WO2023106959A1 - Composition pharmaceutique comprenant de la mélatonine et de la diphénhydramine ou son sel pharmaceutiquement acceptable - Google Patents

Composition pharmaceutique comprenant de la mélatonine et de la diphénhydramine ou son sel pharmaceutiquement acceptable Download PDF

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WO2023106959A1
WO2023106959A1 PCT/RU2021/000567 RU2021000567W WO2023106959A1 WO 2023106959 A1 WO2023106959 A1 WO 2023106959A1 RU 2021000567 W RU2021000567 W RU 2021000567W WO 2023106959 A1 WO2023106959 A1 WO 2023106959A1
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diphenhydramine
pharmaceutically acceptable
melatonin
magnesium stearate
acceptable salt
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PCT/RU2021/000567
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English (en)
Russian (ru)
Inventor
Рустам Мунирович Иксанов
Елена Юрьевна ЛИТВИНОВА
Захар Наумович ЛЕЙКИН
Ирина Геннадьевна КУЗНЕЦОВА
Дамир Хизбуллаевич САЛАХЕТДИНОВ
Елена Алексеевна РОГОЖКИНА
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ОБЩЕСТВО С ОГРАНИЧЕННОЙ ОТВЕТСТВЕННОСТЬЮ "НоваМедика"
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Priority to PCT/RU2021/000567 priority Critical patent/WO2023106959A1/fr
Publication of WO2023106959A1 publication Critical patent/WO2023106959A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • 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.
  • 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.
  • 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.
  • Melatonin 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.
  • GABA gamma-aminobutyric acid
  • 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
  • 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.
  • a hormone selected from the group consisting of melatonin, estrogens, progesterone, testosterone and dihydroxytestosterone
  • 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.
  • 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.).
  • 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.
  • melatonin In some cases, however, it is necessary to combine melatonin with other therapeutically active substances in order to achieve or enhance the therapeutic effect.
  • 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]).
  • 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.
  • a pharmaceutical composition 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • diphenhydramine or its pharmaceutically acceptable salt in an amount of 20 to 60 mg and melatonin in an amount of 1.5
  • 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.
  • the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride.
  • 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.
  • a pharmaceutical composition 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.
  • 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.%).
  • 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 ratio of polyvinylpyrrolidone and polyvinyl acetate (w/w) in a mixture of polyvinylpyrrolidone with polyvinyl acetate is 80.81/19.19.
  • 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:
  • the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride.
  • the ratio of polyvinylpyrrolidone and polyvinyl acetate (wt./wt.) in a mixture of polyvinylpyrrolidone with polyvinyl acetate is 80.81/19.19.
  • 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.%:
  • the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride.
  • 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 hydroxy
  • 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.
  • 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.%:
  • the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride.
  • 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 hydroxy
  • 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.
  • 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.
  • 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:
  • the pharmaceutically acceptable diphenhydramine salt is diphenhydramine hydrochloride.
  • 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.
  • 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.
  • 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
  • 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.
  • a solution of a humidifier consisting mainly of polyvinylpyrrolidone. Use its concentration in solution in the range of 20-45 May. %,.
  • May 40 is prepared as a humidifier. % Povidone solution.
  • 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:
  • a humidifier solution consisting mainly of polyvinylpyrrolidone with a concentration of 20-45 wt. %.
  • the mixing/mixing time is from 2 to 8 minutes.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • Polyvinylpyrrolidone 4.00-8.25 Pregelatinized starch 3.00-6.19 Colloidal silicon dioxide 0.50-1.03 Magnesium stearate 1.00-2.06
  • 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.
  • 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.
  • 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 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.
  • 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
  • filler is lactose monohydrate.
  • binder is polyvinylpyrrolidone
  • disintegrant is pregelatinized starch
  • the glidant is colloidal silicon dioxide
  • the lubricant is magnesium stearate.
  • excipients, binders, disintegrants, glidants and lubricants used in the art may also be used in alternative embodiments of the invention.
  • 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
  • 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.%:
  • Polyvinyl acetate 80 wt.%), povidone (19 wt.%), sodium 2.09 lauryl sulfate (0.8 wt.%), silicon dioxide (0.2 wt.%)
  • 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
  • Polyvinyl acetate 80 wt.%), povidone (19 wt.%), sodium lauryl sulfate 6.00 (0.8 wt.%), silicon dioxide (0.2 wt.%)
  • 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)
  • 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.%:
  • 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
  • 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
  • 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 tablet
  • the premixing parameters are selected based on the volume laboratory series in 1000 capsules. Most preferably (without limitation), the following mixing parameters are used:
  • 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:
  • 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.
  • the residual moisture content of the granulate is from 1.0 to 3.0%.
  • 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.
  • 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:
  • 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:
  • 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:
  • 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:
  • the mixing parameters at the dusting stage are selected based on
  • tableting is carried out on a FutorqueX-1 tablet press, namely, on a press tool with a geometry of 3.00 mm, round shape.
  • the tablet press is adjusted according to the remaining indicators:
  • the tableting process is carried out until the tableting mixtures are completely consumed.
  • the average weight of the tablets and the hardness of the tablets are monitored.
  • 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.
  • 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.
  • 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.
  • 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.
  • the tablets are heated to 37-39°C with periodic stirring in the coater drum, including the BOSCH “Solidlabl” modular unit.
  • 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.
  • 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.
  • the mixture for encapsulation (Diphenhydramine) is packed, which is carried out, among other things, on an automatic capsule unit BOSCH GKF702.
  • the packaging of the film-coated tablets is carried out in hard gelatin capsules No. 0, filled with a mixture for encapsulation. (Diphenhydramine),
  • the BOSCH GKF702 capsule unit is set up on empty capsules. Based on the results of the settings, the correct operation is checked:
  • Capsule plant - encapsulation plant - BOSCH GKF702 is considered to be configured correctly if all nodes work correctly, with empty capsules at the exit:
  • 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:
  • the film-coated tablets are packed into capsules.
  • one film-coated tablet is placed in a capsule containing a mixture with Diphenhydramine.
  • 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
  • filled capsules are collected in labeled containers.
  • 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.
  • 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.
  • 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:
  • 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 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.
  • 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:
  • 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,
  • 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.
  • 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.

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Abstract

L'invention concerne une composition pharmaceutique et des formes médicamenteuses comprenant de la mélatonine et de la diphénhydramine ou son sel pharmaceutiquement acceptable, ainsi que des procédés de production et d'utilisation des ces compositions et formes médicamenteuses afin de réguler les changements quotidiens de l'activité locomotrice, la température du corps, le rythme biologique du sommeil et de l'éveil, la normalisation du sommeil de nuit, la diminution ou la prévention de spasmes des muscles lisses induits par histamines, une amélioration de l'état des fonctions intellectuelles-mnésiques et de l'état émotionnel-de personnalité.
PCT/RU2021/000567 2021-12-10 2021-12-10 Composition pharmaceutique comprenant de la mélatonine et de la diphénhydramine ou son sel pharmaceutiquement acceptable WO2023106959A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1729970A (zh) * 2005-08-29 2006-02-08 陈彦方 一种治疗失眠的黑白制剂组方
KR20070070307A (ko) * 2005-08-24 2007-07-04 에스에스 세야쿠 가부시키 가이샤 수면 개선 의약 조성물
US20070292498A1 (en) * 2003-11-05 2007-12-20 Warren Hall Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070292498A1 (en) * 2003-11-05 2007-12-20 Warren Hall Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers
KR20070070307A (ko) * 2005-08-24 2007-07-04 에스에스 세야쿠 가부시키 가이샤 수면 개선 의약 조성물
CN1729970A (zh) * 2005-08-29 2006-02-08 陈彦方 一种治疗失眠的黑白制剂组方

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "(Arcoxia®) Instruktsiia po primeneniiu", 19 June 2021 (2021-06-19), Russia, pages 1 - 15, XP009547317, Retrieved from the Internet <URL:https://www.vidal.ru/drugs/arcoxia__31721> *

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