leptin has also been shown to have beneficial effects on Alzheimer's disease. It is::: combined with melatonin, it is likely that the effect of leptin will also be improved, both in 30 Alzheimer's patients and in many others, at least because of improved sleep quality. <'· The combination of the hormone leptin and melatonin can be used alone in the treatment of psychiatry, such as the treatment of depression, or, if necessary, an antipsychotic such as an antidepressant may be added. As an example of the aforementioned 116037 8 psychiatric drug to be added, any so-called "serotonin uptake" in the serum can be represented, e.g. An SSRI drug such as fluoxetine, fluvoxamine, paroxetine, sertaline, and citalopram. Leptin can also be used in combination with any antidepressant drug, e.g. the above mentioned drug, in the absence of melatonin. In this case, leptin helps, for example, to get to sleep, stay asleep and / or reduce the dose of the actual antidepressant. Again, leptin reduces the need for evening or night-time eating. It is easier for a person to go to bed without eating a lot, and he does not wake up hungry at night.

10

Leptin therapy achieves a target level whereby the level of serum leptin is slightly raised during the evening and night, e.g., to a level that occurs in a normal person after a meal. The normal level can be understood, for example, in the light of the following studies. (Blum WF, Englaro P, Heiman M, et al., Plasma leptin levels in healty children 15 and ac depedence on body mass index, body fat mass, gender, pubertal stage and testosterone. Encordinol Metab 1997; 82: 2904-2910.), and (Hu FB, Chen C, Wang B, Stampfer MJ, Xu X. Concentrations of Leptin in Relation to Overal Adiposity, Fat Distribution, and Blood Pressure in a Rural Chinece Population, International Journal of Obesity (2001) 25, 121-125) , and (Adam JA, Menheere PP, van Dielen FM, Decreased 20 plasma orexin-A levels in obesity individuals. Int J Obes Relat Metab Disord, 2002; 26 (2); 274-6).

. · · ·. Melatonin and circadian rhythm

It is generally known that sleep is a complex process that is controlled by the brain and that: 1 ”. 25 follows a 24 hour biological rhythm. The human biological clock is controlled by chemical substances, many of which are already known. One of these substances is the hormone melatonin, which: drowsiness. Melatonin is formed in the brain, and according to some researchers:: is responsible for slowing down the metabolism before falling asleep. Melatonin . reduces body heat, reduces blood volume in the brain, and gradually reduces 30 muscle tension, and relaxes muscles. The body's heat drops, for example, early in the afternoon, which is associated with sleepiness in the early afternoon, for example, after lunch.

',. Medical use of melatonin, at least known from US 2002/0156121 A1, ZISAPEL October 24, 2002. That publication No. 1 1 6037 9 discloses melatonin for use in the treatment of persons who have become dependent on at least one benzodiazepine used to treat their sleep problems. The melatonin treatment disclosed in that patent is likely to at least reduce the amount of benzodiazepine, or to completely stop the benzodiazepine treatment.

Linking SSR1 to hormone therapy for the treatment of depression

It is therefore an object of the present invention to use melatonin in combination with leptin for the treatment of various sleep disorders. In addition, treatment can advantageously be combined with an increase in the body's serotin level, particularly when treating persons suffering from depression in addition to sleep disorders, or where sleep problems are clearly associated with depression. In addition to melatonin and / or leptin, the patient is then given e.g. An SSRI drug, exemplified by fluoxetine, fluvoxamine, paroxetine, certalin, and citalopram. Any amount conventionally used in the treatment of depression can also be used in the treatment of the present invention. However, it is most evident that the amount required in the treatment of the present invention can be kept below the amounts used for the treatment of depression, e.g., by half. In this case, for example, a patient who would otherwise be prescribed, for example, 100 mg fluvoxamine in the evening, is prescribed only 50 mg of the drug in question, in combination with leptin 20 and / or preferably in combination with leptin and melatonin.

': Melatonin and leptin alone in the treatment of depression:: However, it is possible, and even likely, that at least mild depression I' · 'will also be treated when the person suffering from sleep problems gets through their sleep problems: 25 leptin and melatonin. This is because the negative factors associated with sleep deprivation, such as mood swings, drowsiness, memory impairment and fatigue .. 'are reduced and creativity, concentration, planning, and performance return and •' '· ·.' exhaustion disappears. Here too, at least for a large part of the causes of depression, such as misery::: and dissatisfaction with oneself may disappear, and a person's self-confidence and happier; '30 life attitude will return.

, 0 1 1 6037

Dosage of melatonin

Melatonin can be administered to a patient, e.g., orally, and in a controlled manner. For example, 0.5 to 10 mg of melatonin is a suitable amount, but the present invention does not exclude, for example, any amount from 0.01 mg to 100 mg. Preferably, the amount of melatonin 5 is proportional to, e.g., at least the patient's weight, preferably also age and the like, which is a routine practice in the pharmaceutical field. Determination is best done by the attending physician. As small as an experimental amount of 2 mg has been sufficient, at least according to US 2002/0156121 A1, ZISAPEL, October 24, 2002, to two female patients aged 73 and 80 years of age who were treated for 10 years with that dose. Both patients had previously been treated with oral doses of 1-2 mg flunitrazepam in the evening. After two months of flunitrazepam weaning and after a trial period, treatment was continued for almost 2 years by September 24, 2002. Both patients have first reported good sleep patterns and improved sleep quality. Figure 1 shows Table C showing the amount of 6-15 sulfatoxymelatonin in the urine before and after that treatment. Patients did not experience any side effects such as morning fatigue or feeling stuporous or hanging.

Similar melatonin moiety The melatonin moiety of the invention is preferably analogous to the melatonin described in U.S. Patent Application Serial No. 2002/0156121 A1, ZISAPEL October 24, 2002. but it can also be some other known or as yet unknown form.

. ·, 25 Leptin dosing

The leptin may be administered by any means known in the art such that the leptin concentration in the serum and / or spinal fluid is increased as desired. Thus, the present invention does not exclude any mode of administration. The administration may be effected, e.g., such that both ingredients, the melatonin hormone and the leptin, are in the same preparation, and administered, e.g., orally or transdermally, or else, by depot administration according to a particular regimen, e.g. FI 953926 is explained. However, a more advantageous route of administration is achieved if the melatonin hormone is administered, e.g., orally, preferably at bedtime, for example, 0.5 to 3 hours before bedtime, so that serum levels of the hormone in question are sufficiently elevated before bedtime. Because leptin is a protein, it is likely to be cleaved and degraded in the stomach and gastrointestinal tract, at least in part, to a form, i.e. individual 5 amino acids, that is not of sufficient utility within the meaning of the present invention. Therefore, it is probably more cost effective to look for alternatives to oral administration. However, an alternative for oral administration can be provided by a carrier which is degraded so slowly in the gastrointestinal tract that the release of leptin only begins in the small intestine or even in the colon. Even if successful, this would leave the problem with 10 timing, which would have to raise serum leptin levels just in the evening and overnight.

It is preferable that serum leptin levels can be determined before and during treatment to achieve optimal treatment results. Likewise, it is preferable that serum melatonin levels can be determined before and during treatment to achieve optimal treatment results. When additional SSRI preparations, such as fluoxetine, fluvoxamine, paroxetine, certalin, and citalopram, are to be used in therapy, it is preferable that serum serotonin levels be determined before and during treatment to achieve optimal treatment results.

, -; (Alternative modes of administration of leptin, including melatonin, ···, leptin may be administered by any of the methods well known in the art for use in pharmacy. A suitable leptin, or equivalent, e.g., produced by recombinant technology, may be formulated for example. can be administered by transdermal absorption through a transdermal patch, within an inert matrix inoculated into the body and in the depot, or intravaginal in a matrix which releases: 'leptin slowly (such a graft is disclosed in U.S. Patent Nos. 4,957, 119 and 5, .., · 088, 505, and the like) It is also possible to administer the leptin e.g. rectally or 30 into the vagina, for example the body be set a suitable pin, wherein the "absorption takes place through the vaginal or rectal mucosa such a stick.";.. may be the best use of adjuvants, By which absorption occurs relatively quickly, the site n that all active ingredients are absorbed during the evening and night. Excipients 116037 12 are known to use agents which slow down the release and dissolve in that organ in a known manner. Such suppositories are known, for example, for the administration of painkillers and for the treatment of hemorrhoids, but with the aid of various adjuvants, it is advantageous to delay the digestion somewhat compared to said suppositories. The choice of suitable excipients 5 does not present a problem to one skilled in the art. Leptin can also be administered by the use of microcapsules as described, for example, in Finnish Patent Publication FI 96278. Microcapsules dosage form can be used for injection, transitions, as well as those that are absorbed through the rectum, or endometrium. The present invention does not exclude a dosage form in which, for example, leptin is released slowly over a prolonged period of time, e.g., 10 months or more. However, for the treatment of sleep disorders alone (and not for any other disease, or for low levels of serum leptin or melatonin in general), it is most preferable for both leptin and melatonin to be released during the evening and night. Leptin can also be absorbed into the body by nasal spray or by sublingual administration.

15 Dosing with a patch

FI 100380 B describes in more detail a drug patch that can release some other hormones, namely estrogen and gastogen. This patent describes how estrogen and gastrogen are released: · from the adhesive relatively slowly through the skin to the patient, for example, when an insulating film is present. ·. removed so that the active substance can come in contact with the skin. A similar method can be:. also applies to the administration of leptin, or more preferably, to the administration of both hormones, leptin and melatonin. This is a simple method for the patient, since the patient can put on that patch suitably before going to bed and get: * ': 25 both hormones that are released simultaneously. It is also possible to make said patches so that at least two ""; way to release active substance patches. In these patches, the total dose in one of the same regions is e.g. 2 mg melatonin and in another e.g.

:: '; 4 mg melatonin, in the same range, or greater, at a delivery rate; ' ''; 30 in the latter double. Thus, leptin can be administered, e.g., to persons of different sizes and / or ages in the most optimal manner. The present invention does not ....; however, is not limited to the particular type of patch described in that patent, but the present invention serves only as an example of the application of a drug patch at 13 116037. Thus, for example, any of the competing patch types mentioned in that patent reference may be applicable to the present invention. If necessary, microcapsules can also be used in any known manner in connection with a drug patch.

5

leptin

Leptin is a 16 kilodalton peptide hormone that is so well-researched and well-known that there are over 3,000 scientific publications on the Internet. Leptin is known to have at least five leptin receptors that differ in length from their 10 cytoplasmic portions (Friedman JM, Halaas JL. Leptin and regulation of body weight of mammals. Nature 1998, 395: 763-770). Of these, Ob-ra is a receptor with a short cytoskeleton-like portion and is thought to act as a transport protein for leptin across the cerebrospinal fluid. Ob-Rb is a long form of the leptin receptor that plays an important role in intracellular signaling. The Ob-Rb receptor messenger RNA is abundant in the hypothalamus, which is thought to be a key region for the appetite and weight control effect of leptin. Such a receptor is probably most useful in terms of the primary use of the invention, the treatment of sleep problems.

20 Leptin produced by recombinant technology. * · Obese protein was produced by recombinant technology, e.g., for the aforementioned studies (Campfield LA, Smith FJ, Guisez Y, Devos R Bum P. Recombinant '·' 'mouse OB protein: evidence for peripheral signal linking adiposity and central neural networks. Science 1995; 269: 543-546.), and (Halaas JL, Gajiwala KS, Maffei M,: '25 Cohen SL, Chait BT, Rabinovits D, et al., Encoded by Weight-Reducing Effects of Plasma Protein). by the obese gene. Science 1995; 269: 540-543.) and (Pelleyrmounter MA,

Cullen MJ, Baker MB, Hect R, Winters D, Boone T, Collins F: Effects of obese gene product on body weigt regulation in ob / ob mice. Science 1995; 269: 540-543).

I · '·' In the case of the present invention, the said protein may be produced, e.g., by the same known technique. The leptin portion of the invention may also be another known or as yet unknown form, for example, analogous to a known form of leptin for Alzheimer's disease and memory enhancement described in U.S. Patent 6,151,235 B1. Different forms of leptin are obtained when, for example, a portion of the amino acid chain 116037 14 is cleaved off at the start or end, leaving the desired active moiety.

Leptin and Alzheimer's Disease 5 American Patent US 6,518,235 B1 describes the treatment of leptin for Alzheimer's disease. This patent specification further describes what alternative compounds are used for the treatment in question. The leptin component of the present invention may correspond to, and be compatible with, any compound suitable for the treatment in question. Thus, it is also likely that the preparation of the present invention will also have beneficial effects in patients with Alzheimer's disease. The dosage amount in the context of the present invention is preferably lower than in the actual treatment of Alzheimer's disease, at least when the patient has not been diagnosed with Alzheimer's disease, e.g. However, the present invention does not limit, for example, the amount of leptin or melatonin to a value sufficient to treat a particular insomnia, but may increase the amount, e.g.

Alzheimer's disease.

The drugs are administered by any active route of administration

The present invention does not exclude any route of drug delivery, e.g.

Leptin is active, and neither is the route of administration by which melatonin is active. An antidepressant, such as The route of administration of an SSRI drug, exemplified by fluoxetine, fluvoxamine, paroxetine, certalin, and, citalopram, may also be any other route of administration that is active, rather than oral administration. For example, melatonin may be packaged in the same packaging unit as leptin with leptin, each individually removable. The route of administration of leptin may then be different from that of melatonin. For example, melatonin may be administered orally;

: ': in a patch or in any known or unknown way described above.

30 Through the digestive system

Alternatively, melatonin and leptin are both packaged e.g. in microcapsules in a common carrier such as a capsule. If desired, any medicament may be added as a third component to the capsule, such as, for example, one of the previously mentioned antidepressants. However, at least a drug without said third component is best available. The capsule in question is made from a material which is slowly digested and not yet in the stomach, so that the leptin is best transported in the intestine to the small intestine, or at least in part up to the colon, whereupon the final absorption into the body occurs. Preferably, the outer shell of said capsule protects the microcapsules from the action of stomach acids. Leptin and melatonin in microcapsules, in turn, are mixed with some fat, which prolongs their release time in the gut. Here too, part of the leptin is degraded to amino acids, with 10% of the potency lost.

Administration of leptin by injection

None of the leptin administrations described are as effective as injecting a needle through the skin subcutaneously or, for example, intramuscularly. In this way, any form of leptin or a molecule similar to leptin can be passed through the skin in a safe and sufficient manner. Leptin is then best contained in microcapsules that release the active ingredient at a specific rate, e.g. during the evening and night. However, the pharmaceutical composition for injection, for example, may be prepared using leptin, or leptin and melatonin, or even leptin and melatonin, and in addition, an antidepressant, in admixture with a pharmaceutically acceptable excipient. Unfortunately, injecting is not a very user-friendly tool, and so other means are used wherever possible.

*

It is to be understood that the invention is not limited to the embodiments shown, but it is possible to carry out a plurality of variations in various combinations of all the means set forth in this specification and the following claims.

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Claims (11)

116037 16 Use of leptin, or obeseprotein, in the preparation of a pharmaceutical preparation for the treatment of insomnia. 5 Use according to claim 1, characterized in that melatonin hormone is used as a second hormone component in the preparation of said pharmaceutical preparation. 10 Use according to Claim 1 or 2, characterized in that the pharmaceutical preparation contains leptin or leptin and melatonin in an amount which facilitates the attainment and maintenance of sleep, as well as the achievement of a suitable daily sleep rhythm and natural REM and NREM sleep patterns. Use according to any one of claims 1 to 3, characterized in that in the pharmaceutical preparation leptin is used in an amount which is produced after about two meals without treatment with leptin after a meal of a healthy person of normal weight. t · Use according to any one of claims 1 to 4, characterized in that in addition to leptin, or a combination of leptin and melatonin, a psychiatric drug is used in the pharmaceutical preparation. • * »• · /. Use according to claim 1 or 2, characterized in that leptin, or leptin, ··· 'and melatonin are used in the pharmaceutical preparation in an amount such that the preparation * t 30 is suitable for daily use. 116037 17 Use according to claim 1 or 2, characterized in that the pharmaceutical preparation containing leptin or the leptin and the melatonin hormone is in a form that is absorbed into the body in an appropriate amount within 0.5 to 3 hours after administration of the drug. 5 Use according to claim 1 or 2, characterized in that the pharmaceutical preparation is in the form of a spray or sublingual preparation to be absorbed into the body (e.g., through the nasal secretion membrane or oropharynx). 10 Use according to claim 1 or 2, characterized in that the pharmaceutical preparation is in the form of an injection under the skin. Use according to claim 5, 8 or 9, characterized in that the antipsychotic drug is combined with leptin and melatonin so that they can be administered by the same route. V · 20 Use according to claim 1 or 2, characterized in that the desired form of leptin is obtained by cleaving part of the amino acid chain forming a particular leptin, leaving the active part. »T I» 1 · ta • »is 1 1 6037