WO2023106959A1 - Pharmaceutical composition containing melatonin and diphenhydramine or its pharmaceutically acceptable salt - Google Patents

Abstract

Claimed are a pharmaceutical composition and dosage forms containing melatonin and diphenhydramine or its pharmaceutically acceptable salt, as well as methods for producing and using said compositions and dosage forms for regulating circadian fluctuations in locomotor activity, body temperature and a person's biological sleep-wake rhythm, improving nighttime sleep, reducing or preventing histamine-induced smooth muscle spasms and enhancing the thought and memory functions of the brain, as well as emotional wellbeing.

Description

PHARMACEUTICAL COMPOSITION INCLUDING MELATONIN AND DIPHENGYDRAMINE OR ITS PHARMACEUTICALLY ACCEPTABLE SALT

APPLICATION AREA

The present inventions relate to the field of pharmaceuticals and relate to pharmaceutical compositions, including melatonin, as well as dosage forms made on the basis of melatonin, methods for the preparation and use of such compositions and dosage forms used primarily to regulate the daily rhythms of sleep and wakefulness, as well as to facilitate symptoms of episodic and acute insomnia.

BACKGROUND OF THE INVENTION

The actual direction of pharmaceuticals is the creation of effective dosage forms used mainly to regulate the daily rhythms of sleep and wakefulness, to alleviate the symptoms of episodic and acute insomnia.

Thus, various pharmaceutical compositions and drugs containing melatonin are increasingly appearing on the pharmaceutical market, because if the human body is adversely affected by numerous stresses, the rhythms of sleep and wakefulness fail, then the sleep hormone melatonin cannot be produced fully, which leads to to a number of serious violations.

In order to ensure a rhythmic alternation of sleep and wakefulness or to eliminate insomnia, sleeping pills are sometimes used - "Melatonin", which is a fairly common drug. Melatonin is intended for people with the following problems: insomnia of various nature. The hypnotic effect of the drug is based on an increase in the amount of melanin produced by the pituitary gland, which helps to fall asleep, get rid of periodic disturbances in the daily rhythms of sleep and wakefulness. The drug helps to adapt and controls biorhythms, and in case of nervous overstrain, this remedy helps to inhibit the processes of the nervous system, giving relaxation.

Melatonin, or M-[2-(5-methoxy-1H-indol-3-yl)ethyl]ethanamide, or M-acetyl-5-methoxytryptamine is a substance with an antioxidant, adaptogenic, hypnotic effect. It inhibits the secretion of gonadotropins, to a lesser extent - other hormones of the adenohypophysis - corticotropin, thyrotropin, somatotropin. Normalizes circadian rhythms. Increases the concentration of gamma-aminobutyric acid (GABA) in the central nervous system and serotonin in the midbrain and hypothalamus, changes the activity of pyridoxalkinase involved in the synthesis of GABA, dopamine and serotonin. Regulates the sleep-wake cycle, daily changes in locomotor activity and body temperature, positively affects the intellectual-mnestic functions of the brain, the emotional-personal sphere. Promotes the organization of the biological rhythm of sleep and wakefulness and the normalization of night sleep.

Diphenhydramine (Dimedrol), or 2-(difsnilmethoxy)-M,M-dimethylethanamine, is an antiallergic, local anesthetic, antihistamine, antiemetic, anticholinergic, hypnotic, sedative. It blocks histamine Hi receptors and eliminates the effects of histamine mediated through this type of receptor. Reduces or prevents histamine-induced spasms of smooth muscles, increased capillary permeability, tissue swelling, itching and hyperemia; suppresses the cough reflex by acting directly on the cough center in the medulla oblongata

It is known, for example, the invention [1] according to the patent of the Russian Federation No. 2485949 (published on 06/27/2013). which discloses a solid dosage form for sublingual or buccal administration of a hormone having low to insufficient water solubility, containing a hormone selected from the group consisting of melatonin, estrogens, progesterone, testosterone and dihydroxytestosterone, in a dissolved state, wherein said dissolved hormone is associated with a pharmaceutically acceptable carrier, wherein said hormone is present in a dissolved state in the final dosage form.

Patent [1] also discloses:

- a method for manufacturing a pharmaceutical composition according to claim 1, comprising the steps of dissolving said hormone in a pharmaceutically acceptable solvent to form a drug solution, mixing the drug solution with particles of a pharmaceutically acceptable carrier to form a coating of said solution on the carrier particles, adsorbing or absorbing said solution on carrier particles;

- a method for providing a patient with hormonal therapy, including making a dosage form according to claim 1 and administering said dosage form by sublingual or buccal method to a patient in need of said therapy.

Solid dosage form according to the patent [1] provides rapid (within a time not exceeding 15 minutes) release of melatonin and rapid provision of a therapeutic effect. However, in some cases it may be a delayed (prolonged) release of melatonin from the dosage form is necessary.

In addition, an invention is known [2] according to the patent of the Russian Federation No. 2560840 (published on August 20, 2015) related to the use of melatonin orally in a composition with a sustained release in the manufacture of a drug for the treatment of subjectively assessed non-restorative sleep in patients suffering from primary insomnia, as defined by the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, ^4th ed. (DSM-IV), by the American Psychiatric Association. - Washington, DC, APA, 1994, 873 pp.). According to the patent [2], melatonin is the only therapeutically active agent of the specified drug, and the specified drug also includes at least one pharmaceutically acceptable diluent, preservative, antioxidant, solvent, emulsifier, adjuvant or carrier, and the specified melatonin is present in the specified drug in an effective amount ranging from 0.0025 to 50 mg.

The patent also protects a medicinal product for the treatment of subjectively assessed non-restorative sleep in patients suffering from primary insomnia, as defined by DSM-IV, containing melatonin in effective amounts ranging from 0.0025 to 50 mg, orally in a sustained release formulation, and at least one pharmaceutically acceptable diluent, preservative, antioxidant, solvent, emulsifier, adjuvant or carrier, wherein melatonin is the sole therapeutically active agent in the drug.

In some cases, however, it is necessary to combine melatonin with other therapeutically active substances in order to achieve or enhance the therapeutic effect.

Also known is a solid pharmaceutical dosage form for oral administration containing a core (core) coated with at least one film coating, in which the specified core contains at least one active pharmaceutical ingredient, while organoleptically discomfort caused by one or more active pharmaceutical ingredients or one or more inactive components of a solid pharmaceutical dosage form is reduced due to the content of the components providing the specified film coating, these components contain at least one film-forming polymer and at least one flavor additive or at least one sweetener and do not contain nicotine (RF application for invention No. 2015156033, published on 07/13/2017, hereinafter - [3]). IN . in a particular embodiment of the invention [3], the active pharmaceutical ingredient of said solid pharmaceutical dosage form may be diphenhydramine.

Said at least one film coating of the solid pharmaceutical dosage form [3] contains a flavoring agent or sweetener, which gives the said solid pharmaceutical dosage form attractive organoleptic properties, which in some cases is undesirable, since it can lead to unauthorized use of the said dosage form by children.

In addition, a pharmaceutical composition is known for initiating and maintaining the sleep process and preventing conditions in animals and humans that are accompanied by sleep disorders of various nature, characterized in that it includes a combination of active agents consisting of doxylamine succinate in an amount of 0.5-45 mg and melatonin prolonged release in the amount of 0.1-20 mg (RF patent for the invention No. 2620855, published on May 30, 2017 [4]).

The pharmaceutical composition [4] contains doxylamine succinate as one of the active ingredients, which is a prescription drug, which limits the availability of such a pharmaceutical composition for patients suffering from sleep disorders of various nature. With the presence on the world pharmaceutical market of a different number of drugs using melatonin, however, it became necessary to create a pharmaceutical composition and offer such a dosage form based on the created pharmaceutical composition, which would increase the therapeutic activity of the claimed quantitative and qualitative composition of the ingredients, effective when administered in the claimed dosage form to combat insomnia, nervous tension, depression and other symptoms of a similar nature caused by insufficient production of the sleep hormone melatonin.

The technical results achieved in the present invention include, firstly, an increase in the therapeutic activity of the claimed quantitative and qualitative composition of the ingredients due to the instant onset of action and the subsequent effective and prolonged action of the pharmaceutical composition and dosage form, and secondly, the simplification of the scheme of action on daily rhythms of sleep and wakefulness, as well as alleviating the symptoms of episodic and acute insomnia, and, thirdly, expanding the assortment list of drugs intended to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, as well as to reduce or prevent spasms of smooth muscles caused by histamine, to reduce tissue edema, providing an improvement in the state of intellectual-mnestic functions of the brain and emotional-personal state.

Technical results are achieved in the present invention by providing:

- a pharmaceutical composition that would increase the therapeutic activity of the claimed quantitative and qualitative composition of ingredients due to the instant onset of action and due to the effective and long-term action of the composition of ingredients,

- a dosage form that would provide, with the introduction of the specified pharmaceutical composition, a simplification of the scheme of action of the claimed qualitative and quantitative composition of ingredients to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent caused histamine spasms of smooth muscles, to reduce tissue edema, providing an improvement in the state of the intellectual and mnestic functions of the brain and emotional and personal state,

- as well as a method for obtaining the specified dosage form based on the proposed pharmaceutical composition intended for regulation daily changes in locomotor activity, body temperature, biological rhythm of sleep and wakefulness and normalization of night sleep, to reduce or prevent spasms of smooth muscles caused by histamine, to reduce tissue edema, providing an improvement in the intellectual-mnestic functions of the brain and emotional-personal state.

DISCLOSURE OF THE INVENTION

The technical result of the present invention is achieved due to the pharmaceutical composition proposed in the present invention, designed to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, providing an improvement in the intellectual-mnestic functions of the brain and emotional-personal state, including diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg and melatonin in an amount of 1.5 to 6.0 mg, as well as a dosage form made on the basis of the above pharmaceutical composition, which is a modified-release hard gelatin capsule containing powder with diphenhydramine or its pharmaceutically acceptable salt and granules with diphenhydramine or its pharmaceutically acceptable salt with immediate release in an amount of 20 to 60 mg and a tablet (microtablet) containing from 1.5 to 6.0 mg sustained release melatonin. Also, the technical result is achieved due to the method proposed in the present invention for obtaining a dosage form made on the basis of the above pharmaceutical composition, where this method includes obtaining granules and powder of diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg and obtaining microtablets of melatonin in amount from 1.5 to 6.0 mg, placement of these active substances in a hard gelatin capsule with modified release. In the most preferred (non-limiting) embodiment of the invention, the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride. In other particular, also non-limiting, embodiments of the invention, the pharmaceutically acceptable salt of diphenhydramine can be selected from diphenhydramine hydrochloride, diphenhydramine hydrobromide, diphenhydramine hydroiodide, diphenhydramine perchlorate, diphenhydramine fumarate, diphenhydramine glutarate, diphenhydramine nitrate, diphenhydramine phosphate, diphenhydramine succinate, diphenhydramine sulfate, phenhydramine, tartrate diphenhydramine, diphenhydramine malonate, diphenhydramine maleate, diphenhydramine malate, diphenhydramine oxalate, diphenhydramine salicylate, diphenhydramine tannate, diphenhydramine acetate, diphenhydramine besylate (benzenesulfonate), diphenhydramine benzoate, diphenhydramine citrate, and diphenhydramine hydroxyethanesulfonate. This list of pharmaceutically acceptable salts of diphenhydramine is provided for illustrative purposes and is non-limiting. The specialist will understand that for the purposes of the present invention, other pharmaceutically acceptable diphenhydramine salts not expressly listed in the present description can also be used.

The technical result is also achieved by the fact that a pharmaceutical composition is proposed that provides an increase in the therapeutic activity of the claimed quantitative and qualitative composition of the ingredients, effective for regulating daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalizing night sleep, to reduce or prevent spasms caused by histamine smooth muscles, to reduce tissue edema, providing an improvement in the state of the intellectual and mnestic functions of the brain and emotional and personal state, including powder and granules containing diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg, and microtablets containing melatonin in an amount of 1.5 to 6.0 mg combined with pharmaceutically acceptable excipients.

The content of powder and granules of diphenhydramine or its pharmaceutically acceptable salt in one capsule is from 20 to 60 mg. Percentage diphenhydramine or its pharmaceutically acceptable salt in the specified capsule is from 4.37 to 20.92 May. %. The composition of the powder and granules of diphenhydramine or its pharmaceutically acceptable salt per capsule is presented in Table 1. The amounts of diphenhydramine hydrochloride and auxiliary components are given in Table 1 as: minimum value - maximum value.

The preferred content of lactose monohydrate is 152.16 mg (47.59 wt. %); the preferred content of polyvinylpyrrolidone is 7.76 mg (2.41 wt. %); the preferred content of pregelatinized starch is 5.82 mg (1.81 wt. %); the preferred content of colloidal silicon dioxide is 0.97 mg (0.30 wt.%); the preferred content of magnesium stearate is 1.94 mg (0.59 wt.%).

Examples of formulations (powder and granules) of diphenhydramine hydrochloride per capsule, May. % are presented in Table 2. Capsules contain from 20 to 60 mg of diphenhydramine hydrochloride (in percentage terms, from 4.37 to 20.92 wt. wt. %). The number of auxiliary components are shown in Table 2 in the form: minimum value - maximum value.

The preferred content of lactose monohydrate in accordance with this embodiment of the invention is 152.16 mg (47.59 wt.%); the preferred content of polyvinylpyrrolidone is 7.76 mg (2.41 wt. %); the preferred content of pregelatinized starch is 5.82 mg (1.81 wt. %); the preferred content of colloidal silicon dioxide is 0.97 mg (0.30 wt.%); the preferred content of magnesium stearate is 1.94 mg (0.59 wt.%).

The content of melatonin in one capsule is from 1.5 to 6.0 mg. The percentage of melatonin in the specified capsule is 0.32-24.76 May. %. Examples of melatonin microtablet compositions are presented in Table 3. The amounts of melatonin and auxiliary components are given in Table 3 as: minimum value - optimal values - maximum value.

The content of melatonin in one capsule is from 1.5 to 6.0 mg. The percentage of melatonin in the specified pharmaceutical composition is 0.32-24.76 May. %. Examples of melatonin microtablet formulations are shown in Table 4. The amounts of melatonin and auxiliary components of microtablets are given in Table 4 as: minimum value - maximum value. The preferred content of melatonin is 3.00 mg (7.95 wt. %); the preferred content of microcrystalline cellulose is 34.95 mg (12.5 wt. %); the preferred content of a mixture of polyvinylpyrrolidone with polyvinyl acetate - 23.38 mg (8.34%); the preferred content of magnesium stearate - 0.20 mg (0.87 wt.%); the preferred content of the film shell is 0.80 mg (3.38 wt.%). The preferred ratio of polyvinylpyrrolidone and polyvinyl acetate (w/w) in a mixture of polyvinylpyrrolidone with polyvinyl acetate is 80.81/19.19.

Table 1. Composition of Diphenhydramine Hydrochloride Powder and Granules per Capsule (Embodiment I)

Table 2. Composition examples of diphenhydramine hydrochloride powder and granules per capsule (Embodiment II)

Table 3 Melatonin Microtablet Composition per Capsule (Embodiment III)

Table 4 Melatonin Microtablet Composition per Capsule (Embodiment IV)

Also, the technical result is achieved by the pharmaceutical composition proposed in the present invention, which provides an increase in the therapeutic activity of the claimed quantitative and qualitative composition of the ingredients, effective for regulating daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalizing night sleep, to reduce or prevent spasms caused by histamine smooth muscles, to reduce tissue edema, as well as providing an improvement in the intellectual and mnestic functions of the brain and emotional and personal state, including diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg and melatonin in an amount of 1.5 to 6.0 mg, with the following composition of ingredients, mg:

Diphenhydramine or its

20.00-60.00 pharmaceutically acceptable salt Lactose monohydrate 51.67-265.83 Polyvinylpyrrolidone (Povidone) 4.00-8.25 Pregelatinized starch 3.00-6.19 Silicon dioxide colloidal 0.50-1.03

Magnesium stearate 1.00-2.06

Melatonin 1.5-6.0

Cellulose microcrystalline 10.54-47.25

A mixture of polyvinyl acetate with

5.86-41.58 polyvinylpyrrolidone

Magnesium stearate 0.19-0.21

Film casing 0.78-0.82

Preferably (without limitation), in this embodiment, the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride. Also preferably (without limitation), the ratio of polyvinylpyrrolidone and polyvinyl acetate (wt./wt.) in a mixture of polyvinylpyrrolidone with polyvinyl acetate is 80.81/19.19.

Also, these technical results are achieved by the pharmaceutical composition proposed in the present invention, which provides an increase in the therapeutic activity of the claimed quantitative and qualitative composition of the ingredients, effective for regulating daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalizing night sleep, to reduce or prevent those caused by histamine spasms of smooth muscles, to reduce tissue edema, as well as providing an improvement in the state of intellectual and mnestic functions of the brain and emotional and personal state, including diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg and melatonin in an amount of 1.5 to 6, 0 mg, with the following composition of ingredients, wt.%:

Diphenhydramine or its

4.37-20.92 pharmaceutically acceptable salt

Lactose monohydrate 16.16 - 83.14

Polyvinylpyrrolidone (Povidone) 1.39-2.58 Pregelatinized starch 0.32-1.93

Silicon dioxide colloidal 0.17-0.32

Magnesium stearate 0.35-0.64

Melatonin 0.32-24.76

Cellulose microcrystalline 3.77-16.9

A mixture of polyvinyl acetate with

2.09-14.83 polyvinylpyrrolidone

Magnesium stearate 0.07-1.01

Film shell 0.28-4.13

Preferably (without limitation), in this embodiment, the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride. In other particular, also non-limiting, embodiments of the invention, the pharmaceutically acceptable salt of diphenhydramine can be selected from diphenhydramine hydrochloride, diphenhydramine hydrobromide, diphenhydramine hydroiodide, diphenhydramine perchlorate, diphenhydramine fumarate, diphenhydramine glutarate, diphenhydramine nitrate, diphenhydramine phosphate, diphenhydramine succinate, diphenhydramine sulfate, phenhydramine, tartrate diphenhydramine, diphenhydramine malonate, diphenhydramine maleate, diphenhydramine malate, diphenhydramine oxalate, diphenhydramine salicylate, diphenhydramine tannate, diphenhydramine acetate, diphenhydramine besylate (benzenesulfonate), diphenhydramine benzoate, diphenhydramine citrate and diphenhydramine hydroxyethanesulfonate and other pharmaceuticals and acceptable diphenhydramine salts known to those skilled in the art.

Also preferably (without limitation), the ratio of polyvinylpyrrolidone and polyvinyl acetate (wt./wt.) in a mixture of polyvinylpyrrolidone with polyvinyl acetate in this embodiment of the invention is 80.81/19.19.

The content of powder and granules of diphenhydramine hydrochloride in one capsule is from 20 to 60 mg. The percentage of diphenhydramine hydrochloride in said pharmaceutical composition is 4.37 - 20.92 May. %. The composition according to this embodiment of the invention is presented in Table 1. Another private embodiment of the invention, characterized by a percentage of diphenhydramine hydrochloride, which is 4.37-20.92 May. % and the content of diphenhydramine hydrochloride (mg) ranging from 20 to 60 mg is presented in Table 2.

The third particular embodiment of the invention, characterized by the content of melatonin per capsule, which is 1.5 - 6.0 mg and the percentage of melatonin, which is 0.32-24.76 wt. % is presented in Table 3.

The fourth particular embodiment of the invention, characterized by the content of melatonin per capsule, which is in the range of 1.5-6.0 mg and the percentage of melatonin, which is 0.32-24.76 wt. % is presented in Table 4.

The above technical results in the present invention are also achieved by the fact that, based on the above pharmaceutical composition, a dosage form is proposed for regulating daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalizing night sleep, for reducing or preventing histamine-induced spasms of smooth muscles. , to reduce tissue edema, providing an improvement in the intellectual-mnestic functions of the brain and emotional-personal state, which is a modified-release hard gelatin capsule containing powder and granules containing diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg, together with pharmaceutically acceptable auxiliary components, including lactose monohydrate, polyvinipyrrolidone, pregelatinized starch, colloidal silicon dioxide and magnesium stearate, and a microtablet containing melatonin in an amount of 1.5 to 6.0 mg together with pharmaceutically acceptable auxiliary components, including microcrystalline cellulose, a mixture of polyvinyl acetate with polyvinipyrrolidone , magnesium stearate and film shell, in the following ratio of ingredients, wt.%:

Diphenhydramine or its

4.37-20.92 pharmaceutically acceptable salt of Lactose monohydrate 16.16 - 83.14 Polyvinylpyrrolidone 1.39-2.58

Pregelatinized starch 0.32-1.93

Silicon dioxide colloidal 0.17-0.32

Magnesium stearate 0.35-0.64

Melatonin 0.32-24.76

Cellulose microcrystalline 3.77-16.9

A mixture of polyvinyl acetate with

2.09-14.83 polyvinylpyrrolidone

Magnesium stearate 0.07 -1.01

Film shell 0.28-4.13

Preferably (without limitation), in this embodiment, the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride. In other particular, also non-limiting, embodiments of the invention, the pharmaceutically acceptable salt of diphenhydramine can be selected from diphenhydramine hydrochloride, diphenhydramine hydrobromide, diphenhydramine hydroiodide, diphenhydramine perchlorate, diphenhydramine fumarate, diphenhydramine glutarate, diphenhydramine nitrate, diphenhydramine phosphate, diphenhydramine succinate, diphenhydramine sulfate, phenhydramine, tartrate diphenhydramine, diphenhydramine malonate, diphenhydramine maleate, diphenhydramine malate, diphenhydramine oxalate, diphenhydramine salicylate, diphenhydramine tannate, diphenhydramine acetate, diphenhydramine besylate (benzenesulfonate), diphenhydramine benzoate, diphenhydramine citrate and diphenhydramine hydroxyethanesulfonate and other pharmaceuticals and acceptable diphenhydramine salts known to those skilled in the art.

Also preferably (without limitation), the ratio of polyvinylpyrrolidone and polyvinyl acetate (wt./wt.) in a mixture of polyvinylpyrrolidone with polyvinyl acetate in this embodiment of the invention is 80.81/19.19. The composition of the powder and granules of diphenhydramine hydrochloride according to the first embodiment of the invention is presented in Table 1.

Examples of diphenhydramine hydrochloride powder and granules according to the second embodiment of the invention are shown in Table 2.

The composition of tablets (microtablets) of melatonin according to the third embodiment of the invention, containing from 1.5 to 6.0 mg (from 0.32 to 24.76 wt. %) of melatonin, is presented in Table 3.

Examples of tablets (microtablets) according to the fourth embodiment of the invention containing 1.5 to 6.0 mg (0.32 to 24.76%) of melatonin are shown in Table 4.

In addition, the above technical results are also achieved by the dosage form proposed in the present invention, designed to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize nocturnal sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema , providing an improvement in the intellectual-mnestic functions of the brain and emotional-personal state, which is a hard gelatin capsule with a modified release of active substances containing powder and granules containing diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg and a microtablet containing melatonin in an amount of 1.5 to 6.0 mg, with the following ratio of ingredients, mg:

Diphenhydramine or its

20.00-60.00 pharmaceutically acceptable salt of Lactose monohydrate 51.67-265.83

Polyvinylpyrrolidone (Povidone) 4.00-8.25

Pregelatinized starch 3.00-6.19

Silicon dioxide colloidal 0.50-1.03

Magnesium stearate 1.00-2.06

Melatonin 1.5-6.0 Cellulose microcrystalline 10.54-47.25

A mixture of polyvinyl acetate with

5.86-41.58 polyvinylpyrrolidone

Magnesium stearate 0.19-0.21

Film casing 0.78-0.82

Preferably (without limitation), in this embodiment, the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride.

Also preferably (without limitation), the ratio of polyvinylpyrrolidone and polyvinyl acetate (wt./wt.) in a mixture of polyvinylpyrrolidone with polyvinyl acetate in this embodiment of the invention is 80.81/19.19.

An illustrative (non-limiting) example of the composition of powder and granules containing 20-60 mg (4.37-20.92 wt. %) of diphenhydramine or its pharmaceutically acceptable salt - hydrochloride - per capsule according to this embodiment of the invention is presented in Table 1.

Another illustrative (non-limiting) example of the composition of powder and granules containing 20-60 mg (4.37-20.92 wt. %) of diphenhydramine or its pharmaceutically acceptable salt - hydrochloride - per capsule according to another embodiment of the invention is presented in Table 2.

An illustrative (non-limiting) example of the composition of microtablets containing 1.5-6.0 mg (0.32-24.76 wt. %) of melatonin per capsule according to one of the most preferred embodiments of the invention is presented in Table 3.

Another illustrative (non-limiting) example of the composition of microtablets containing 1.5-6.0 mg (0.32-24.76 wt.%) melatonin per capsule according to another of the most preferred embodiments of the invention is presented in Table 4.

The above technical results are achieved in the present invention also by the fact that a method for obtaining a dosage form with modified release of the active substance, designed to regulate diurnal changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, providing an improvement in the state of intellectual-mnestic functions of the brain and emotional and personal state, in which granules with diphenhydramine or its pharmaceutically acceptable salt are obtained, a microtablet of melatonin is obtained, granules and tablets are assembled into a hard gelatin capsule containing powder and granules with diphenhydramine hydrochloride from 20 to 60 mg and a microtablet of melatonin from 1.5 to 6.0 mg, obtained by any available method, the components are packaged, the quantitative and qualitative criteria for the composition of a hard gelatin capsule containing powder and granules with a modified release of the active substance are used for packaging, where the specified powder and these granules contain diphenhydramine or its pharmaceutically acceptable substance as an active substance. salt in an amount of 20 to 60 mg; and a microtablet containing 1.5 to 6.0 mg of melatonin.

The process of obtaining powder and granules of the pharmaceutically acceptable salt of diphenhydramine - diphenhydramine hydrochloride.

At the first stage, to obtain powder and granules of diphenhydramine hydrochloride, the ingredients of the dosage form, such as diphenhydramine hydrochloride, lactose monohydrate, pregelatinized starch and colloidal silicon dioxide, are sifted through sieves with a hole diameter of 0.25 to 1.00 mm, including on a vibrating sieve CISA RP 200 N.

Next, prepare a solution of a humidifier, consisting mainly of polyvinylpyrrolidone. Use its concentration in solution in the range of 20-45 May. %,.

Including, for example, May 40 is prepared as a humidifier. % Povidone solution.

Further, in a mixer, for example, a paddle, with moving blades or another similar, diphenhydramine hydrochloride, lactose monohydrate, starch are mixed pregelatinized and colloidal silicon dioxide under the following conditions:

- mixing speed from 10 to 55 rpm,

- mixing time 1-15 minutes.

Then, without stopping the rotation of the mixer, a humidifier solution is added, consisting mainly of polyvinylpyrrolidone with a concentration of 20-45 wt. %.

Wherein:

- increase mixer rotation speed up to 30-400 rpm.

- the mixing/mixing time is from 2 to 8 minutes.

After that, the mixer speed is reduced to 10-30 rpm and magnesium stearate is added to the mixer to carry out the process of dusting the mixture.

Continue stirring for another 2-6 minutes.

The process of obtaining melatonin tablets.

At the first stage of obtaining melatonin tablets, melatonin and a part of microcrystalline cellulose are loaded into the mixer in a ratio of 1:1 to 1:1.35 and the components are mixed until a homogeneous state is observed, as a rule, under the following conditions:

- mixing speed from 10 to 55 rpm

- and mixing time 1-15 minutes.

Then add the rest of the microcrystalline cellulose, continue mixing under the same conditions for another 10 to 20 minutes.

After that, a ready-made mixture of polyvinyl acetate with polyvinylpyrrolidone is added to the resulting mixture, and the components are mixed until homogeneous, subject, as a rule, to the following conditions:

- mixing speed from 10 to 55 rpm,

- mixing time 1-15 minutes.

Next, the mixer speed is reduced to 10-30 rpm and magnesium stearate is added to the mixer to carry out the process of dusting the mixture.

Continue stirring for another 2-6 minutes. The resulting mixture is subjected to compression on a tablet press to obtain tablets with a diameter of 3 mm and the following criteria

- hardness - 40-50-70 N;

- abrasion - no more than 0.5%;

The resulting tablets are coated with a film coating consisting of a mixture of hydroxypropyl methylcellulose, lactose monohydrate, polyethylene glycol 4000 and titanium dioxide.

Coating is carried out in devices operating on the principle of a fluidized bed at a temperature of application from 27 to 37°C.

The resulting granulate and microtablets are packed into hard gelatin capsules.

The composition of the powder and granules of diphenhydramine hydrochloride per capsule is in the range of 20-60 mg, and its percentage: 4.37-20.92 May. % in the specified pharmaceutical composition is presented in Table 1.

Examples of powder and granules of diphenhydramine hydrochloride per capsule - in the range of 20-60 mg, and its percentage: 4.37-20.92 May. % in the specified pharmaceutical composition is presented in Table 2.

The composition of melatonin microtablets per capsule is in the range of 1.5 to 6.0 mg, and the percentage: 0.32-24.76 May. % in the specified pharmaceutical composition is presented in Table 3.

Examples of microtablets of melatonin per capsule - in the range of 1.5 to 6.0 mg, and the percentage: 0.32-24.76 wt. % in the specified pharmaceutical composition is presented in Table 4.

In addition, the technical result is achieved by the fact that a method is proposed for obtaining a dosage form intended to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema , providing an improvement in the state of the intellectual-mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule containing powder and granules with diphenhydramine hydrochloride from 20 to 60 mg and a melatonin microtablet from 1.5 to 6.0 mg, in which powder and granules with diphenhydramine hydrochloride are obtained, a melatonin microtablet is obtained, granules and tablets are assembled into a hard gelatin capsule containing powder and granules with diphenhydramine hydrochloride from 20 to 60 mg and a melatonin microtablet from 1.5 to 6.0 mg, obtained, including by any available method, the above granules and microtablets are packaged, used for packaging, quantitative and qualitative criteria for the composition of a hard gelatin capsule containing diphenhydramine hydrochloride granules from 20 to 60 mg and a melatonin microtablet from 1.5 to 6.0 mg, in the following ratio of ingredients, May. %:

Diphenhydramine hydrochloride 4.37-20.92

Lactose monohydrate 16.16 - 83.14

Polyvinylpyrrolidone 1.39-2.58

Pregelatinized starch 0.32-1.93

Silicon dioxide colloidal 0.17-0.32

Magnesium stearate 0.35-0.64

Melatonin 0.32-24.76

Cellulose microcrystalline 3.77-16.9

A mixture of polyvinyl acetate with

2.09-14.83 polyvinylpyrrolidone

Magnesium stearate 0.07 - 1.01

Film casing 0.28-4.13

An illustrative (non-limiting) example of the composition of powder and granules containing 20-60 mg (4.37-20.92 wt. %) of diphenhydramine or its pharmaceutically acceptable salt - hydrochloride - per capsule according to this embodiment of the invention is presented in Table 1.

Another illustrative (non-limiting) example of the composition of powder and granules containing 20-60 mg (4.37-20.92 wt. %) diphenhydramine or its pharmaceutical acceptable salt - hydrochloride - per capsule according to another embodiment of the invention is presented in Table 2.

An illustrative (non-limiting) example of the composition of microtablets containing 1.5 - 6.0 mg (0.32 - 24.76 wt. %) of melatonin per capsule according to one of the most preferred embodiments of the invention is presented in Table 3.

Another illustrative (non-limiting) example of the composition of microtablets containing 1.5 - 6.0 mg (0.32 - 24.76 wt. %) of melatonin per capsule according to another of the most preferred embodiments of the invention is presented in Table 4.

In addition, a method is proposed for obtaining a dosage form intended to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, providing an improvement in the state of intellectual activity. memory functions of the brain and emotional and personal state, which is a hard gelatin capsule containing powder and granules with diphenhydramine hydrochloride from 20 to 60 mg and a melatonin microtablet from 1.5 to 6.0 mg, the granules and tablets are assembled into a hard gelatin capsule and - packed, used for packaging quantitative and qualitative criteria for the composition of a hard gelatin capsule, with the following ratio of ingredients, mg:

Diphenhydramine hydrochloride 20.00-60.00 Lactose monohydrate 51.67-265.83

Polyvinylpyrrolidone (Povidone) 4.00-8.25 Pregelatinized starch 3.00-6.19 Colloidal silicon dioxide 0.50-1.03 Magnesium stearate 1.00-2.06

Melatonin 1.5-6.0

Cellulose microcrystalline 10.54-47.25 A mixture of polyvinyl acetate with

5.86-41.58 polyvinylpyrrolidone

Magnesium stearate 0.19-0.21

Film casing 0.78-0.82

The composition of the powder and granules of diphenhydramine hydrochloride per capsule is in the range of 20-60 mg, and its percentage: 4.37 - 20.92 May. % in the specified pharmaceutical composition is presented in Table 1.

Examples of powder and granules of diphenhydramine hydrochloride per capsule - in the range of 20-60 mg, and its percentage: 4.37 - 20.92 May. % in the specified pharmaceutical composition is presented in Table 2.

The composition of melatonin microtablets per capsule is in the range of 1.5 to 6.0 mg, and the percentage: 0.32-24.76 May. % in the specified pharmaceutical composition is presented in Table 3.

Examples of melatonin microtablets per capsule - in the range of 1.5 to 6.0 mg, and the percentage: 0.32-24.76 wt. % in the specified pharmaceutical composition is presented in Table 4.

The technical result is also achieved by the proposed dosage form with a modified release, designed to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, providing an improvement in the intellectual and mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule containing diphenhydramine or a pharmaceutically acceptable salt of diphenhydramine (for example, hydrochloride) in an amount of 25 mg with immediate release and melatonin in an amount of 3 mg with prolonged release per one a capsule in which the mixture for encapsulation is made in the form of granules containing diphenhydramine hydrochloride dispersed in the filler as a pharmaceutical substance, as a binder, a disintegrant, a glidant and a lubricant. Preferred (without limitation), filler is lactose monohydrate. Also preferably (without limitation), the binder is polyvinylpyrrolidone, the disintegrant is pregelatinized starch, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate. The person skilled in the art will appreciate that other excipients, binders, disintegrants, glidants and lubricants used in the art may also be used in alternative embodiments of the invention. For example, starch, glucose, sucrose, lactose (milk sugar), basic magnesium carbonate, magnesium oxide, sodium chloride, sodium bicarbonate, gelatin, methylcellulose (MC), sodium carboxymethylcellulose (Na CMC), calcium carbonate, dibasic calcium phosphate, glycine, dextrin, amylopectin, ultramylopectin, sorbitol, mannitol, pectin; Purified water, ethyl alcohol, starch paste, sugar syrup, solutions of: carboxymethylcellulose (CMC), hydroxyethyl cellulose (OEC), hydroxypropyl methylcellulose (OPMC) can be used as binders; polypinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginic acid, sodium algicate, gelatin; as glidants - starch, talc, polyethylene oxide-4000; as a lubricant (lubricant) - stearic acid and its pharmaceutically acceptable salts: calcium stearate and magnesium stearate.

Also, the technical result in the present invention is achieved by providing coated tablets containing melatonin as a pharmaceutical substance, microcrystalline cellulose as a filler, as well as a component that has a prolonged or modified effect, containing: polyvinyl acetate - 80 May. %, povidone - May 19. %, sodium lauryl sulfate - 0.8 May. %, silicon dioxide as a lubricant - 0.2 May. % magnesium stearate, film coating, including hypromellose, iron oxide yellow, lactose monohydrate and triacetin, in the following ratio of ingredients per 1 capsule, wt.%:

Diphenhydramine hydrochloride 8.72

Lactose monohydrate 47.59

Polyvinylpyrrolidone 1.39

Pregelatinized starch 0.32 Silicon dioxide colloidal 0.17

Magnesium stearate 0.35

Melatonin 0.32

Cellulose microcrystalline 3.77

Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium 2.09 lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%)

Magnesium stearate 0.07

Film coating (G ipromellose, Iron oxide yellow, Lactose 0.28 monohydrate, Triacetin)

The technical result in the present invention is also achieved by the proposed dosage form with a modified release, designed to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, providing an improvement in the state of the intellectual and mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule with a modified release of active substances, containing as active substances diphenhydramine or its pharmaceutically acceptable salt in an amount of 25 mg with immediate release and melatonin in an amount 3 mg with prolonged release per capsule containing a mixture for encapsulation in the form of granules containing diphenhydramine or its pharmaceutically acceptable salt as a pharmaceutical substance, lactose monohydrate as a filler, polyvinylpyrrolidone as a binder, pregelatinized starch as a disintegrant, in as a glidant - colloidal silicon dioxide, as a lubricant - magnesium stearate, and coated microtablets containing melatonin as a pharmaceutical substance, as a filler microcrystalline cellulose, a component that has a prolonged or modified effect, the composition of which contains: polyvinyl acetate - 80 May. %, povidone - May 19. %, sodium lauryl sulfate - 0.8 May. %, silicon dioxide - 0.2 May. %, V as a lubricant - magnesium stearate, film coating, including hypromellose, iron oxide yellow, lactose monohydrate and triacetin, with the following ratio of ingredients per 1 capsule, mg:

Diphenhydramine hydrochloride 25.00

Lactose monohydrate 136.50

Polyvinylpyrrolidone 4.00

Pregelatinized starch 3.00

Silicon dioxide colloidal 0.50

Magnesium stearate 1.00

Melatonin 3.00

Cellulose microcrystalline 10.80

Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium lauryl sulfate 6.00 (0.8 wt.%), silicon dioxide (0.2 wt.%)

Magnesium stearate 0.20

Film coating (Hypromellose, Iron oxide yellow, Lactose 0.80 monohydrate, Triacetin)

Formulation examples of modified-release hard gelatin capsules containing 25 mg of diphenhydramine or a pharmaceutically acceptable salt thereof and 3 mg of melatonin per capsule are shown in Table 5. Table 5. Composition of modified-release hard gelatin capsules containing diphenhydramine hydrochloride (25 mg) and melatonin (3 mg)

The technical result in the present invention is also achieved by the fact that a pharmaceutical composition and a modified-release dosage form made on its basis, designed to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent induced spasms of smooth muscles with histamine, to reduce tissue edema, providing an improvement in the intellectual-mnestic functions of the brain and emotional-personal state, which is a modified-release hard gelatin capsule containing diphenhydramine or its pharmaceutically acceptable salt as active substances in an amount of 25 mg with immediate release and melatonin in the amount of 3 mg with prolonged release per capsule, as well as auxiliary components, including a filler, a disintegrant, a glidant and a lubricant, moreover, this dosage form contains lactose monohydrate as a filler, colivinylpyrrolidone as a binder, and colivinylpyrrolidone as a disintegrant. pregelatinized starch, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, and coated tablets containing melatonin as a pharmaceutical substance, microcrystalline cellulose as a filler, a component that has a prolonged or modified effect, containing: polyvinyl acetate - May 80 %, povidone - May 19. %, sodium lauryl sulfate - 0.8 May. %, silicon dioxide - 0.2 May. %, as a lubricant - magnesium stearate, film shell, including hypromellose, iron oxide yellow, lactose monohydrate and triacetin, in the following ratio of ingredients per 1 capsule, wt.%:

Diphenhydramine hydrochloride 10.95

Lactose monohydrate 59.76

Paul ivinylpyrrolidone 1.75

Pregelatinized starch 1.31

Silicon dioxide colloidal 0.22

Magnesium stearate 0.44

Melatonin 0.66 Cellulose microcrystalline 2.36

Polyvinyl acetate - 80 May. %, povidone - 19 wt.%, sodium 1.31 lauryl sulfate - 0.8 wt.%, silicon dioxide - 0.2 wt.%

Magnesium stearate 0.04

Film coating (Hypromellose, Iron oxide yellow, Lactose 0.18 monohydrate, Triacetin)

The technical result in the present invention is also achieved by the fact that the proposed dosage form is designed to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, providing an improvement in the intellectual-mnestic functions of the brain and emotional-personal state, which is a hard gelatin capsule with a modified release of active substances, containing as active substances diphenhydramine or its pharmaceutically acceptable salt in an amount of 25 mg with immediate release and melatonin in an amount of 3 mg with prolonged release per capsule, in which the mixture for encapsulation in the form of granules containing diphenhydramine or its pharmaceutically acceptable salt as a pharmaceutical substance, lactose monohydrate as a filler, polyvinylpyrrolidone as a binder, pregelatinized starch as a disintegrant, as glidant - colloidal silicon dioxide, as a lubricant - magnesium stearate, and coated tablets containing melatonin as a pharmaceutical substance, microcrystalline cellulose as a filler, a component that has a prolonged or modified effect, the composition of which contains polyvinyl acetate 80%, povidone 19%, sodium lauryl sulfate 0.8%, silicon dioxide 0.2%, as a lubricant - magnesium stearate, film coating, including hypromellose, iron oxide yellow, lactose monohydrate and triacetin, in the following ratio of ingredients per 1 capsule, mg: Diphenhydramine hydrochloride 50.00

Lactose monohydrate 273.00

Polyvinylpyrrolidone 8.00

Pregelatinized starch 6.00

Silicon dioxide colloidal 1.00

Magnesium stearate 2.00

Melatonin 3.00

Cellulose microcrystalline 10.80

Polyvinyl acetate 80%, povidone 19%, sodium lauryl sulfate 0.8%, 6.00 silicon dioxide 0.2%

Magnesium stearate 0.20

Film coating (Hypromellose, Iron oxide yellow, Lactose 0.80 monohydrate, Triacetin)

Formulation examples of modified-release hard gelatin capsules including diphenhydramine hydrochloride (50 mg) and melatonin (3 mg) are shown in Table 6. Table 6. Formulation of modified-release hard gelatin capsules containing diphenhydramine hydrochloride (50 mg per one capsule) and melatonin (3 mg per capsule).

A detailed example of the method for producing hard gelatin capsules with a modified release of diphenhydramine hydrochloride and melatonin, which includes: preparation of raw materials, including sifting raw materials, in which magnesium stearate is manually sieved through a 0.5 mm sieve, the residues on the sieve are wiped manually, diphenhydramine hydrochloride sifted through a 0.25 mm sieve, melatonin is sieved, including on a CISA RP 200 N vibrating sieve through a 0.50 mm sieve, microcrystalline cellulose 102, lactose monohydrate 200, pregelatinized starch, colloidal silicon dioxide, Kollidon SR are sifted, including , on vibrating screen CISA RP200 N through a 0.5 mm sieve; weighing of raw materials, in which each item of raw materials is weighed into separate clean containers, labeled and transferred to the next stages. preparation of a 40% solution of a humidifier, in which povidone is added to the purified water with constant stirring, and stirring is carried out until the povidone is completely dissolved (with visual control), preparation of a mixture for encapsulation (diphenhydramine), including: preliminary mixing, during which diphenhydramine hydrochloride, lactose monohydrate, pregelatinized starch, aerosil are loaded into the mixer-granulator and the components are mixed until homogeneous (visual control), wet granulation, at which the entire humidifier solution is added to the mixer-granulator while stirring the mixture, with mixing until a homogeneous crumbly granulate is obtained (with visual control), drying the granulate, in which the granulate is dried in an oven (fluidized bed dryer), calibrating the granulate, in which the granulate is sifted, dusting, in which the resulting granulate and magnesium stearate are loaded into the mixer, and the components are mixed to a homogeneous state under visual control, the mixture for tableting based on Melatonin is prepared, including preliminary mixing (trituration), during which Melatonin, a part of microcrystalline cellulose (in an amount equal to the amount of Melatonin) is loaded into the mixer, and the components are mixed until a homogeneous state is visual control, main mixing, in which the remaining part of the Cellulose is loaded into the mixer and the components are mixed until homogeneous under visual control, Kollidon SR is loaded into the mixer and the components are mixed until a homogeneous state is carried out under visual control, dusting, in which the resulting mixture is loaded into the mixer, magnesium stearate and the components are mixed until homogeneous under visual control, and the tableting process is carried out.

In some preferred (non-limiting) embodiments of the invention, the premixing parameters are selected based on the volume laboratory series in 1000 capsules. Most preferably (without limitation), the following mixing parameters are used:

Bowl volume - 1,0 l.

Mixing speed - 15 rpm.

Mixing time - 2 minutes.

Also in certain preferred (non-limiting) embodiments of the invention, the mixing parameters for the wet granulation step are selected based on a laboratory batch volume of 1000 capsules. Most preferably (without limitation), the following mixing parameters are used:

Bowl volume - 1,0 l.

Mixing speed - 300 rpm.

Mixing time - 2 minutes.

The person skilled in the art can modify the above mixing parameters depending on the volume of the series.

Also in certain preferred (non-limiting) embodiments of the invention, the parameters for drying the granulate are selected, depending on the equipment used, based on the volume of a laboratory batch of 1000 capsules. Most preferably (without limitation), the following drying parameters are used:

The temperature of the incoming air is 50-60°C.

Drying time 1-3 hours

The residual moisture content of the granulate is from 1.0 to 3.0%.

Also in certain preferred (non-limiting) embodiments of the invention, during the granulate calibration step, the granulate is screened on a CIS A RP200 N Vibrating Screen through a 0.500 mm (0.710 mm) sieve, and the residues are manually rubbed through a 0.500 mm (0.710 mm) sieve.

Also, in certain preferred (non-limiting) embodiments of the invention, the mixing parameters for the dusting step are selected based on a laboratory batch volume of 1000 capsules. Most preferably (without limitation), the following mixing parameters are used:

Bowl volume - 1,0 l. Mixing speed - 15.0 rpm.

Mixing time - 3 minutes.

Also, in certain preferred (non-limiting) embodiments of the invention, the mixing parameters for the preparation of the Melatonin-based tableting mixture are selected based on a batch size of 15,000 tablets. Most preferably (without limitation), the following mixing parameters are used:

Bowl volume - 1,0 l.

Mixing speed - 15 rpm.

Mixing time - 10 minutes.

Also in some preferred (non-limiting) embodiments of the invention, the mixing parameters for the main mixing step are selected based on the volume of a laboratory batch of 15,000 tablets. Most preferably (without limitation), the following mixing parameters are used:

Bowl volume - 1,0 l.

Mixing speed - 15 rpm.

Mixing time - 10 minutes.

Also in certain preferred (non-limiting) embodiments of the invention, the mixing parameters after the addition of Kollidon SR are selected based on the volume of a laboratory batch of 15,000 tablets. Most preferably (without limitation), the following mixing parameters are used:

Bowl volume - 1,0 l.

Mixing speed - 15 rpm.

Mixing time - 10 minutes.

Also, in some preferred (non-limiting) embodiments of the invention, the mixing parameters at the dusting stage are selected based on

Bowl volume - 1,0 l.

Mixing speed - 15 rpm.

Mixing time - 3 minutes. Finally, in certain preferred (non-limiting) embodiments of the invention, tableting is carried out on a FutorqueX-1 tablet press, namely, on a press tool with a geometry of 3.00 mm, round shape.

In all of the above stages, the person skilled in the art can modify the above mixing, drying or tableting parameters depending on the batch size and the type of equipment used.

After adjusting the average weight of the tablets, the tablet press is adjusted according to the remaining indicators:

- hardness - 40-70 N;

- abrasion - no more than 0.5%;

- height - no more than 2.5 mm;

- deviations from the average weight of 20 tablets - deviations from the average weight should not exceed 10.0%.

After setting up the tablet press, the tableting process is carried out until the tableting mixtures are completely consumed. In the process of tableting, at least once every 10 minutes, the average weight of the tablets and the hardness of the tablets are monitored.

During the tableting process, the tablets are collected in labeled containers. After the end of the process, the containers are closed. Spend a representative selection of tablets for intermediate control, according to the specification.

Next, the tablet-cores are coated with a shell, which includes the process of preparing a film suspension, in the process of applying a film shell, an 18% film suspension is used. Set the mixing of purified water so that a funnel forms on the surface of the water. A dry film coating is introduced gradually, preventing the formation of agglomerates on the surface of the solution, then after that the stirring speed is reduced so that foaming does not occur, and the solution is left to mix for 45 minutes.

The coating is then carried out using, among other things, the BOSCH "Solidlabl" modular plant. Before the coating process is carried out, the tablets are heated to 37-39°C with periodic stirring in the coater drum, including the BOSCH "Solidlabl" modular unit.

When the temperature of the tablets is reached, spraying of the film suspension is started. The coating process is carried out at a product temperature of 35-40°C. In the process, the appearance of the tablets and the weight gain of the shell are controlled. The coating process is carried out until an average tablet weight of 20.80 mg ± 10.0% is obtained.

When the predetermined mass of tablets is reached, the process is stopped and the tablets are cooled to a temperature not exceeding 33 °C. After the end of the process, the containers are closed.

Then carry out a representative selection of tablets for intermediate control, according to the specification. Coated tablets are stored in closed containers.

Next, encapsulation is carried out, which is carried out in 2 stages:

At the first stage, the mixture for encapsulation (Diphenhydramine) is packed, which is carried out, among other things, on an automatic capsule unit BOSCH GKF702.

Further, the packaging of the film-coated tablets is carried out in hard gelatin capsules No. 0, filled with a mixture for encapsulation. (Diphenhydramine),

At the beginning of the process, the BOSCH GKF702 capsule unit is set up on empty capsules. Based on the results of the settings, the correct operation is checked:

- node orientation capsules;

- capsule opening unit;

- capsule rejection unit;

- capsule closing unit;

- capsule ejection unit. Capsule plant - encapsulation plant - BOSCH GKF702 is considered to be configured correctly if all nodes work correctly, with empty capsules at the exit:

- must have the correct shape without jams;

- the capsules must be closed.

After setting up the encapsulation unit, the mixture is loaded into the hopper and, among other things, the unit is set up for the production of capsules with an average weight:

- for a dosage of 25 mg + 3 mg - total weight - 266.00 mg

- for a dosage of 50 mg + 3 mg - total weight - 436.00 mg

Upon receipt of filled capsules of the required average weight, control is carried out:

- disintegration of capsules with a mixture - no more than 20 minutes;

- deviations from the average weight on 20 capsules - + 10.0% (for a dosage of 25 mg + 3 mg) and ± 7.5% (for a dosage of 50 mg + 3 mg).

After setting up the process of filling the capsules with the mixture, the film-coated tablets are packed into capsules.

During packaging, one film-coated tablet is placed in a capsule containing a mixture with Diphenhydramine.

After setting up the encapsulation machine, the tablets are loaded into the hopper and the encapsulation machine is set up to release capsules with an average weight: Including for a dosage of 25 mg + 3 mg with a total weight of 286.80 mg or, including for a dosage of 50 mg + 3 mg total weight 456.80 mg

Upon receipt of filled capsules of the required average weight, control is carried out:

- disintegration of capsules with a mixture - no more than 20 minutes;

- deviations from the average weight on 20 capsules - ± 10.0% (for a dosage of 25 mg + 3 mg) and + 7.5% (for a dosage of 50 mg + 3 mg). If the result of the intermediate control is positive, the encapsulation process is carried out until the encapsulation mixture and tablets are completely consumed. At least once every 10 minutes, control is carried out:

- average weight of filled capsules;

- the appearance of the capsules.

During the process, filled capsules are collected in labeled containers.

After the end of the process, the containers with capsules are closed. Carry out a representative selection of filled capsules for control, according to the specification.

With a positive control, the capsules are transferred to the packaging stage, which is carried out as follows:

Film-coated tablets are packed, for example, in a PVC/Alu blister on an automatic blister machine, including the DPP260ki-2.

Blister cell forming parameters:

Pressure - 6 bar;

Forming temperature - 110 - 120°С

Sealing options:

Sealing temperature - 130 - 140°С;

Pressure - 6 bar;

Speed - 18 cycles/min;

Coolant temperature - 10°С.

At the end of the process, the tightness of the blisters is checked using, among other things, the Erweka VDT/S tester. The first and last received blisters are subject to mandatory tightness control.

The developed compositions in the indicated ranges of values of the proposed pharmaceutical compositions, as well as the proposed dosage form, manufactured by the described method on the basis of the proposed compositions, provide stability and stability of properties. The resulting dosage form provides stability, storage stability and virtually no side effects. Thanks to the proposed inventions, which formed the basis of the dosage forms manufactured according to the specified method, it is possible to increase the therapeutic efficacy of the claimed composition by:

- dosage form of modified release, made on the basis of a pharmaceutical composition,

- the effective period of action of the drug based on the claimed composition,

- by simplifying the scheme of action of the dosage form used.

The above examples illustrate, but do not limit the use of these compositions and methods of the claimed inventions.

All presented inventions are industrially applicable, have passed laboratory tests, are practically implemented and will be widely used in the pharmaceutical industry, namely, it is confirmed:

- the use of the above pharmaceutical composition,

- application of the proposed dosage form,

- application of the method for obtaining the proposed dosage form.

Each of the proposed inventions is industrially applicable in the field of pharmaceuticals, ensures the stability of the claimed properties, maintaining the stability of the properties for a period of at least 3 years.

The application of the proposed inventions increases the assortment list of dosage forms.

In addition, the proposed method for obtaining a dosage form ensures the stability of the properties of the dosage form, maintaining the stability of the properties for a period of at least 3 years.

Thus, the desired technical result has been achieved by creating daily changes in locomotor activity, body temperature, biological rhythm of sleep and wakefulness and normalization of night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, intended to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness, to improve the state of intellectual-mnestic brain functions and emotional-personal state:

- a pharmaceutical composition that enhances the therapeutic activity of the claimed quantitative and qualitative composition of the ingredients due to the instantaneous the onset of action and due to the effective and long-lasting action of the composition of the ingredients,

- dosage form, through which, with the introduction of the specified pharmaceutical composition, simplification of the scheme of action of the claimed qualitative and quantitative composition of the ingredients is ensured,

- as well as a method for obtaining the indicated dosage form based on the proposed pharmaceutical composition, as well as the technical result is achieved by increasing the assortment list of pharmaceutical compositions, dosage forms intended to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, for reduction or prevention of histamine-induced spasms of smooth muscles, to reduce tissue edema, providing an improvement in the state of intellectual-mnestic functions of the brain and emotional-personal state.

INDUSTRIAL APPLICABILITY

The proposed group of inventions is industrially applicable, implemented in practice, as evidenced by the provided examples of the invention, will be widely used in pharmaceuticals, both in Russia and abroad to regulate daily changes in locomotor activity, body temperature, biological rhythm of sleep and wakefulness and normalization night sleep, to reduce or prevent spasms of smooth muscles caused by histamine, to reduce tissue edema, which improves the state of the intellectual-mnestic functions of the brain and the emotional-personal state.

INFORMATION SOURCES

1. RF patent for the invention No. 2485949 "MELATONIN TABLET AND METHODS FOR MANUFACTURING AND APPLICATION", patent holder - Pharmaceutical Productions Inc. (US), published on 06/27/2013, IPC: A61K 31/40, A61K 31/70, A61K 47/48 , A61K 47/32, A61R 25/20. 2. RF patent for the invention No. 2560840 "METHOD FOR TREATMENT OF INSOMNIA", patent holder - "NEURIM PHARMACEUTICALS (1991) LTD." (IL) published 20.08.2015, IPC: А61К 31/4045, А61К 9/22, А61К 9/52, А61Р 25/20.

3. Application for the invention of the Russian Federation No. 2015156033 "SOLID PHARMACEUTICAL DOSAGE FORM INTENDED TO RELEASE AT LEAST ONE ACTIVE PHARMACEUTICAL INGREDIENT IN THE ORAL CAVITY", applicant - "McNeil AB" (SE), published 13.07.20 17, IPC: A61C 9/ 36.

4. Patent of the Russian Federation No. 2620855 "Pharmaceutical composition for the prevention and treatment of sleep disorders", patent holder - Limited Liability Company "VALENTA-INTELLECT" (RU), published on May 30, 2017, IPC: A61K 9/48, A61K 9/20, A61K 9/16, A61K 31/4402, A61K 31/4045, A61R 25/20.

Claims

42 CLAIMS 1. Pharmaceutical composition for regulating diurnal changes in locomotor activity, body temperature, biological rhythm of sleep and wakefulness and normalization of night sleep, to reduce or prevent spasms of smooth muscles caused by histamine, to reduce tissue edema and to improve the state of intellectual-mnestic functions of the brain and emotional- a personal condition comprising diphenhydramine or a pharmaceutically acceptable salt thereof in an amount of 20 to 60 mg and melatonin in an amount of 1.5 to 6.0 mg. 2. Pharmaceutical composition for regulating diurnal changes in locomotor activity, body temperature, biological rhythm of sleep and wakefulness and normalizing night sleep, for reducing or preventing histamine-induced spasms of smooth muscles, for reducing tissue edema and for improving the state of intellectual-mnestic functions of the brain and emotional and personal state, including diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg and melatonin in an amount of 1.5 to 6.0 mg, with the following composition of ingredients, mg: Diphenhydramine or its 20.00-60.00 pharmaceutically acceptable salt Lactose monohydrate 51.67-265.83 Polyvinylpyrrolidone (Povidone) 4.00-8.25 Pregelatinized starch 3.00-6.19 Colloidal silicon dioxide 0.50-1.03 Magnesium stearate 1.00-2.06 Melatonin 1.5-6.0 Microcrystalline cellulose 10.54-47.25 Mixture of Polyvinyl acetate with 5.86-41.58 polyvinylpyrrolidone Magnesium stearate 0.19-0.21 Film coat 0.78-0.82 43 3. Pharmaceutical composition for regulating daily changes in locomotor activity, body temperature, biological rhythm of sleep and wakefulness and normalizing night sleep, to reduce or prevent spasms of smooth muscles caused by histamine, to reduce tissue edema and to improve the state of intellectual-mnestic functions of the brain and emotional personal condition, including diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg and melatonin in an amount of 1.5 to 6.0 mg, with the following composition of ingredients, wt.%: Diphenhydramine or its 4.37-20.92 pharmaceutically acceptable salt Lactose monohydrate 16.16-83.14 Polyvinylpyrrolidone 1.39-2.58 Pregelatinized starch 0.32-1.93 Colloidal silicon dioxide 0.17-0.32 Magnesium stearate 0, 35-0.64 Melatonin 0.32-24.76 Cellulose microcrystalline 3.77-16.9 Mixture of Polyvinyl acetate with 2.09-14.83 polyvinylpyrrolidone Magnesium stearate 0.07-1.01 Film shell 0.28-4.13 4. Pharmaceutical composition according to any one of paragraphs. 1-3, wherein the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride. 5. Dosage form intended to regulate diurnal changes in locomotor activity, body temperature, biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema and to improve the state of the intellectual-mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule containing powder and granules containing diphenhydramine or its pharmaceutically acceptable salt with immediate release in an amount of 20 to 60 mg and pharmaceutically acceptable 44 excipients and an extended or modified release microtablet containing 1.5 to 6.0 mg of melatonin and pharmaceutically acceptable excipients. 6. A modified-release dosage form intended to regulate diurnal changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize nocturnal sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema and to improve the state of intellectual-mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule containing powder and granules containing diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg with immediate release and pharmaceutically acceptable auxiliary components, including lactose monohydrate, polyvinylpyrrolidone, pregelatinized starch , colloidal silicon dioxide and magnesium stearate, and a prolonged release microtablet containing from 1.5 to 6.0 mg of melatonin and pharmaceutically acceptable auxiliary components, including components of the microtablet core - microcrystalline cellulose, a mixture of polyvinyl acetate with polyvinylpyrrolidone and magnesium stearate - and a film shell microtablets, with the following ratio of ingredients, wt.%: Hard gelatin capsule: Diphenhydramine or its 4.37-20.92 pharmaceutically acceptable salt Lactose monohydrate 16.16 - 83.14 Polyvinylpyrrolidone 1, 39-2.58 Pregelatinized starch 1.05-1.93 Silicon dioxide colloidal 0.17-0.32 Magnesium stearate 0.35-0.64 Microtablet: Melatonin 0.32-24.76 Cellulose microcrystalline 3.77-16.9 A mixture of polyvinyl acetate with 2.09-14.83 polyvinylpyrrolidone Magnesium stearate 0.07-1.01 Film shell 0.28-4.13 7. A modified release dosage form intended to regulate diurnal changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema and to improve the state of intellectual-mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule containing powder and granules containing diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg and pharmaceutically acceptable auxiliary components, including lactose monohydrate, polyvinylpyrrolidone (povidone), pregelatinized starch , colloidal silicon dioxide and magnesium stearate, and a microtablet containing from 1.5 to 6.0 mg of melatonin and pharmaceutically acceptable auxiliary components, including the components of the microtablet core - microcrystalline cellulose, a mixture of polyvinyl acetate with polyvinylpyrrolidone and magnesium stearate - and a microtablet film shell, with the following ratio of ingredients, mg: Hard gelatin capsule: Diphenhydramine or its 20.00-60.00 pharmaceutically acceptable salt Lactose monohydrate 51.67-265.83 Polyvinylpyrrolidone (Povidone) 4.00-8.25 Pregelatinized starch 3,00-6, 19 Silicon dioxide colloidal 0.50-1.03 Magnesium stearate 1.00-2.06; Microtablet: Melatonin 1.5-6.0 Cellulose microcrystalline 10.54-47.25 A mixture of polyvinyl acetate with 5.86-41.58 polyvinylpyrrolidone Magnesium stearate 0.19-0.21 Film shell 0.78-0.82. 8. A method for producing a modified-release dosage form designed to regulate diurnal changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, and to improve intellectual state - mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule containing powder and granules containing from 20 to 60 mg of diphenhydramine or its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary components, and a microtablet containing from 1.5 to 6, 0 mg of melatonin and pharmaceutically acceptable excipients, including components of the microtablet core and film shell of the microtablet, in which powder and granules with diphenhydramine or its pharmaceutically acceptable salt are obtained, a melatonin microtablet is obtained, the powder with granules and tablets are assembled into a hard gelatin capsule. 9. A method for producing a modified-release dosage form designed to regulate diurnal changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, and to improve intellectual state - mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule containing powder and granules containing from 20 to 60 mg of diphenhydramine or its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary components, including lactose monohydrate, polyvinylpyrrolidone, pregelatinized starch, silicon dioxide colloidal and magnesium stearate, and a microtablet containing from 1.5 to 6.0 mg of melatonin and pharmaceutically acceptable auxiliary components, including the components of the microtablet core - microcrystalline cellulose, a mixture of polyvinyl acetate with polyvinylpyrrolidone and magnesium stearate - and a microtablet film shell, in which a powder is obtained and granules with diphenhydramine or a pharmaceutically acceptable salt thereof, a melatonin microtablet is obtained, the powder is formulated with 47 granules and tablets into a hard gelatin capsule by any available method, the above granules and microtablets are packaged, the quantitative and qualitative criteria for the composition of a modified release hard gelatin capsule containing powder and granules containing from 20 to 60 mg of diphenhydramine or its pharmaceutically acceptable salt are used for packaging and pharmaceutically acceptable excipients, including lactose monohydrate, polyvinylpyrrolidone, pregelatinized starch, colloidal silicon dioxide and magnesium stearate, and a microtablet containing from 1.5 to 6.0 mg of melatonin and pharmaceutically acceptable excipients, including components of the microtablet core - microcrystalline cellulose, a mixture polyvinyl acetate with polyvinylpyrrolidone and magnesium stearate - and a film shell of a microtablet, in the following ratio of ingredients, wt.%: Hard gelatin capsule: Diphenhydramine or its 4.37-20.92 pharmaceutically acceptable salt Lactose monohydrate 16.16 - 83.14 Polyvinylpyrrolidone 1.39-2.58 Pregelatinized starch 0.32-1.93 Silicon dioxide colloidal 0.17-0.32 Magnesium stearate 0.35-0.64; Microtablet: Melatonin 0.32-24.76 Cellulose microcrystalline 3.77-16.9 A mixture of polyvinyl acetate with 2.09-14.83 polyvinylpyrrolidone Magnesium stearate 0.07-1.01 Film shell 0.28-4.13. 10. A method for producing a dosage form intended to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema and 48 to improve the state of the intellectual-mnestic functions of the brain and the emotional and personal state, which is a hard gelatin capsule containing powder and granules containing from 20 to 60 mg of diphenhydramine or its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary components, and a microtablet containing from 1.5 up to 6.0 mg of melatonin and pharmaceutically acceptable auxiliary components, including the components of the microtablet core - microcrystalline cellulose, a mixture of polyvinyl acetate with polyvinylpyrrolidone and magnesium stearate - and a microtablet film shell, in which powder and granules with diphenhydramine hydrochloride are obtained, a melatonin microtablet is obtained, the powder is combined with granules and tablets into a hard gelatin capsule by any available method, the above-described granules and microtablets are packaged, using quantitative and qualitative criteria for the composition of a modified-release hard gelatin capsule containing powder and granules containing from 20 to 60 mg of diphenhydramine or its pharmaceutically acceptable salt and the specified pharmaceutically acceptable auxiliary components, and a microtablet containing from 1.5 to 6.0 mg of melatonin and the indicated pharmaceutically acceptable auxiliary components, in the following ratio of ingredients, mg: Hard gelatin capsule: Diphenhydramine or its 20.00-60.00 pharmaceutically acceptable salt Lactose monohydrate 51.67-265.83 Polyvinylpyrrolidone (Povidone) 4.00-8.25 Pregelatinized starch 3,00-6, 19 Silicon dioxide colloidal 0.50-1.03 Magnesium stearate 1.00-2.06 Microtablet: Melatonin 1.5-6.0 Cellulose microcrystalline 10.54-47.25 A mixture of polyvinyl acetate with 5.86-41.58 polyvinylpyrrolidone Magnesium stearate 0.19-0.21 Film casing 0.78-0.82 11. A dosage form intended to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent spasms of smooth muscles caused by histamine, to reduce tissue edema, providing an improvement in the state of intellectual-mnestic functions of the brain and emotional state, which is a hard gelatin capsule with diphenhydramine or its pharmaceutically acceptable salt in the amount of 25 mg and melatonin in the amount of 3 mg per modified-release capsule, in which the mixture for encapsulation in the form of granules containing diphenhydramine or its pharmaceutical substance as a pharmaceutical substance acceptable salt, as a filler - lactose monohydrate, as a binder - polyvinylpyrrolidone, as a disintegrant - pregelatinized starch, as a glidant - colloidal silicon dioxide, as a lubricant - magnesium stearate, and coated tablets containing as a pharmaceutical substance melatonin, as a filler - microcrystalline cellulose, a component that has a modified effect, the composition of which contains polyvinyl acetate (May 80. %), povidone (19 wt. %), sodium lauryl sulfate (0.8 wt. %), silicon dioxide (0.2 wt. %), as a lubricant - magnesium stearate, film coating, including components such as hypromellose, iron oxide yellow, lactose monohydrate, triacetin, in the following ratio of ingredients per 1 capsule, wt.%: Granules: Diphenhydramine or its pharmaceutically acceptable salt 8.72 Lactose monohydrate 47.59 Polyvinylpyrrolidone 1.39 Pregelatinized starch 1.05 Silicon dioxide colloidal 0.17 Magnesium stearate 0.35; Coated tablets: Melatonin 1.05 Cellulose microcrystalline 3.77 50 Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium 2.09 lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%) Magnesium stearate 0.07 Film coating (hypromellose, iron oxide yellow, lactose 0.28 monohydrate, triacetin) 12. A dosage form intended to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, and to improve the state of the intellectual-mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule with a modified release of diphenhydramine or its pharmaceutically acceptable salt in the amount of 25 mg and melatonin in the amount of 3 mg per capsule, in which the mixture for encapsulation in the form of granules containing diphenhydramine or its pharmaceutically acceptable salt, lactose monohydrate as a filler, polyvinylpyrrolidone as a binder, pregelatinized starch as a disintegrant, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, and coated tablets containing as pharmaceutical substance melatonin, as a filler - microcrystalline cellulose, a component that has a modified effect, containing polyvinyl acetate (May 80. %), povidone (19 wt. %), sodium lauryl sulfate (0.8 wt. %) and silicon dioxide (0.2 wt. %), as a lubricant - magnesium stearate, film coating, including components such as hypromellose, iron oxide yellow, lactose monohydrate, triacetin, with the following ratio of ingredients per 1 capsule, mg: Granules: Diphenhydramine or its pharmaceutically acceptable salt 25.00 Lactose monohydrate 136.50 Polyvinylpyrrolidone 4.00 Pregelatinized starch 3.00 Silicon dioxide colloidal 0.50 51 Magnesium stearate 1.00 Coated tablets: Melatonin 3.00 Cellulose microcrystalline 10.80 Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium lauryl sulfate 6.00 (0.8 wt.%), silicon dioxide (0.2 wt.%) Magnesium stearate 0.20 Film coating (Hypromellose, Iron oxide yellow, Lactose 0.80 monohydrate, Triacetin) 13. Dosage form intended to regulate diurnal changes in locomotor activity, body temperature, biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, and to improve the state of the intellectual-mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule with a modified release of diphenhydramine or its pharmaceutically acceptable salt in the amount of 50 mg and melatonin in the amount of 3 mg per capsule, in which the mixture for encapsulation in the form of granules containing diphenhydramine or its pharmaceutically acceptable salt, lactose monohydrate as a filler, polyvinyl pyrrolidone as a binder, pregelatinized starch as a disintegrant, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, and coated tablets containing melatonin as a pharmaceutical substance, microcrystalline cellulose as a filler, a component that has a modified effect, containing polyvinyl acetate (May 80. %), povidone (19 wt. %), sodium lauryl sulfate (0.8 wt. %), silicon dioxide (0.2 wt. %), magnesium stearate as a lubricant, film coating, including components such as hypromellose, iron oxide yellow, lactose monohydrate, triacetin, in the following ratio of ingredients per 1 capsule, wt.%: Granules: Diphenhydramine or its pharmaceutically acceptable salt 10.95 52 Lactose monohydrate 59.76 Paul ivinylpyrrole idone 1.75 Pregelatinized starch 1.31 Silicon dioxide colloidal 0.22 Magnesium stearate 0.44 Coated tablets: Melatonin 0.66 Cellulose microcrystalline 2.36 Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium 1.31 lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%) Magnesium stearate 0.04 Film shell (Hypromellose, Iron oxide yellow, 0.18 Lactose monohydrate, Triacetin) 14. A dosage form intended to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema and to improve the state of the intellectual-mnestic functions of the brain and emotional and personal state, which is a hard gelatin capsule with a modified release of active substances, containing as active substances diphenhydramine or its pharmaceutically acceptable salt in an amount of 50 mg and melatonin in an amount of 3 mg per capsule, in which the mixture for encapsulation in the form of granules, containing diphenhydramine or its pharmaceutically acceptable salt as a pharmaceutical substance, lactose monohydrate as a filler, polyvinylpyrrolidone as a binder, pregelatinized starch as a disintegrant, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, and tablets coated, containing melatonin as a pharmaceutical substance, microcrystalline cellulose as a filler, a component that has a modified effect, containing polyvinyl acetate (May 80. %), povidone (19 wt. %), sodium lauryl sulfate (0.8 wt. %), silicon dioxide (0.2 wt. %), as a lubricant - magnesium stearate, film coating, including components such as hypromellose, iron oxide yellow, 53 lactose monohydrate, triacetin, with the following ratio of ingredients per 1 capsule, mg: Granules: Diphenhydramine or its pharmaceutically acceptable salt 50.00 Lactose monohydrate 273.00 Polyvinylpyrrolidone 8.00 Pregelatinized starch 6.00 Silicon dioxide colloidal 1.00 Magnesium stearate 2.00 Coated tablets: Melatonin 3.00 Cellulose microcrystalline 10.80 Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium lauryl sulfate 6.00 (0.8 wt.%), silicon dioxide (0.2 wt.%) Magnesium stearate 0.20 Film shell (Hypromellose, Iron oxide yellow, 0.80 Lactose monohydrate, Triacetin) 15. Dosage form according to any one of paragraphs. 5-7 and 11-14, characterized in that the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride. 16. The use of a pharmaceutical composition according to any one of paragraphs. 1-3 to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema, and to improve the state of intellectual and mnestic functions of the brain and emotional personal state. 17. The use of the dosage form according to any one of paragraphs. 5-7 and 11-14 to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce 54 or prevention of histamine-induced spasms of smooth muscles, to reduce tissue edema and to improve the state of intellectual-mnestic functions of the brain and emotional-personal state. 18. The use of a method for obtaining a dosage form according to any one of paragraphs. 8-10 to regulate daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalize night sleep, to reduce or prevent spasms of smooth muscles caused by histamine, to reduce tissue edema and to improve the state of the intellectual-mnestic functions of the brain and emotional-personal states.