RU2620855C1 - Pharmaceutical composition for sleep disorders prevention and treatment - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention relates to a pharmaceutical composition for sleep initiating and maintaining and prophylaxis of animal and human states that are accompanied by sleep disorders of a different nature, including a combination of active agents consisting of 0.5-45 mg of doxylamine succinate and long-acting melatonin in amount of 0.1-20 mg.

EFFECT: synergistic therapeutic effect and reduced side effects.

2 cl, 1 tbl, 5 ex

Description

The invention relates to the field of medicine and the pharmaceutical industry and relates to means for use in sleep disorders.

One of the definitions of sleep is a special genetically determined state of the human body (and warm-blooded animals, ie mammals and birds), characterized by a regular sequential change of certain printing patterns in the form of cycles, phases and stages [Kovalzon V.M. On the sleep functions // Zh. evolutionary biochemistry and physiology. 1993; 29 (5-6): 627-634]. Sleep disorders are multicomponent and widespread, especially in cities in which approximately 30% of the adult population have at least irregular sleep difficulties. According to other sources, half of the population suffering from sleep disorders, the disease lasts for years.

The large socioeconomic scale of sleep disturbance is also important in large part because it affects the most active part of the population. In a study conducted in the province of Quebec (Canada), it was shown that the annual costs associated with only one category of sleep disorders - insomnia, amount to 6.6 billion Canadian dollars. Moreover, the largest part of all financial losses (76%) is associated with a decrease in labor productivity and absenteeism (absence from the workplace) [Daley M., Morin S.M., Le Blanc M., Gregoire J.-P., Savard J The economic burden of insomnia: direct and indirect costs for individuals wit hinsomnia syndrome, insomnia symptoms, and good sleepers.// Sleep.2009; 32 (1): 55-64]. Another severe sleep disorder, Obstructive Sleep Apnea Syndrome (OSAS), then car accidents caused by this syndrome cost the United States $ 15.9 billion in 2000.

In the period from 25 to 45 years, sleep disturbances have the greatest impact on quality and life expectancy from the categories defined by the 2005 International Classification of Sleep Disorders (ICRS-2) as insomnia and sleep breathing disorders [American Academy of Sleep Medicine. Internationa lclassification of sleep disorders, revised: Diagnostic and coding manual. Westchester, I11 .: American Academy of Sleep Medicine, 2005].

Insomnia is a clinical syndrome characterized by the presence of repeated disturbances in the initiation, duration, totality and / or quality of sleep that occur despite the presence of a sufficient amount of time and conditions for sleep. This syndrome is manifested by violations of daytime activity of various kinds.

There are three main properties of insomnia. The clinical manifestations of this syndrome can be:

- The first is any disturbance in the course of the sleep process - initiation, maintenance or termination.

- The second is sleep disturbances, with the conscious limitation of oneself in a dream.

- The third is a disturbed sleep, as a result of a disturbance in daytime activity.

This disorder manifests itself in various forms: fatigue, impaired attention, concentration or remembering information, social dysfunction, mood disorders, irritability, daytime sleepiness, decreased motivation and initiative, a tendency to make mistakes while driving and at work, muscle tension, headache, impaired activity gastrointestinal tract, concern for the state of his sleep [Schutte-Rodin S., Broch L., Buysse D., Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults // J Clin. Sleep Med. 2008; 4 (5): 487-504].

These values of the prevalence of insomnia can vary widely and significantly depend on the survey methodology. When answering the question: “Do you think that your dream is disturbed?” Or similar questions, 30% of respondents answered positively. In the case of adding information about the presence of violations of daytime wakefulness, insomnia was determined in 10% of cases. Using the strict diagnostic criteria for insomnia, taken from the classification of mental disorders DSM-IV, the prevalence of insomnia was 6% [Roth T. Insomnia: Definition, Prevalence, Etiology, and Consequences // J Clin Sleep Med. 2007; 3 (5 Suppl): S7-S10].

Social problems are a 2.5-4.5-fold increase in the risk of road traffic accidents and a 2-fold decrease in the productivity of poorly sleeping people.

Insomnia leads to an increased risk of developing mental disorders; alcoholism; drug dependence. Mental disorders in the case of insomnia are diagnosed 2.5 times more often than in healthy people. The risk of developing depressive disorders with insomnia increases by 4 times.

Quite often, two of the nine forms of insomnia mentioned in the classification are found, in particular among young people aged 25-40.

- Adaptive insomnia (acute insomnia) - the development of sleep disorders due to exposure to an identifiable stress factor. It is a common sleep disorder in everyday life. The epidemiology of adaptive insomnia in the adult population is 15-20%.

- Sleep disorders in this case are often realized by emotional stresses, violations of the stereotypes of sleep environments, in particular, moving to a new place, hospitalization, the influence of physical factors, such as construction work, a highway, and entertainment venues.

The diagnosis of adaptive insomnia is established with a duration of sleep disorders for no more than three months. With a longer duration of insomnia, it usually goes into one of two other common forms - psychophysiological insomnia or insomnia when taking medications and other substances.

Treatment of adaptive insomnia is based on the influence of a stress factor through a change of environment (rest, travel, change of residence) and / or taking sedatives / sleeping pills.

For this, non-prescription drugs (valerian, motherwort, homeopathic mixtures) are used, and prescription, having a pronounced and drastic effect, sedatives are benzodiazepines (tofisopam, diazepam) and non-benzodiazepine tranquilizers (hydroxyzine, aminophenylbutyric acid).

Over the past few decades, central histamine receptor blockers have been established. They have sufficient capabilities for the correction of sleep disorders with adaptive insomnia. The histaminergic system of the brain belongs to the group of activating systems. The main source of cerebral histamine is the tuberomamillary nucleus, located in the region of the gray nucleus of the hypothalamus. In this area there are approximately 64 thousand histaminergic neurons. 4 types of histamine receptors are distinguished; an activating effect on the brain is provided by stimulation of type 1 receptors (HI). The blockade of these receptors leads to an increase in somnogenic effects and, as a consequence, the development of drowsiness [Haas N., Sergeeva O., Selbach O., Histamine in the nervous system. // Physiol Rev. 2008; 88: 1183-1241.].

This explains the clinical effect of doxylamine succinate, which has hypnotic properties of H1-blockers. Doxylamine succinate is taken 15 minutes before bedtime in a dose of 7.5 to 15 mg (0.5-1 tablets). The time to reach the maximum concentration of the drug in plasma is 2 hours, the half-life is 10 hours. When taking doxylamine succinate as a sleeping pill, the natural structure of sleep is preserved, addiction and dependence are absent (withdrawal syndrome does not develop). The use of the drug is not accompanied by a deterioration in cognitive functions, which is important for the elderly. Moreover, doxylamine succinate has important advantages, such as: use for apnea, no effect on circadian rhythms, use during pregnancy.

Doxylamine succinate is more effective in presomnic disorders, i.e. problems preceding the onset of sleep. This means that intrasomnic disorders are distributed as follows:

- frequent nocturnal awakenings, after which the patient cannot fall asleep for a long time, and feelings of “superficial” sleep;

- Awakenings are caused by both external (for example, noise) and internal factors (scary dreams, increased motor activity, urge to urinate);

- the threshold of awakening is sharply reduced and the process of falling asleep after an episode of awakening is difficult,

cannot be leveled by taking only one doxylamine succinate. Since the "entrance" to sleep is provided, and interruptions in the sleep process are no longer provided by external help, and internal mechanisms are insufficient for the effective functioning of the mechanism of re-falling asleep. Therefore, a situation arises when the body needs pharmacological support to ensure the process of the current sleep.

According to the authors of this invention, such an important, effective and safe agent is Melatonin.

In the patent RU 2493838, it is said that: Melatonin is a neuropeptide synthesized by the pineal gland and having a unique effect on the human and animal body. Melatonin is involved in the organization of daily periodism and in the regulation of cyclic processes, acting as an intermediary between the pacemaker mechanism of suprachiasmatic nuclei (SCN) and peripheral organs. The pineal gland along with the SCN of the hypothalamus is included in the so-called biological clock system of the body, which plays a key role in the mechanisms of “counting internal time” and aging [Arushanyan EB, 2005; Anisimov V.N., 2007]. According to the initial data, the main functions of the pineal gland in the body are: regulation of circadian and seasonal rhythms; regulation of reproductive function; antioxidant protection and antitumor protection [Anisimov VN, 1998, 2003].

According to the chemical structure, melatonin or N-acetyl-5-methoxytryptamine is a derivative of the biogenic amine serotonin, which, in turn, is synthesized from the exogenous amino acid tryptophan. It is known that melatonin is formed in the cells of the pineal gland, and is then secreted into the bloodstream, mainly in the dark, at night. Light, and especially in the morning and afternoon hours, the production of the hormone dramatically suppresses. The pineal gland receives information about the light load along the complex neural pathway. The dispatching role in this way is played by the SCN hypothalamus. Information from the retina through the optic nerve branch enters the SCN, then these signals descend through the hypothalamus along the pathways along the brain stem to the cervical spinal cord, from where they enter the brain through the sympathetic nerves through the openings in the skull and finally reach the pineal gland. At night, in the dark, when most SCN neurons are inactive, these nerve endings secrete norepinephrine, which activates the synthesis of melatonin enzymes in the pineal gland cells (pinealocytes). The pineal gland of a healthy adult releases about 30 micrograms of melatonin into the blood per night. Bright light instantly blocks its synthesis, while in constant darkness the daily rhythm of ejection, supported by the periodic activity of SCN, is maintained. Therefore, the maximum level of melatonin in the pineal gland and in the blood of a person is observed at night, and the minimum - in the morning and afternoon. Although the main source of melatonin circulating in the blood is the pineal gland, paracrine synthesis of melatonin is also found in almost all organs and tissues: thymus, gastrointestinal tract, gonads, connective tissue [Reiter R.J .; Raikhlin I.M., Kvetnoy I.M .; Huether G.]. Such a high level of melatonin in the body emphasizes its need for human life. At the same time, melatnoni has many other positive effects (patent RU 2493838).

In addition to the circadian / rhythm-organizing effect, Melatonin also has a number of other established properties, namely, a pronounced antioxidant and immunomodulating effect. A number of authors believe that the pineal gland, through Melatonin, exercising control over the endocrine, nervous and immune systems, integrates a systemic response to adverse factors, acting on the body's resistance. Although this statement is debatable, since in turn, Melatonin is subject to higher regulation. Melatonin directly, independently binds oxygen free radicals, while simultaneously triggering a natural antioxidant defense system through the activation of SOD and catalase. As an antioxidant, Melatonin acts generically, as it is able to penetrate all biological barriers.

In vitro studies revealed that Melatonin has significantly greater antioxidant activity in terms of interrupting the processes of lipid peroxidation and inactivation of the active free radicals —OH and ROO– than the known antioxidants [Reiter et al., 1995].

It is established that Melatonin plays an essential role in immunoregulation [IM Kvetnoy]. According to research, it is able to have a dual effect on the function of the immune system. So, against the background of its preliminary inhibition, a distinct stimulation is observed, and the repeated administration of low doses of Melatonin to animals weakens the impaired production of antibodies and at the same time increases antiviral resistance. In a situation of initial hyperactivity of the immune system, Melatonin, in a dose-dependent manner, inhibits the formation of a number of cytokines in response to the introduction of phytohem-glutinin, inhibits the function of activated macrophages and T-helpers.

It is assumed that the basis of melatonin immunocorrection is a direct effect through specific receptors on the function of cells of lymphoid organs and cellular blood elements. There is evidence of a mediated effect through regulation of opioid mechanisms and a modification of the production of corticosteroids by the adrenal cortex.

Melatonin has a regulatory effect on fat and carbohydrate metabolism. It is able to normalize the process of lipid oxidation, thus reducing, among other things, the likelihood of developing atherosclerosis, affects the hormonal regulation of blood pressure (BP), lowers the release of ACTH, the production of norepinephrine, vasopressin and renin [Slepushkin VD, 1990; Dolgov G.V., 2004].

The amount of melatonin changes throughout a person’s life. The hormone secretion begins at the 3rd month of the child's development, and its concentration reaches a maximum in the first years of life (no later than 5 years). Until puberty, Melatonin synthesis remains at a constant and high level, after which its production drops sharply and continues to decrease for another 5 years. After this, changes in the formation of Melatonin do not occur until 40-45 years, after which its amount begins to decrease steadily, which coincides with the onset of menopause, and this process continues until the end of a person’s life.

Over the past decades, factual material has been accumulated indicating that Melatonin has a combination of numerous effects, which can probably be estimated as a positive effect on the biological functioning of a mammalian organism. And not only in a state of functional balance and health, but also with the development and actual presence of pathological conditions.

Some publications characterize Melatonin as a therapeutic agent for the correction and / or stabilization of various pathological conditions:

“Intravenous administration of melatonin reduces intracerebral cellular inflammatory disease resulting from transient (transient) focal cerebral ischemia in rats.” [J PinealRes. 2007 Apr; 42 (3): 297-309], show the ability of Melatonin to inhibit cell inflammation after cerebral ischemia and has a pluripotent effect.

"Preclinical Evaluation of the Pharmacokinetics and Safety of Melatonin in Propylene Glycol for Intravenous Administration" [J Pineal Res. 2006 Nov; 41 (4): 337-43], Melatonin in propylene glycol markedly increases plasma levels of melatonin without serious toxic effects. "Melatonin reduces the release of serotonin in the brain, blood pressure and heart rate in rats" [Pharmacology. 1993 Aug; 47 (2): 91-7].

“Melatonin improves cerebral circulation in rats with extreme tolerance” [Am J Physiol. 1998 Jul; 275 (l Pt 2): H139-44].

“Melatonin increases the tone of the arteries of the pia mater and reduces the lower limit of autoregulation of cerebral blood flow” [Fundam Clin Pharmacol. 2001 Aug; 15 (4): 233-8.]. "Effects of melatonin on rat arterioles of the pia in the vivo" [Br. J. Pharmacol. 1999 Aug; 127 (7): 1666-70].

"PET (Positron emission tomography) and plasma pharmacokinetic studies after bolus intravenous administration of melatonin in the human body" [Int J Rad Appllnstrum B. 1991; 18 (3): 357-62] - melatonin easily penetrates the blood-brain barrier.

“Delayed melatonin therapy enhances electrophysiological recovery after transient focal cerebral ischemia in rats” [J Pineal Res. 2004 Jan; 36 (1): 33-42.]. “Melatonin mitigates damage to the gray and white matter in a mouse model with transient focal cerebral ischemia” [J Pineal Res. 2005 Jan; 38 (1): 42-52].

“Melatonin reduces neurovascular oxidative / nitrate-dependent (nitrosative) damage and protects against premature permeability of the blood-brain barrier after transient focal cerebral ischemia in mice” [J Pineal Res. 2006 Sep; 41 (2): 175-82].

“Melatonin reduces the spread of neuronal death after moderate focal ischemia in mice by inhibiting caspase-3 and is suitable as an additional treatment for the treatment of tissue plasminogen activators” [J Pineal Res. 2004 Apr; 36 (3): 171-6].

“Melatonin improves the condition of neurological damage and neurophysiological deficiency in experimental stroke models” [Ann N Y Acad Sci. 2003 Mau; 993: 35-47; discussion 48-53].

Patent RU2560840 is known in which melatonin is the only therapeutically active agent in an amount of from 0.0025 to 50 mg in a drug of the same purpose. At the same time, melatonin acts as an initiator of sleep, in combination with various active substances selected from anxiolytics, antidepressants, hypnotics (both benzodiazepines and nonbenzodiazepines), sedatives, antihypertensives, analgesics, antipsychotic drugs, dopaminergic agonists, and anti-anxiolytic drugs funds. Doxylamine succinate is not mentioned among these agents. It is also necessary to state that, as a sleep initiator, melatonin does not have such a pronounced and effective agent. To a greater extent, the role of melatonin is to regulate circadian rhythms, namely, to support sleep, because “... bright light instantly blocks its synthesis, while in constant darkness the daily rhythm of ejection, supported by the periodic activity of SCN, is maintained. Therefore, the maximum level of melatonin in the pineal gland and in the blood of a person is observed at night, and the minimum - in the morning and afternoon. " And melatonin is having a "... on receptors MT1, MT2 and MT3 enhances hypnotic effect, since these receptors (mainly MT1 and MT2) are involved in the regulation of circadian rhythms and sleep. The content of endogenous melatonin decreases with age, so the drug can significantly improve the quality of sleep with primary insomnia, especially in patients older than 55 years ... in the evening hours it increases the duration and improves sleep quality, and also improves activity during wakefulness, without worsening psychomotor reactions during the day ... "(instructions for medical use). Those. more regulation of sleep than its initiation.

The closest analogue (prototype) for this solution is the application US 20150352038 Kind Code Al PEROVITCH; Philippe; et al. December 10, 2015. The source discloses dosage forms for accelerated induction of sleep and / or for the treatment of sleep disorders and / or for the treatment of diseases of the central nervous system. The forms are oral solutions through the mucous membranes containing agents selected from the family of sedatives, including Doxylamine and Cyproheptadine and / or the Melatonin family, including Melatonin.

The objective of the invention is to develop a tool that provides a universal and safe approach to solving problems for the treatment of insomnia.

The problem is solved by the combined use of doxylamine succinate and prolonged release melatonin.

It is proposed the introduction to the needy, a combined dosage form of doxylamine succinate and melatonin, in which doxylamine succinate initiates the onset of sleep, and melatonin provides the sleep process.

The proposed combination contains in therapeutically effective doses of Doxylamine succinate (INN) and Melatonin (INN) in a prolonged form, which allows to provide such a technical result as maintaining the therapeutic effect of combined use, and improving the quality of life, with such a complex and cascading process as sleep, namely, with the dysregulation of this process. At the same time, a consistent biological effect is achieved, which allows us to simultaneously solve several problems: increasing mental and physical performance, psycho-emotional stability, normalizing disturbances in the rhythm of sleep and wakefulness in people with organic diseases of the central nervous system of various origins.

Therapeutically effective is the content of components in mg: Doxylamine succinate in an amount of 0.5 to 45 mg and Melatonin in an amount of 0.01 mg to 20 mg. The preferred ratio is from 1: 2 to 1: 100.

The combination can be used once a day. The dosage form can be presented in the form of tablets, including sublingual forms, capsules, modified release dosage forms, suppositories, granulated drink mixes

Technical result: synergistic therapeutic effects, biological succession and, reduced side effects.

Formulations can contain active ingredients up to and more than 90%, the minimum number of excipients is used, and provides cost-effective production on an industrial scale.

In one possible embodiment, the pharmaceutical composition is a solid dosage form containing Melatonin and Doxylamine succinate, as an active principle and excipients, including at least one diluent selected from lactose, starch, a starch derivative, microcrystalline cellulose, sucrose, inverted sugar, dextrose and dextrate, at least one disintegrating agent selected from sodium carboxymethyl cellulose, croscarmellose, gelatinized starch, St. binder selected from a polyvinylpyrrolidone, gelatin, cellulose derivatives, natural gums, polyethylene glycol, sodium alginate, an antifriction agent selected from stearic acid and / or its salts, colloidal silica, talc, sodium benzoate, sodium acetate, and sodium oleate.

For the implementation of the present invention, but not exclusively, a composition is provided that includes Memantine and Melatonin not containing magnesium silicate or talc. In a number of preferred embodiments, the described composition comprises Memantine and Melatonin, one or more diluents, each independently selected from starch and / or its modifications, lactose monohydrate or microcrystalline cellulose, one or more disintegrants, each independently selected from gelatinized starch or carboxymethyl cellulose, a binder and an antifriction agent, which is a lubricant. In other preferred embodiments, the binder is polyvinylpyrrolidone and the lubricant is magnesium stearate. In other, but not exclusive embodiments of the invention, the diluent may be lactose, including the form of monohydrate, the disintegrant may be croscarmellose (for example, in the form of the sodium salt), and the binder is povidone.

A necessary condition for excipients is inertness, chemical and physical compatibility with Memantine and Melatonin, as well as the possibility of prolonged release of Melatonin. Excipients used in solid dosage forms, such as tablets and capsules, may further include colorants and pigments, taste masking agents, flavors, sweeteners and adsorbents.

Diluents are used to increase the size of the tablet when the amount of active drug substance is not high. Diluents include lactose, in forms - alpha-lactose or beta-lactose. Different types of lactose may consist of lactose monohydrate, alpha-lactose monohydrate, anhydrous alpha-lactose, anhydrous beta-lactose and agglomerated lactose. Other diluents may include sugars such as sucrose, invert sugar, dextrose, and dextrates. A more preferred diluent is lactose monohydrate. Another diluent may be microcrystalline cellulose, including micronized.

Diluents include starch and starch derivatives. Starches are natural starches obtained from various cereals and / or other crops. Starches may also include pre-starch and modified starch. Starches and starch derivatives also carry the property of disintegrants. Many diluents also act as disintegrants and binders, and these additional properties should be taken into account when manufacturing a pharmaceutical composition. Disintegrants are added to break down the tablets into particles of the active pharmaceutical component and auxiliary, to facilitate dissolution and increase the bioavailability of therapeutically active ingredients. Starch and starch derivatives, including the sodium salt of starch carboxymethyl ester such as starch modified with sodium glycolate, are disintegrants used. Gelatinized starch may be a preferred, but not exclusive, disintegrant. Another preferred, but not exclusive, disintegrant is sodium carboxymethyl cellulose.

Binders are used as excipients. A binder is added to improve the fluidity of the powder and to improve compression. Binders include cellulose derivatives such as microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Other binders are selected from substances such as povidone, polyvinylpyrrolidone, gelatin, natural gum, namely acacia, tragacanth, guar and pectin resin, starch paste, pregelatinized starch, polyethylene glycols and sodium alginate. A commonly used binder is polyvinylpyrrolidone, in particular povidone.

Thickeners are lubricants and lubricants that are used to prevent the tablet mass from adhering to technological surfaces and to reduce sticking during the pressing or compaction stages. Such materials include stearic acid, salts of stearic acid, for example calcium stearate, magnesium stearate and sodium stearyl fumarate, talc, sodium benzoate, sodium acetate and sodium oleate. A choice for a lubricant, but not exclusive, is magnesium stearate.

To improve fluidity, in order to reduce friction between particles, lubricants in solid dosage forms are used. Lubricants have the property of both thinners and a thickener.

In embodiments of the manufacture of the pharmaceutical composition of doxylamine succinate and melatonin, the content of active substances is about 25-50% by weight of the combination. Preferably, the composition contains a diluent, which is a lactose monohydrate, but not exclusively, the second diluent is microcrystalline cellulose, but not exclusively; a disintegrant selected from gelatinized starch, but not exclusively, a second disintegrant selected from carboxymethyl cellulose, but not exclusively, a binder selected from polyvinylpyrrolidone, but not exclusively, and a lubricant that is selected from magnesium stearate, but not exclusively.

In some embodiments, lactose monohydrate is about 20-40% by weight of the composition, microcrystalline cellulose is about 10-15%, gelatinized starch is about 5-10%, sodium carboxymethyl cellulose is about 1-5%, polyvinylpyrrolidone is about 1-5% and magnesium stearate is from about 0.1-2.0%.

In additional embodiments, the implementation of Doxylamine succinate and Melatonin is from about 70-80% by weight of the composition. Preferably, the composition comprises a diluent, such as lactose monohydrate, preferably from about 3-20% by weight of the composition, a disintegrant, such as sodium carboxymethyl cellulose, preferably from about 2-10% by weight of the composition; a binder such as, for example, polyvinylpyrrolidone, preferably from about 2-10% by weight of the composition; and a lubricant, such as magnesium stearate, preferably from about 0.2-2.0% by weight of the composition.

In additional embodiments, the implementation of Doxylamine succinate and Melatonin is about 80% by weight of the composition, the diluent is lactose monohydrate, which is from 8 to 15% by weight of the composition; the disintegrant is carboxymethyl cellulose, which is from 1 to 10% by weight of the composition; the binder is polyvinylpyrrolidone, which is from 1 to 10% by weight of the composition; and the anti-friction lubricant is magnesium stearate, which is 0.2-2.0% by weight of the composition.

In some more preferred embodiments, the diluent is lactose monohydrate and it can be about 9.5% by weight of the composition, the disintegrant is croscarmellose and it can be about 5% by weight of the composition, the binder is povidone, and it may comprise approximately 5% by weight of the composition, and the lubricant is magnesium stearate, and it may comprise approximately 0.5% by weight of the composition.

In other embodiments, doxylamine succinate and melatonin comprise about 90% by weight of the composition. Preferably, but not exclusively, the composition comprises a diluent, such as lactose monohydrate, in the range of 3-10% by weight of the composition; a disintegrant, for example carboxymethyl cellulose, preferably from about 2-5% by weight of the composition; a binder, such as polyvinylpyrrolidone, preferably from about 2-5% by weight of the composition; and a lubricant, for example magnesium stearate, preferably from about 0.2-2.0% by weight of the composition.

In other more preferred embodiments, the diluent is lactose monohydrate and it can be about 3.5% by weight of the composition, the disintegrant is croscamelose and it can be about 3% by weight of the composition, the binder is povidone and it may comprise about 3% by weight of the composition, and the lubricant is magnesium stearate, and it may comprise about 1% by weight of the composition.

In another embodiment of the described invention provides 5, 15 or 30 mg of Doxylamine succinate and 3 mg, 5 mg or 10 mg of Melatonin, where Doxylamine / Melatonin comprise from 45 to 90% by weight of the composition. In other embodiments, Doxylamine with Melatonin comprises from about 60 to 90% or 70-80% of the composition. In another embodiment, these compositions comprise one or more of starches, such as corn starch, lactose monohydrate, microcrystalline cellulose, gelatinized starch, carboxymethyl cellulose; sodium salt of carboxymethyl starch ether; polyvinylpyrrolidone; hydroxypropyl methylcellulose; magnesium stearate; and a mineral salt such as talc.

In a further embodiment, these compositions comprise lactose monohydrate, corn starch, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, talc and magnesium stearate.

In a further embodiment, these compositions comprise lactose monohydrate, microcrystalline cellulose, gelatinized starch, carboxymethyl cellulose, polyvinylpyrrolidone and magnesium stearate. In another embodiment, these compositions comprise lactose monohydrate, sodium carboxymethyl cellulose, polyvinyl pyrrolidone and magnesium stearate.

In a further embodiment, Doxylamine succinate in a new formulation is used in conjunction with lactose monohydrate; croscarmellose sodium; microcrystalline cellulose; magnesium stearate. Melatonin, in turn, with a prolonged release using excipients selected from methyl methacrylate, trimethylammonium ethyl methacrylate chloride and ethyl acrylate, mixtures or copolymers thereof; hydroxypropyl methylcellulose in amounts of from 20 to 65 wt. %, if necessary, calcium hydrophosphate dihydrate or lactose monohydrate - 10-30% of the mass; silicon dioxide colloidal and / or talcum powder 1-2% wt.

Unit doses of doxylamine succinate and melatonin are in solid dosage form, such as a tablet or capsule, and more preferably is a tablet. In particular, this tablet may include 5.10, 20.25, or preferably 15 mg, of doxylamine succinate and 3, 5, 10 mg of melatonin in a pharmaceutical composition weighing about 300 mg.

In some cases, it is possible to apply film coatings or coatings slowing down the release of active substances, for example, based on PVP, HHHMC, Opadra white.

The presented materials, methods and examples are illustrative, and in no way should be interpreted as limiting the completeness and / or content of the invention. Only if the technological, scientific and experimental data are well known in the art using the described invention.

The manufacturing process of the finished drug according to this invention.

Example 1

The production process of tablet cores is carried out by direct tabletting.

Melatonin in an amount of 2 mg mixed with sifted hydroxypropyl methylcellulose (HPMC) 100 mg, a complex compound of microcrystalline cellulose (MCC) 50 mg and silicon dioxide 2 mg are loaded into the mixer based on the dosage in a tablet. The mixture of dry components is mixed for about 10 minutes (the rotation speed of the main mixer is 80 ÷ 110 rpm. Then, sieved magnesium stearate 1 mg is added to the mixture of dry components and mixing is continued for 3 minutes (rotation speed of the main mixer 80 ÷ 110 rpm ) At the end of mixing, doxylamine succinate in the amount of 15 mg is added to the tablet mass, further mixed and discharged from the mixer, then transferred to the tabletting step.

Tableting is carried out on a RTM-41 M rotary press using round punches (deep sphere).

In the process of tabletting, the appearance, average weight and fracture strength of the tablet cores are controlled. The breaking strength of the tablet cores ranges from 120 N to 180 N, the average weight of 0.40 g ± 2% (from 0.38 g to 0.42 g). Yellow core tablets, biconvex, with solid edges, without cracks and chips, have a rough or smooth surface.

The obtained tablet core is dedusted, rejected (by weight or appearance) and kept at room temperature in a closed container, in a dark place for 6-8 hours. The abrasion resistance of the tablet cores is at least 99.8%.

Core tablets are sent to the film-coating step. Apply a film coating to the tablet cores on a BGB-10 apparatus using an aqueous suspension of OPADRYII powder with a mass concentration of 19% ± 1%.

Example 2

In the production of tablet cores, HPMC (Metocel®) in the amount of 568.0 g (35%), Doxylamine succinate, Melatonin, 750.0 g (46.15%), MCC with MDK (Prosolv®) 290.06 g ( 17.85%) and magnesium stearate 16.25 g (1%). The mass of tablet cores is 0.650 g ± 5% (from 0.618 g to 0.682 g).

In the process of tabletting, the appearance and fracture strength of the tablet cores are controlled. The breaking strength of tablet cores is from 60-70 N. The tablet cores are white or almost white, biconvex, with solid edges, a smooth and uniform surface, without cracks and chips.

The obtained tablet core is dedusted, kept at room temperature in a closed container for 6-8 hours, in a dark place. The abrasion resistance of tablet cores is at least 99.7%.

The obtained core tablets are passed to the film coating step.

Example 3

A composition for immediate release of doxylamine succinate and sustained release of melatonin for oral administration is prepared by direct compression (compression) with a powdered mass of acrylic rubber, for example Eudragit. Melatonin (2 mg) was mixed with 40 mg of calcium hydrogen phosphate and 80 mg of lactose in dry form and added to the chopped food mass (40 mg of Eudragit RSPO), the mixture was pressed (with a load of more than 2 tons) into a core with a diameter of 7 mm, then added to the prepared mixture Doxylamine succinate (15 mg). Then transferred to the tabletting process.

Example 4

Intragranular components: Melatonin 2 mg, Avicel PH 1015 mg, Metocel K100LV 5 mg, Aerosil 200, Magnesium stearate 1 mg; Extragranular components: Doxylamine succinate 15 mg, Avicel PH 101 15 mg, Aerosil 200 20 mg, Magnesium stearate 1 mg; Coating components: Opadry white.

Production process

1. Weighed portions of API and excipients

2. Screening of intragranular excipients:

- AFI and Metocel K 100 LV are sifted through an ASTM # 40 sieve

- Avicel PH 101 is sieved through ASTM # 40 sieve, Aerosil 200 Pharma is sieved through mesh # 40.

- Magnesium stearate is sieved through an ASTM # 60 sieve of a vibratory screening machine.

3. Pre-compacting:

- Co-sifted excipients (excluding Magnesium stearate) were placed in a 5 L double-cone mixer.

- The mixing time was 20 minutes at 15 rpm.

4. Humidification:

- Sifted Magnesium stearate was placed in a 5 L double-cone mixer.

- Humidification was performed for 3 minutes at 15 rpm.

5. Rolling granulation:

The pre-compacted mixture was transferred to a roller press, which was put into operation.

Density after compaction 0.58-0.6

To obtain good quality granules, a hydraulic pressure of 50 bar is most preferred.

6. Screening of extragranular auxiliary components:

- Avicel PH 101 and Aerosil 200 Pharma were sieved through an ASTM # 40 sieve.

- Magnesium stearate was sieved through an ASTM # 60 sieve of a vibratory screening machine.

7. Mixing:

- Sifted auxiliary substances (except magnesium stearate) together with pre-compacted granules were placed in a 5 L two-cone mixer.

- The mixing time was 5 minutes at 15 rpm.

8. Lubrication:

The sieved magnesium stearate was placed in a two-cone 5-liter mixer and humidified for 3 minutes at 15 rpm.

9. Pressing

The lower and upper punches 8 * 13 mm are installed on a tablet press to determine the limit of the corresponding compressive strength.

The speed of the tablet press turret was set to 15-30 rpm, and the feeder for feeding in pressure mode to 20-30 rpm, the mixture was pressed further.

10. Coating

- In a propeller-type mixer, an 8% (percent by weight) film-forming solution of Opadrai white Y - 1 - 7000 in purified water was prepared.

- The core tablets were loaded into the boiler and warmed up before starting the process

- Upon receipt of the desired process parameters, the spraying process was started using Opadray white solution Y - 1 - 7000, until an increase in weight was achieved.

- At the end of the spraying, the physical condition of the tablets was checked.

Example 5

The experiments were carried out on white outbred rats, males weighing 350-380 g. 4 groups of 12 animals were formed in accordance with the tested samples:

Group 1 animals were injected with saline (control group);

2nd group-prepared solution of doxylamine succinate;

3rd group-solution of melatonin;

4th group - the claimed pharmaceutical composition (doxylamine tablets + prolonged melatonin, crushed and dispersed in water, example 4 *);

Administration of doxylamine succinate in animals caused an increase in ptosis in animals (33 ± 8). At the same time, a similar increase in ptosis, to a lesser extent, caused the introduction of melatonin (18 ± 10). The highest indicator of ptosis is reliably shown by the composition of doxylamine succinate + melatonin. The number of jumps characterizes the threshold of perception of external stimuli, nerve reflexes after the use of biologically active substances, in this case, the studied agents. The use of doxylamine succinate causes a significant increase in the total number of jumps (85) compared with the jump indicators in the first and third groups (41 and 39, respectively). The introduction of the doxylamine composition succinate + melatonin caused a statistically significant increase in the number of jumps in animals of the fourth group (144). These data indicate that doxylamine succinate lowers the threshold for sensitivity to stress factors. Moreover, the combination of doxylamine succinate + melatonin has an even greater effect of lowering the threshold of sensitivity to stress factors. Moreover, the combination of doxylamine succinate ÷ melatonin does not have such an effect, and moreover, this indicator is close to that of the control group that received the physiological solution. As unexpected, the claimed pharmaceutical composition has an additional anxiolytic effect. Time to find a way out of the stressful situation spent by animals of different groups shows the differences in the groups and the studied compositions. When using doxylamine succinate in animals of this group, an increase in the time to exit the stressful situation was observed (about 90 seconds), which indicates the ambiguous effect of doxylamine succinate on the search reflexes after awakening. Animals in the control group and the doxylamine group succinate ÷ melatonin emerged from a stressful situation (14 and 16 seconds) compared with animals of other groups.

Since particular embodiments of the invention have been partially described above, it should be noted that the present invention is not limited to them, since, as specialists can easily imagine, many modifications or variations can be made. Such modifications or variations, not discussed in detail here, are considered obvious equivalents of the present invention.

Claims (2)

1. A pharmaceutical composition for initiating and maintaining a sleep process and preventing conditions in animals and humans that are accompanied by sleep disorders of various nature, characterized in that it comprises a combination of active agents consisting of Doxylamine Succinate in an amount of 0.5-45 mg and Sustained Release Melatonin in an amount of 0.1-20 mg. 2. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of tablets, including sublingual forms, capsules, granular mixture for preparing a drink.