RU2818092C1 - Pharmaceutical composition comprising melatonin and diphenhydramine or pharmaceutically acceptable salt thereof, dosage form based on pharmaceutical composition comprising melatonin and diphenhydramine or pharmaceutically acceptable salt thereof, method for preparing and using dosage form based on pharmaceutical composition containing melatonin and diphenhydramine or pharmaceutically acceptable salt thereof - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: declared group of inventions relates to pharmaceutics and discloses a dosage form intended for regulating the biological rhythm of sleep and wakefulness and normalizing nocturnal sleep, which is a solid gelatinous capsule containing powder and granules containing diphenhydramine or a pharmaceutically acceptable salt thereof with immediate release in amount of 20 to 60 mg and pharmaceutically acceptable auxiliary components, and a prolonged release microtablet containing 1.5 to 6.0 mg of prolonged release melatonin and pharmaceutically acceptable adjuvants (embodiments). Also disclosed is a method of producing a modified release dosage form for regulating the biological rhythm of sleep and wakefulness and normalizing nocturnal sleep (embodiments), and the use of the dosage form for regulating the biological rhythm of sleep and wakefulness and normalizing night sleep.

EFFECT: technical result consists in increasing the therapeutic activity of the claimed quantitative and qualitative composition of the ingredients, simplifying the scheme of action on daily rhythms of sleep and wakefulness, as well as in relieving symptoms of episodic and acute insomnia and expanding the range of drugs intended for regulating the biological rhythm of sleep and wakefulness and normalizing night sleep.

10 cl, 6 tbl

Description

APPLICATION AREA

The proposed 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 obtaining and using such compositions and dosage forms, used mainly to regulate the circadian rhythms of sleep and wakefulness, as well as to alleviate symptoms of episodic and acute insomnia.

BACKGROUND OF THE ART

A current direction in pharmaceuticals is the creation of effective dosage forms used primarily to regulate the circadian rhythms of sleep and wakefulness and to alleviate the symptoms of episodic and acute insomnia.

Thus, various pharmaceutical compositions and medications 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 are disrupted, 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, sometimes a sleeping pill is used - Melatonin, which is a fairly common drug. Melatonin is intended for people with the following problems: insomnia of various natures. 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 and get rid of periodic disturbances in the circadian rhythms of sleep and wakefulness. The drug helps to adapt and controls biorhythms, and in case of nervous overstrain, this drug helps to inhibit the processes of the nervous system, giving relaxation.

Melatonin, or N-[2-(5-methoxy-1H-indol-3-yl)ethyl]ethanamide, or N-acetyl-5-methoxytryptamine, is a substance with antioxidant, adaptogenic, and hypnotic effects. Inhibits the secretion of gonadotropins, and 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 pyridoxal kinase involved in the synthesis of GABA, dopamine and serotonin. Regulates the sleep-wake cycle, daily changes in locomotor activity and body temperature, has a positive effect on the intellectual and mnestic functions of the brain, the emotional and personal sphere. Helps organize the biological rhythm of sleep and wakefulness and normalize night sleep.

Diphenhydramine (Diphenhydramine), or 2-(diphenylmethoxy)-N,N-dimethylethanamine, is an antiallergic, local anesthetic, antihistamine, antiemetic, anticholinergic, hypnotic, sedative. Blocks histamine _H1 receptors and eliminates the effects of histamine mediated through this type of receptor. Reduces or prevents histamine-induced smooth muscle spasms, increased capillary permeability, tissue swelling, itching and hyperemia; suppresses the cough reflex by directly acting on the cough center in the medulla oblongata

It is known, for example, the invention [1] according to RF patent No. 2485949 (published on June 27, 2013). which discloses a solid dosage form for sublingual or buccal administration of a hormone, having low to insufficient solubility in water, 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, where the specified hormone is presented in a dissolved state in the final dosage form.

The patent [1] also discloses:

- a method for manufacturing a pharmaceutical composition according to claim 1, including the stages of dissolving the specified 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 the specified solution on the carrier particles, adsorption or absorption of the specified solution onto carrier particles;

- a method of providing a patient with hormonal therapy, including manufacturing a dosage form according to claim 1 and administering said dosage form sublingually or buccally to a patient in need of said therapy.

The solid dosage form according to the patent [1] provides rapid (over a period of time not exceeding 15 minutes) release of melatonin and rapid provision of a therapeutic effect. However, in some cases, a slow (prolonged) release of melatonin from the dosage form may be necessary.

In addition, an invention is known [2] under RF patent No. 2560840 (published on August 20, 2015) relating to the use of melatonin orally in a sustained-release composition in the production of a medicinal product 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 covers 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 composition, and at least one pharmaceutically acceptable diluent, preservative, antioxidant, solvent, emulsifier, adjuvant or carrier in which melatonin is the only therapeutically active agent in the drug.

In some cases, however, it turns out to be necessary to combine melatonin with other therapeutically active substances 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 said core contains at least one active pharmaceutical ingredient, with organoleptically unpleasant sensations caused by one or more active pharmaceutical ingredients or one or more inactive components of the solid pharmaceutical dosage form, are weakened by the content of components providing said film coating, these components containing at least one film-forming polymer and at least one flavoring agent or at least one sweetener and do not contain nicotine (RF application for invention No. 2015156033, published on July 13, 2017, hereinafter referred to as [3]). 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 is in some cases 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 natures, characterized by the fact 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 an amount of 0.1-20 mg (RF patent for invention No. 2620855, published May 30, 2017 [4]).

The pharmaceutical composition [4] contains doxylamine succinate, which is a prescription drug, as one of the active ingredients, which limits the availability of such a pharmaceutical composition for patients suffering from sleep disorders of various natures. Given the presence of a varying number of drugs using melatonin on the global pharmaceutical market, however, there was a need to create a pharmaceutical composition and offer such a dosage form based on the created pharmaceutical composition that would increase the therapeutic activity of the declared quantitative and qualitative composition of ingredients, effective when administered in the declared 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, increasing the therapeutic activity of the claimed quantitative and qualitative composition of ingredients due to the immediate onset of action and subsequent effective and long-lasting action of the pharmaceutical composition and dosage form, and secondly, simplifying the scheme of action on circadian rhythms of sleep and wakefulness, as well as relief of symptoms of episodic and acute insomnia, and thirdly, expansion of the range of medications designed to regulate daily changes in locomotor activity, body temperature, biological rhythm of sleep and wakefulness and normalization of night sleep, as well as to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue swelling, providing an improvement in the intellectual and mnestic functions of the brain and the emotional and personal state.

Technical results are achieved in the present invention by providing:

- a pharmaceutical composition that would increase the therapeutic activity of the stated quantitative and qualitative composition of ingredients due to the immediate onset of action and due to the effective and prolonged action of the composition of ingredients,

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

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

DISCLOSURE OF INVENTION

The technical result of the present invention is achieved due to the proposed in the present inventionpharmaceutical composition, 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 swelling, providing an improvement in the state of the intellectual and mnestic functions of the brain and the emotional and personal state , including 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, anddosage form made on the basis of the above pharmaceutical composition, which is a modified-release hard gelatin capsule containing diphenhydramine powder or a pharmaceutically acceptable salt thereof and immediate-release diphenhydramine granules or a pharmaceutically acceptable salt thereof in an amount of from 20 to 60 mg and a tablet (microtablet) containing from 1.5 to 6.0 mg extended release melatonin. Also the technical result is achieved due to what is proposed in the present inventionmethod for producing a dosage form made on the basis of the above pharmaceutical composition, where the specified method includes obtaining granules and powder of diphenhydramine or its pharmaceutically acceptable salt in an amount from 20 to 60 mg and obtaining microtablets of melatonin in an amount from 1.5 to 6.0 mg, placing these active ingredients in a hard gelatin capsule with a 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 tartrate ata 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 diphenhydramine salts is provided for illustrative purposes and is non-limiting. One skilled in the art will appreciate that other pharmaceutically acceptable diphenhydramine salts not expressly listed herein may also be used for the purposes of the present invention.

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 stated quantitative and qualitative composition of 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 swelling, providing improvement in the intellectual and mnestic functions of the brain and the 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 auxiliary components.

The content of diphenhydramine powder and granules or its pharmaceutically acceptable salt in one capsule ranges from 20 to 60 mg. The percentage of diphenhydramine or a pharmaceutically acceptable salt thereof in said capsule ranges from 4.37 to 20.92 wt. %. The composition of 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 lactose monohydrate content 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 colloidal silica content is 0.97 mg (0.30 wt%); the preferred magnesium stearate content is 1.94 mg (0.59 wt.%).

Examples of compositions (powder and granules) of diphenhydramine hydrochloride per capsule, wt. % are presented in Table 2. Capsules contain from 20 to 60 mg of diphenhydramine hydrochloride (as a percentage, from 4.37 to 20.92 wt. wt.%). The quantities of auxiliary components are given 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 colloidal silica content is 0.97 mg (0.30 wt%); the preferred magnesium stearate content is 1.94 mg (0.59 wt.%).

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

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

Table 1. Composition of diphenhydramine hydrochloride powder and granules per capsule (embodiment I)

Name of components Content in wt. % Content in mg/capsule Diphenhydramine hydrochloride 4.37-20.92 20.00-60.00 Lactose monohydrate 16.16 -83.14 51.67- 265.83 Polyvinylpyrrolidone (Povidone) 1.39-2.58 4.00-8.25 Pregelatinized starch 1.05-1.93 3.00-6.19 Silicon dioxide colloidal 0.17-0.32 0.50-1.03 Magnesium stearate 0.35-0.64 1.00-2.06

Table 2. Examples of the composition of diphenhydramine hydrochloride powder and granules per capsule (embodiment II)

Name of components Content in wt. % Content in mg/capsule Diphenhydramine hydrochloride 4.37 -20.92 20.00-60.00 Lactose monohydrate 16.16 -83.14 51.67-265.83 Polyvinylpyrrolidone (Povidone) 1.39-2.58 4.00-8.25 Pregelatinized starch 1.05-1.93 3.00-6.19 Silicon dioxide colloidal 0.17-0.32 0.50-1.03 Magnesium stearate 0.35-0.64 1.00-2.06

Table 3. Composition of melatonin microtablets per capsule (embodiment III)

Name of components Content in wt. % Content in mg/capsule Melatonin 0.32-24.76 1.5-6.0 Microcrystalline cellulose 3.77-16.9 10.54-47.25 A mixture of polyvinyl acetate and polyvinylpyrrolidone 2.09-14.83 5.86-41.58 Magnesium stearate 0.07-1.01 0.19-0.21 Film casing 0.28-4.13 0.78-0.82

Table 4. Composition of melatonin microtablets per capsule (embodiment IV)

Name of components Content in wt. % Content in mg/capsule Melatonin 0.32-24.76 1.5-6.0 Microcrystalline cellulose 3.77-16.9 10.54-47.25 A mixture of polyvinyl acetate and polyvinylpyrrolidone 2.09-14.83 5.86-41.58 Magnesium stearate 0.07-1.01 0.19-0.21 Film casing 0.28-4.13 0.78-0.82

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 stated quantitative and qualitative composition of 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 histamine-induced spasms smooth muscles, to reduce tissue swelling, and also provide improvement in the intellectual and mnestic functions of the brain and the 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 a pharmaceutically acceptable salt thereof 20.00-60.00 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 Microcrystalline cellulose 10.54-47.25 A mixture of polyvinyl acetate and polyvinylpyrrolidone 5.86-41.58 Magnesium stearate 0.19-0.21 Film casing 0.78-0.82

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

Also preferably (without limitation), the ratio of polyvinylpyrrolidone to polyvinyl acetate (w/w) in the mixture of polyvinylpyrrolidone and polyvinyl acetate is 80.81/19.19.

Also, the specified technical results are achieved by the pharmaceutical composition proposed in the present invention , which provides an increase in the therapeutic activity of the declared quantitative and qualitative composition of 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 swelling, as well as providing an improvement in the intellectual and mnestic functions of the brain and the 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 a pharmaceutically acceptable salt thereof 4.37-20.92 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 Microcrystalline cellulose 3.77-16.9 A mixture of polyvinyl acetate and polyvinylpyrrolidone 2.09-14.83 Magnesium stearate 0.07-1.01 Film casing 0.28-4.13

Preferably (without limitation), in this embodiment, the pharmaceutically acceptable salt of diphenhydramine 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 tartrate ata 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 acceptable diphenhydramine salts known to one skilled in the art.

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

The content of diphenhydramine hydrochloride powder and granules in one capsule ranges from 20 to 60 mg. The percentage of diphenhydramine hydrochloride in the specified pharmaceutical composition is 4.37 - 20.92 wt. %. The composition according to this embodiment of the invention is presented in Table 1.

Another particular embodiment of the invention, characterized by a percentage of diphenhydramine hydrochloride of 4.37-20.92 wt. % and diphenhydramine hydrochloride content (mg) ranging from 20 to 60 mg are presented in Table 2.

A third particular embodiment of the invention, characterized by a melatonin content per capsule of 1.5 to 6.0 mg and a melatonin percentage of 0.32 to 24.76 wt. %, presented in Table 3.

A fourth particular embodiment of the invention, characterized by a melatonin content per capsule in the range of 1.5-6.0 mg and a melatonin percentage of 0.32-24.76 wt. %, 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 intended for regulating daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalizing night sleep, to reduce or prevent histamine-induced smooth muscle spasms , to reduce swelling of tissues that provide improvement in the intellectual and mnestic functions of the brain and the emotional and personal state, which is a hard gelatin capsule with a modified release 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, polyvinypyrrolidone, 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 polyvinypyrrolidone, magnesium stearate and film shell, with the following ratio of ingredients, wt.%:

Diphenhydramine or a pharmaceutically acceptable salt thereof 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 Microcrystalline cellulose 3.77-16.9 A mixture of polyvinyl acetate and polyvinylpyrrolidone 2.09-14.83 Magnesium stearate 0.07-1.01 Film casing 0.28-4.13

Preferably (without limitation), in this embodiment, the pharmaceutically acceptable salt of diphenhydramine 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 tartrate ata 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 acceptable diphenhydramine salts known to one skilled in the art.

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

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

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

In addition, the above technical results are also achieved by the dosage form proposed in the present invention , intended for regulating daily changes in locomotor activity, body temperature, biological rhythm of sleep and wakefulness and normalizing night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema , providing improvement in the state of 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 from 1.5 to 6.0 mg, with the following ratio of ingredients, mg:

Diphenhydramine or a pharmaceutically acceptable salt thereof 20.00-60.00 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 Microcrystalline cellulose 10.54-47.25 A mixture of polyvinyl acetate and polyvinylpyrrolidone 5.86-41.58 Magnesium stearate 0.19-0.21 Film casing 0.78-0.82

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

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

An illustrative (non-limiting) example of a powder and granule formulation containing 20-60 mg (4.37-20.92 wt%) of diphenhydramine or a pharmaceutically acceptable hydrochloride salt thereof per capsule according to this embodiment is shown in Table 1.

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

An illustrative (non-limiting) example of a microtablet formulation containing 1.5-6.0 mg (0.32-24.76 wt%) 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 a microtablet formulation 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 is proposed for obtaining a dosage form with a modified release of the active substance, intended 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 swelling, providing improvement in the intellectual and mnestic functions of the brain and the emotional and personal state, in which granules with diphenhydramine or its pharmaceutically acceptable salt are obtained, a melatonin microtablet is obtained, the granules and tablets are assembled into a hard gelatin capsule containing powder and granules with diphenhydramine hydrochloride from 20 to 60 mg and melatonin microtablets from 1.5 to 6.0 mg, the components obtained by any available method are packaged, 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 wherein said powder and said granules contain diphenhydramine or a pharmaceutically acceptable salt thereof as an active substance 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 a 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 humidifier solution consisting mainly of polyvinylpyrrolidone. Use its concentration in solution in the range of 20-45 wt. %.

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

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

- stirring speed from 10 to 55 rpm,

- mixing time 1-15 minutes.

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

Wherein:

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

- mixing/mixing time ranges from 2 to 8 minutes.

After this, reduce the speed of the mixer to 10-30 rpm and add magnesium stearate 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 producing melatonin tablets, melatonin and 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 homogeneous, subject, as a rule, to the following conditions:

- mixing speed from 10 to 55 rpm

- and mixing time 1-15 minutes.

Then add the remaining microcrystalline cellulose and continue stirring under the same conditions for another 10 to 20 minutes.

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

- stirring speed from 10 to 55 rpm,

- mixing time 1-15 minutes.

Next, reduce the speed of the mixer to 10-30 rpm and add magnesium stearate to the mixer to carry out the process of powdering the mixture.

Continue stirring for another 2-6 minutes.

The resulting mixture is pressed 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.

The coating is applied in devices operating on the principle of a fluidized bed at an application temperature of 27 to 37°C.

The resulting granules and microtablets are packaged into hard gelatin capsules.

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

Examples of diphenhydramine hydrochloride powder and granules per capsule - in the range of 20-60 mg, and its percentage: 4.37-20.92 wt. % 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 content is 0.32-24.76 wt. % 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 percentage content: 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 for regulating daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalizing night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue edema , providing improvement in the state of intellectual and 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 microtablet of melatonin from 1.5 to 6.0 mg, from which the powder is obtained and granules with diphenhydramine hydrochloride, obtain a microtablet of melatonin, arrange the granules and tablets 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, among other things, in any available way, the above-described granules and microtablets are packaged, quantitative and qualitative criteria for the composition of a hard gelatin capsule containing granules with diphenhydramine hydrochloride from 20 to 60 mg and a melatonin microtablet from 1.5 to 6.0 mg are used for packaging, with the following ratio of ingredients, wt . %:

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 Microcrystalline cellulose 3.77-16.9 A mixture of polyvinyl acetate and polyvinylpyrrolidone 2.09-14.83 Magnesium stearate 0.07-1.01 Film casing 0.28-4.13

An illustrative (non-limiting) example of a powder and granule formulation containing 20 to 60 mg (4.37 to 20.92 wt%) of diphenhydramine or a pharmaceutically acceptable hydrochloride salt thereof per capsule according to this embodiment is shown in Table 1.

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

An illustrative (non-limiting) example of a microtablet formulation containing 1.5 - 6.0 mg (0.32 - 24.76 wt%) 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 a microtablet formulation 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.

In addition, a method has been proposed for obtaining a dosage form intended for regulating daily changes in locomotor activity, body temperature, the biological rhythm of sleep and wakefulness and normalizing night sleep, to reduce or prevent histamine-induced spasms of smooth muscles, to reduce tissue swelling, providing improvement in intellectual and mental health. 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 microtablet of melatonin from 1.5 to 6.0 mg, the granules and tablets are assembled into a hard gelatin capsule and packaged , quantitative and qualitative criteria for the composition of a hard gelatin capsule are used for packaging, 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 Silicon dioxide colloidal 0.50-1.03 Magnesium stearate 1.00-2.06 Melatonin 1.5-6.0 Microcrystalline cellulose 10.54-47.25 A mixture of polyvinyl acetate and polyvinylpyrrolidone 5.86-41.58 Magnesium stearate 0.19-0.21 Film casing 0.78-0.82

The composition of diphenhydramine hydrochloride powder and granules per capsule is in the range of 20-60 mg, and its percentage is 4.37 - 20.92 wt. % 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 wt. % 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 content is 0.32-24.76 wt. % 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 percentage content: 0.32-24.76 wt. % in the specified pharmaceutical composition is presented in Table 4.

The technical result is also achieved by the fact that a modified release dosage form is proposed , designed to regulate daily 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, providing improvement in the state of intellectual-mnestic functions of the brain and emotional-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 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 component, a disintegrant, a glidant and a lubricant. Preferably (without limitation), the filler is lactose monohydrate. Also preferably (without limitation), the binder component is polyvinylpyrrolidone, the disintegrant is pregelatinized starch, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate. It will be appreciated by one skilled in the art that in alternative embodiments of the invention, other fillers, binders, disintegrants, glidants and lubricants used in the art may also be used. For example, starch, glucose, sucrose, lactose (milk sugar), basic magnesium carbonate, magnesium oxide, sodium chloride, sodium bicarbonate, gelatin, methylcellulose (MC), sodium salt of carboxymethylcellulose (Na CMC), calcium carbonate, can be used as a filler. disubstituted calcium phosphate, glycine, dextrin, amylopectin, ultraamylopectin, sorbitol, mannitol, pectin; Purified water, ethyl alcohol, starch paste, sugar syrup, solutions of carboxymethylcellulose (CMC), oxyethylcellulose (OEC), hydroxypropylmethylcellulose (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 wt. %, povidone - 19 wt. %, sodium lauryl sulfate - 0.8 wt. %, silicon dioxide as a lubricant - 0.2 wt. % magnesium stearate, film shell, including hypromellose, yellow iron oxide, lactose monohydrate and triacetin, with 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 Microcrystalline cellulose 3.77 Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%) 2.09 Magnesium stearate 0.07 Film coating (Hypromellose, Yellow iron oxide, Lactose monohydrate, Triacetin) 0.28

The technical result in the present invention is also achieved by the fact that a modified release dosage form is proposed, designed to regulate daily 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 swelling of tissues, providing an improvement in the intellectual and mnestic functions of the brain and the 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 extended 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, microcrystalline cellulose as a filler, a component that has a prolonged or modified effect, the composition of which contains: polyvinyl acetate - 80 wt. %, povidone - 19 wt. %, sodium lauryl sulfate - 0.8 wt. %, silicon dioxide - 0.2 wt. %, as a lubricant - magnesium stearate, film shell, including hypromellose, yellow iron oxide, 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 Microcrystalline cellulose 10.80 Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%) 6.00 Magnesium stearate 0.20 Film coating (Hypromellose, Yellow iron oxide, Lactose monohydrate, Triacetin) 0.80

Examples of modified-release hard gelatin capsule formulations containing diphenhydramine or a pharmaceutically acceptable salt thereof at 25 mg and melatonin at 3 mg 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)

Name of components Content in % Content in mg/drop Purpose Diphenhydramine (encapsulation mixture) Diphenhydramine hydrochloride 8.72 25.00 Pharmaceutical substance Lactose monohydrate 47.59 136.50 Filler Polyvinylpyrrolidone 1.39 4.00 Binder Pregelatinized starch 1.05 3.00 Disintegrant Silicon dioxide colloidal 0.17 0.50 Glidant Magnesium stearate 0.35 1.00 Lubricant Total mixtures for encapsulation: 170.00 - Melatonin (film-coated tablets) Melatonin 1.05 3.00 Pharmaceutical substance Microcrystalline cellulose 3.77 10.80 Filler polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%) 2.09 6.00 Matrix agent Magnesium stearate 0.07 0.20 Lubricant Film coating (Hypromellose, Yellow iron oxide, Lactose monohydrate, Triacetin) 0.28 0.80 Shell Total mass of film-coated tablet: 20.80 - Hard gelatin capsule No. 0 transparent/transparent 33.47 96.00 Capsule Total mass of the filled capsule: 286.80 -

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 are proposed, 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 caused histamine spasms of smooth muscles, to reduce tissue swelling, providing improvement in the intellectual and mnestic functions of the brain and the emotional and personal state, which is a hard gelatin capsule with a modified release, containing diphenhydramine or its pharmaceutically acceptable salt as active substances in an amount of 25 mg with immediate release and melatonin in an amount of 3 mg with prolonged release per capsule , as well as auxiliary components, including a filler, a disintegrant, a glidant and a lubricant, and the specified dosage form contains lactose monohydrate as a filler, polyvinylpyrrolidone as a binder, and polyvinylpyrrolidone as a disintegrant. pregelatinized starch, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, and film-coated tablets containing melatonin as a pharmaceutical substance, microcrystalline cellulose as a filler, a component with a prolonged or modified effect, containing: polyvinyl acetate - 80 wt. %, povidone - 19 wt. %, sodium lauryl sulfate - 0.8 wt. %, silicon dioxide - 0.2 wt. %, as a lubricant - magnesium stearate, film shell, including hypromellose, yellow iron oxide, lactose monohydrate and triacetin, with the following ratio of ingredients per 1 capsule, wt.%:

Diphenhydramine hydrochloride 10.95 Lactose monohydrate 59.76 Polyvinylpyrrolidone 1.75 Pregelatinized starch 1.31 Silicon dioxide colloidal 0.22 Magnesium stearate 0.44 Melatonin 0.66 Microcrystalline cellulose 2.36 Polyvinyl acetate - 80 wt. %, povidone - 19 wt.%, sodium lauryl sulfate - 0.8 wt.%, silicon dioxide - 0.2 wt.% 1.31 Magnesium stearate 0.04 Film coating (Hypromellose, Yellow iron oxide, Lactose monohydrate, Triacetin) 0.18

The technical result in the present invention is also achieved by the fact that a dosage form is proposed, intended to regulate 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, providing an improvement in the intellectual and mnestic functions of the brain and the 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 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, glidant - colloidal silicon dioxide, magnesium stearate as a lubricant, and film-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, yellow iron oxide, lactose monohydrate and triacetin, with 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 Microcrystalline cellulose 10.80 Polyvinyl acetate 80%, povidone 19%, sodium lauryl sulfate 0.8%, silicon dioxide 0.2% 6.00 Magnesium stearate 0.20 Film coating (Hypromellose, Yellow iron oxide, Lactose monohydrate, Triacetin) 0.80

Examples of modified release hard gelatin capsule formulations including diphenhydramine hydrochloride (50 mg) and melatonin (3 mg) are shown in Table 6.

Table 6. Composition of hard gelatin capsules with modified release of active substances containing diphenhydramine hydrochloride (50 mg per capsule) and melatonin (3 mg per capsule).

Name of components Content in % Content in mg/drop Purpose Diphenhydramine (encapsulation mixture) Diphenhydramine hydrochloride 10.95 50.00 Pharmaceutical substance Lactose monohydrate 59.76 273.00 Filler Polyvinylpyrrolidone 1.75 8.00 Binder Pregelatinized starch 1.31 6.00 Disintegrant Silicon dioxide colloidal 0.22 1.00 Glidant Magnesium stearate 0.44 2.00 Lubricant Total mixtures for encapsulation: 340.00 - Melatonin (film-coated tablets) Melatonin 0.66 3.00 Pharmaceutical substance Microcrystalline cellulose 2.36 10.80 Filler Polyvinyl acetate 80%, povidone 19%, sodium lauryl sulfate 0.8%, silicon dioxide 0.2% 1.31 6.00 Matrix agent Magnesium stearate 0.04 0.20 Lubricant Film coating (Hypromellose, Yellow iron oxide, Lactose monohydrate, Triacetin) 0.18 0.80 Shell Total mass of film-coated tablet: 20.80 - Hard gelatin capsule No. 0 transparent/transparent 21.02 96.00 Capsule Total mass of the filled capsule: 456.80 -

A detailed example of a method for producing hard gelatin capsules with modified release of diphenhydramine hydrochloride and melatonin, which includes:

preparation of raw materials, including sifting of raw materials, in which

magnesium stearate is sifted manually through a 0.5 mm sieve, the residue on the sieve is wiped manually, diphenhydramine hydrochloride is sifted through a 0.25 mm sieve, melatonin is sifted, 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 sieved, including on a CISA RP200 N vibrating sieve through a 0.5 mm sieve;

weighing of raw materials , in which each type of raw material is weighed into separate clean containers, labeled and transferred to the next stages.

preparation of a 40% humidifier solution , in which povidone in full is added to purified water with constant stirring, and stirring is carried out until 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 , in which the entire humidifier solution is added to the mixer-granulator while stirring the mixture, stirring until a homogeneous crumbly granulate is obtained (with visual inspection),

granulate drying , in which the granulate is dried in an oven (fluid bed dryer),

granulate calibration, in which the granulate is sieved,

dusting, in which the resulting granulate and magnesium stearate are loaded into the mixer and the components are mixed until homogeneous under visual control,

preparation of a mixture for tableting based on Melatonin, including preliminary mixing (trituration), in which Melatonin and part of microcrystalline cellulose (in an amount equal to the amount of Melatonin) are loaded into the mixer and the components are mixed until homogeneous under visual control,

main mixing, during which the remaining part of the Cellulose is loaded into the mixer and the components are mixed until homogeneous under visual control,

loading into the Kollidon SR mixer and mixing the components until homogeneous under visual control,

dusting, in which the resulting mixture and magnesium stearate are loaded into the mixer and the components are mixed until homogeneous under visual inspection,

and tableting process .

In certain preferred (non-limiting) embodiments of the invention, pre-mixing parameters are selected based on the volume of a laboratory batch of 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 at the wet granulation stage are selected based on the volume of a laboratory batch 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.

One skilled in the art may modify the above mixing parameters depending on the batch size.

Also, in certain preferred (non-limiting) embodiments of the invention, the granulate drying parameters 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:

Inlet air temperature 50-60°С Drying time 1-3 h Residual moisture of granulate from 1.0 to 3.0%

Also in certain preferred (non-limiting) embodiments of the invention, at the granulate calibration stage, the granulate is sieved on a CISA RP200 N Vibrating Screen through a 0.500 mm (0.710 mm) sieve, and the residues are rubbed through a 0.500 mm (0.710 mm) sieve manually.

Also, in certain preferred (non-limiting) embodiments of the invention, the mixing parameters at the dusting stage are selected based on the volume of a laboratory batch 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 at the stage of preparing a mixture for tableting based on Melatonin 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 at the main mixing stage are selected based on the laboratory 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 certain preferred (non-limiting) embodiments of the invention, the mixing parameters after adding Kollidon SR are selected based on the laboratory 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 certain 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, tabletting is carried out on a FutorqueX-1 tablet press, namely, on a pressing tool with a 3.00 mm geometry, round shape.

During all of the above steps, one skilled in the art may modify the above mixing, drying or tabletting parameters depending on the batch size and the type of equipment used.

After setting the average weight of the tablets, the tablet press is adjusted according to other 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 tabletting mixtures are completely consumed. During the tableting process, the average weight of the tablets and the hardness of the tablets are monitored at least once every 10 minutes.

During the tableting process, tablets are collected into labeled containers. After the process is completed, the containers are closed. A representative selection of tablets is carried out for intermediate control, according to the specification.

Next, the core tablets are coated with a shell, which includes the process of preparing a film suspension; in the process of applying the film shell, an 18% film suspension is used. Stir the purified water so that a funnel is formed on the surface of the water. Gradually add a dry film shell, preventing the formation of agglomerates on the surface of the solution, then reduce the mixing speed so that foaming does not occur, and leave the solution to mix for 45 minutes.

Then the shell is applied, using, among other things, the BOSCH "Solidlab1" modular installation.

Before carrying out the coating process, the tablets are heated to 37-39°C with periodic stirring in the coater drum, including the BOSCH "Solidlab1" modular unit.

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

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

Then a representative selection of tablets is carried out for intermediate control, according to the specification. Film-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 installation BOSCH GKF702.

Next, the film-coated tablets are packed into hard gelatin capsules No. 0, filled with a mixture for encapsulation. (Diphenhydramine),

At the beginning of the process, the BOSCH GKF702 capsule installation is set up on empty capsules. Based on the setup results, check the correct operation:

- capsule orientation unit;

- capsule opening unit;

- capsule rejection unit;

- capsule closing unit;

- capsule ejection unit.

Capsule installation - installation for encapsulation - BOSCH GKF702 is considered to be configured correctly when all components operate correctly, with empty capsules at the output:

- must have the correct shape without wrinkles;

- capsules must be closed.

After setting up the encapsulation installation, load the mixture into the hopper and, among other things, set up the installation for producing capsules of average weight:

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

- for dosage 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 the mixture - no more than 20 minutes;

- deviations from the average weight for 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 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 of Diphenhydramine.

After setting up the encapsulation installation, the tablets are loaded into the hopper and the encapsulation installation is configured to produce 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 with a total weight of 456.80 mg

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

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

- deviations from the average weight for 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. The following is monitored at least once every 10 minutes:

- average weight of filled capsules;

- appearance of the capsules.

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

After the process is completed, the containers with capsules are closed. A representative selection of filled capsules is carried out 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 packaged, for example, in a PVC/Alu blister on an automatic blister machine, including the DPP260ki-2.

Parameters for forming blister cells:

Pressure - 6 bar;

Forming temperature - 110 - 120°C

Sealing parameters:

Sealing temperature - 130 - 140°C;

Pressure - 6 bar;

Speed - 18 cycles/min;

Coolant temperature - 10°C.

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

The developed compositions in the specified ranges of values of the proposed pharmaceutical compositions, as well as the proposed dosage form, manufactured in the described manner based on the proposed compositions, ensure stability and stability of properties. The resulting dosage form ensures stability, storage stability and a virtual absence of side effects.

Thanks to the proposed inventions, which formed the basis for the dosage forms manufactured according to the specified method, it is possible to increase the therapeutic effectiveness of the claimed composition by:

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

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

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

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

All presented inventions are industrially applicable, have passed laboratory tests, are practically implementable and will find wide application in the pharmaceutical industry, namely, it is confirmed:

- use of the above pharmaceutical composition,

- use 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 declared properties, and maintains the stability of properties for a period of at least 3 years.

The use of the proposed inventions increases the range 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 properties for a period of at least 3 years.

Thus, the desired technical result has been achieved by creating devices 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 swelling, providing an improvement in the state of intellectual-mnestic brain functions and emotional and personal state:

- a pharmaceutical composition that increases the therapeutic activity of the stated quantitative and qualitative composition of ingredients due to the immediate onset of action and due to the effective and long-lasting action of the composition of ingredients,

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

- as well as a method for obtaining the specified dosage form based on the proposed pharmaceutical composition,

as well as the technical result was achieved by increasing the assortment list of pharmaceutical compositions, dosage forms intended to regulate 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, providing 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 inventions, will find wide application 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 histamine-induced spasms of smooth muscles, to reduce tissue swelling, providing an improvement in the intellectual and mnestic functions of the brain and the emotional and personal state.

INFORMATION SOURCES

1. RF patent for invention No. 2485949 “MELATONIN TABLET AND METHODS OF PRODUCTION AND APPLICATION”, patent holder - “Pharmaceutical Productions Inc” (US), published 06/27/2013, IPC: A61K 31/40, A61K 31/70, A61K 47/48 , A61K 47/32, A61P 25/20.

2. RF patent for invention No. 2560840 "METHOD FOR TREATING INSOMNIA", patent holder - "NEURIM PHARMACEUTICALS (1991) LTD." (IL) published 08/20/2015, IPC: A61K 31/4045, A61K 9/22, A61K 9/52, A61P 25/20.

3. Application for invention of the Russian Federation No. 2015156033 "SOLID PHARMACEUTICAL DOSAGE FORM INTENDED FOR THE RELEASE OF AT LEAST ONE ACTIVE PHARMACEUTICAL INGREDIENT IN THE ORAL CAVITY", applicant - "MCNEIL AB (SE), published July 13, 2017, IPC: A61K 9/ 36.

4. RF Patent No. 2620855 "Pharmaceutical composition for the prevention and treatment of sleep disorders", patent holder - Limited Liability Company "VALENTA-INTELLECT" (RU), published 05/30/2017, IPC: A61K 9/48, A61K 9/20, A61K 9/16, A61K 31/4402, A61K 31/4045, A61P 25/20.

Claims (18)

1. A dosage form intended to regulate the biological rhythm of sleep and wakefulness and normalize night sleep, 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 auxiliary components, and an extended-release microtablet containing from 1.5 to 6.0 mg of extended-release melatonin and pharmaceutically acceptable excipients. 2. A modified-release dosage form intended to regulate the biological rhythm of sleep and wakefulness and normalize night sleep, 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 excipients, including lactose monohydrate, polyvinylpyrrolidone, pregelatinized starch, colloidal silicon dioxide and magnesium stearate, and an extended-release microtablet containing from 1.5 to 6.0 mg of extended-release melatonin and pharmaceutically acceptable excipients, including core components microcrystalline cellulose microtablets, a mixture of polyvinyl acetate with polyvinylpyrrolidone and magnesium stearate, and a film shell of microtablets, with the following ratio of ingredients, wt. %: Hard gelatin capsule: Diphenhydramine or a pharmaceutically acceptable salt thereof 4.37-20.92 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 Microcrystalline cellulose 3.77-16.9 A mixture of polyvinyl acetate and polyvinylpyrrolidone 2.09-14.83 Magnesium stearate 0.07-1.01 Film casing 0.28-4.13 3. A modified-release dosage form intended to regulate the biological rhythm of sleep and wakefulness and normalize night sleep, 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 sustained-release melatonin and pharmaceutically acceptable excipients, including microtablet core components, cellulose microcrystalline, a mixture of polyvinyl acetate with polyvinylpyrrolidone, and magnesium stearate, and film-coated microtablets, with the following ratio of ingredients, mg: Hard gelatin capsule: Diphenhydramine or a pharmaceutically acceptable salt thereof 20.00-60.00 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 Microcrystalline cellulose 10.54-47.25 A mixture of polyvinyl acetate and polyvinylpyrrolidone 5.86-41.58 Magnesium stearate 0.19-0.21 Film casing 0.78-0.82 4. A method for producing a modified-release dosage form intended for regulating the biological rhythm of sleep and wakefulness and normalizing night sleep, 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, colloidal silicon dioxide and magnesium stearate, and a microtablet containing from 1.5 to 6.0 mg of melatonin with prolonged release and pharmaceutically acceptable auxiliary components, including components of the microtablet core - microcrystalline cellulose, a mixture polyvinyl acetate with polyvinylpyrrolidone, and magnesium stearate, and a film-coated microtablet, in which powder and granules with diphenhydramine or a pharmaceutically acceptable salt thereof are obtained, a melatonin microtablet is obtained, the powder with granules and tablets are combined into a hard gelatin capsule, and said dosage form has the following ratio of ingredients , wt. %: Hard gelatin capsule: Diphenhydramine or a pharmaceutically acceptable salt thereof 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 Microtablet: Melatonin 0.32-24.76 Microcrystalline cellulose 3.77-16.9 A mixture of polyvinyl acetate with inylpyrrolidone coating 2.09-14.83 Magnesium stearate 0.07-1.01 Film casing 0.28-4.13 5. A method for producing a dosage form intended for regulating the biological rhythm of sleep and wakefulness and normalizing night sleep, 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 microtablet containing from 1.5 to 6.0 mg of melatonin with prolonged release 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 coating of the microtablet, which produces powder and granules with diphenhydramine hydrochloride, a microtablet of melatonin is obtained, the powder with granules and tablets are combined into a hard gelatin capsule, and the mentioned dosage form has the following ratio of ingredients, mg: Hard gelatin capsule: Diphenhydramine or a pharmaceutically acceptable salt thereof 20.00-60.00 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 Microcrystalline cellulose 10.54-47.25 A mixture of polyvinyl acetate with inylpyrrolidone coating 5.86-41.58 Magnesium stearate 0.19-0.21 Film casing 0.78-0.82 6. A dosage form intended to regulate the biological rhythm of sleep and wakefulness and normalize night sleep, which is a hard gelatin capsule with diphenhydramine or its pharmaceutically acceptable salt in an amount of 25 mg and melatonin with prolonged release in an amount of 3 mg per modified-release capsule, wherein 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, as a lubricant - magnesium stearate, and film-coated tablets containing melatonin as a pharmaceutical substance, as a filler - microcrystalline cellulose, a component that has a prolonged action, the composition of which contains polyvinyl acetate (80 wt. %), povidone (19 wt.%), sodium lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%), as a lubricant - magnesium stearate, film shell, including components such as hypromellose, yellow iron oxide, lactose monohydrate, triacetin, with the following ratio of ingredients per 1 capsule, wt. %: Granules: Diphenhydramine or a pharmaceutically acceptable salt thereof 8.72 Lactose monohydrate 47.59 Polyvinylpyrrolidone 1.39 Pregelatinized starch 1.05 Silicon dioxide colloidal 0.17 Magnesium stearate 0.35 Film-coated tablets: Melatonin 1.05 Microcrystalline cellulose 3.77 Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%) 2.09 Magnesium stearate 0.07 Film coating (hypromellose, iron oxide yellow, lactose monohydrate, triacetin) 0.28 Hard gelatin capsule rest 7. A dosage form intended to regulate the biological rhythm of sleep and wakefulness and normalize night sleep, which is a hard gelatin capsule with a modified release of diphenhydramine or its pharmaceutically acceptable salt in an amount of 25 mg and melatonin with prolonged release in an amount of 3 mg per capsule, with in which 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, colloidal silicon dioxide as a glidant, in magnesium stearate as a lubricant, and film-coated tablets containing melatonin as a pharmaceutical substance, microcrystalline cellulose as a filler, a component with a prolonged action containing polyvinyl acetate (80 wt. %), povidone (19 wt.%), sodium lauryl sulfate (0.8 wt.%) and silicon dioxide (0.2 wt.%), as a lubricant - magnesium stearate, film shell, including components such as hypromellose, yellow iron oxide, lactose monohydrate, triacetin, with the following ratio of ingredients per 1 capsule, mg: Granules: Diphenhydramine or a pharmaceutically acceptable salt thereof 25.00 Lactose monohydrate 136.50 Polyvinylpyrrolidone 4.00 Pregelatinized starch 3.00 Silicon dioxide colloidal 0.50 Magnesium stearate 1.00 Film-coated tablets: Melatonin 3.00 Microcrystalline cellulose 10.80 Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%) 6.00 Magnesium stearate 0.20 Film coating (Hypromellose, Yellow iron oxide, Lactose monohydrate, Triacetin) 0.80 8. A dosage form intended to regulate the biological rhythm of sleep and wakefulness and normalize night sleep, which is a hard gelatin capsule with a modified release of diphenhydramine or its pharmaceutically acceptable salt in an amount of 50 mg and melatonin with prolonged release in an amount of 3 mg per capsule, with in which 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, colloidal silicon dioxide as a glidant, lubricant magnesium stearate, and film-coated tablets containing melatonin as a pharmaceutical substance, microcrystalline cellulose as a filler, a component with a prolonged action containing polyvinyl acetate (80 wt. %), povidone (19 wt.%), sodium lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%), as a lubricant - magnesium stearate, film shell, including components such as hypromellose, yellow iron oxide, lactose monohydrate, triacetin, with the following ratio of ingredients per 1 capsule, wt. %: Granules: Diphenhydramine or a pharmaceutically acceptable salt thereof 10.95 Lactose monohydrate 59.76 Polyvinylpyrrolidone 1.75 Pregelatinized starch 1.31 Silicon dioxide colloidal 0.22 Magnesium stearate 0.44 Film-coated tablets: Melatonin 0.66 Microcrystalline cellulose 2.36 Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%) 1.31 Magnesium stearate 0.04 Film coating (Hypromellose, Yellow iron oxide, Lactose monohydrate, Triacetin) 0.18 Hard gelatin capsule rest 9. A dosage form intended to regulate the biological rhythm of sleep and wakefulness and normalize night sleep, 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 with prolonged release in 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, in as a glidant - colloidal silicon dioxide, as a lubricant - magnesium stearate, and film-coated tablets containing melatonin as a pharmaceutical substance, as a filler - microcrystalline cellulose, a component that has a prolonged action, containing polyvinyl acetate (80 wt. %), 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, oxide iron yellow, lactose monohydrate, triacetin, with the following ratio of ingredients per 1 capsule, mg: Granules: Diphenhydramine or a pharmaceutically acceptable salt thereof 50.00 Lactose monohydrate 273.00 Polyvinylpyrrolidone 8.00 Pregelatinized starch 6.00 Silicon dioxide colloidal 1.00 Magnesium stearate 2.00 Film-coated tablets: Melatonin 3.00 Microcrystalline cellulose 10.80 Polyvinyl acetate (80 wt.%), povidone (19 wt.%), sodium lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%) 6.00 Magnesium stearate 0.20 Film coating (Hypromellose, Yellow iron oxide, Lactose monohydrate, Triacetin) 0.80 10. Use of the dosage form according to any one of paragraphs. 1-3 and 6-9 to regulate the biological rhythm of sleep and wakefulness and normalize night sleep.