CN114831983A - Melatonin sublingual oral cavity instant composition and preparation method thereof - Google Patents

Melatonin sublingual oral cavity instant composition and preparation method thereof Download PDF

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Publication number
CN114831983A
CN114831983A CN202210593022.8A CN202210593022A CN114831983A CN 114831983 A CN114831983 A CN 114831983A CN 202210593022 A CN202210593022 A CN 202210593022A CN 114831983 A CN114831983 A CN 114831983A
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melatonin
parts
sublingual
instant composition
mixing
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Inventor
李聪
虞家鳌
田密
刘娜
刘帅
李亚楠
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Beijing Zhendong Health Technology Co ltd
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Beijing Zhendong Health Technology Co ltd
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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
    • A61K31/33—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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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    • 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
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    • 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets

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Abstract

The invention provides a melatonin sublingual oral cavity instant composition and a preparation method thereof, belonging to the field of medicine/food preparations. The melatonin sublingual buccal instant composition can be directly placed under the tongue when a patient takes the composition without drinking water, can be quickly disintegrated by means of oral mucus and saliva, is beneficial to taking the composition or patients with difficulty in swallowing after less than 10s, can be directly absorbed into blood through oral mucosa and esophagus, can well avoid the first-pass effect, quickly take effect, can be taken shortly before sleeping, obviously shortens the sleeping time by 10min or more, and has high bioavailability.

Description

Melatonin sublingual oral cavity instant composition and preparation method thereof
Technical Field
The invention relates to the technical field of medicine/food preparations, in particular to a melatonin sublingual oral cavity instant composition and a preparation method thereof.
Background
With the daily increase of social pressure, the life style changes, and the occurrence of sleep disorder seriously affects the normal life and rest of people, so that the body of people is tired, hypodynamia, hard to concentrate, low in memory, low in immunity and the like. The world health organization statistics show that 27% of people suffer from a variety of sleep disorders including long sleep latency, wakefulness, short sleep time, and the like. Therefore, melatonin has been receiving wide attention in recent years as a drug which is effective in treating sleep disorders and has relatively few adverse reactions.
Melatonin is an indole hormone secreted by pineal body, is a novel article for treating sleep disorder, and plays a role in regulating circadian rhythm and sleep through specific receptor mediation. Melatonin secretion levels are closely related to sleep quality, and melatonin secretion decreases with age, so sleep disorders are common in the elderly. The exogenous melatonin can improve sleep quality and has therapeutic effect on insomnia. Melatonin has become a common sleep-regulating product, which can improve insomnia by regulating sleep-related neuronal cells and brain endocrine substances.
At present, melatonin products for improving sleep in the market have the problem of long disintegration time, and are required to be taken 30min before sleep in the aspect of taking, so that the time for a patient to fall asleep is delayed, and thus the sleep mental disorder is aggravated.
Disclosure of Invention
In view of the above, the present invention aims to provide a sublingual oral melatonin instant composition and a preparation method thereof. The melatonin sublingual oral cavity instant composition provided by the invention has short disintegration time and high disintegration rate.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a melatonin sublingual oral cavity instant composition which comprises the following components in parts by weight: 1-5 parts of melatonin, 15-40 parts of a film forming agent, 4-38 parts of a disintegrating agent, 0.5-2.0 parts of a plasticizer, 0.5-2.0 parts of a surfactant, 0.1-2.0 parts of a saliva stimulant and 0.1-1.5 parts of a flavoring agent, wherein the disintegrating agent contains calcium carbonate.
Preferably, the film forming agent comprises one or more of pullulan, chitosan, sodium alginate, hyaluronic acid, sodium carboxymethyl cellulose, hypromellose, hyprolose and pectin.
Preferably, the disintegrant further comprises one or more of corn starch, pregelatinized starch, soluble starch, crospovidone, sodium carboxymethyl starch, and sodium cross-linked carboxymethyl starch.
Preferably, the plasticizer comprises one or more of glycerol, polyethylene glycol and propylene glycol.
Preferably, the surfactant comprises a sucrose ester.
Preferably, the saliva stimulating agent comprises one or more of malic acid, ascorbic acid, citric acid, lactic acid and tartaric acid.
Preferably, the flavouring agent comprises one or more of steviol glycosides, mogrosides, ammonium glycyrrhizinate, sucralose, cyclamate, aspartame, alitame, acesulfame k and neotame.
Preferably, vitamin B is also included 6 Or gamma-aminobutyric acid.
Preferably, the melatonin is mixed with vitamin B 6 The mass ratio of melatonin to gamma-aminobutyric acid is 1: 1.
The invention also provides a preparation method of the melatonin sublingual oral cavity instant composition, which comprises the following steps:
mixing the film forming agent, the flavoring agent, the saliva stimulant, part of the surfactant and water to obtain a mixed solution;
mixing a disintegrating agent with water to obtain a disintegrating agent solution;
mixing the mixed solution and the disintegrant solution to obtain a mixture;
mixing melatonin, the rest surfactant and a solvent to obtain a solution containing melatonin;
and mixing the mixture, the melatonin-containing solution and the plasticizer, and drying to obtain the melatonin sublingual oral cavity instant composition.
The invention provides a melatonin sublingual oral cavity instant composition which comprises the following components in parts by weight: 1-5 parts of melatonin, 15-40 parts of a film forming agent, 4-38 parts of a disintegrating agent, 0.5-2.0 parts of a plasticizer, 0.5-2.0 parts of a surfactant, 0.1-2.0 parts of a saliva stimulant and 0.1-1.5 parts of a flavoring agent, wherein the disintegrating agent contains calcium carbonate.
Compared with the prior art, the invention has the following beneficial effects:
the invention relates to a melatonin sublingual buccal instant composition, which can be directly placed under the tongue when a patient takes the composition without drinking water, can be quickly disintegrated by means of oral mucus and saliva, is beneficial to taking the composition for patients with difficulty in taking the composition or swallowing the composition for less than 10s, can be directly absorbed into blood through oral mucosa and esophagus, does not pass through the first pass effect of liver, can well avoid the first pass effect, quickly takes effect, is generally digested by digestive tract, passes through the first pass effect of liver and then enters blood, has long time, reduced medicine concentration and drug effect, can be taken in a short time before sleep, obviously shortens the sleep time by 10min or more, and has high bioavailability.
Furthermore, the invention adds proper disintegrating agent and saliva stimulant, which greatly improves the disintegration time of the product in oral cavity, makes the medicine quickly disintegrate and absorb, and shortens the sleep time.
Detailed Description
The invention provides a melatonin sublingual oral cavity instant composition which comprises the following components in parts by weight: 1-5 parts of melatonin, 15-40 parts of a film forming agent, 4-38 parts of a disintegrating agent, 0.5-2.0 parts of a plasticizer, 0.5-2.0 parts of a surfactant, 0.1-2.0 parts of a saliva stimulant and 0.1-1.5 parts of a flavoring agent, wherein the disintegrating agent contains calcium carbonate.
In the present invention, unless otherwise specified, all the raw materials used are commercially available in the art.
The melatonin sublingual oral cavity instant composition provided by the invention preferably comprises 2-5 parts of melatonin, and more preferably 3-5 parts. In the present invention, the melatonin is used as an active ingredient.
In the present invention, the melatonin sublingual buccal instant composition preferably further comprises vitamin B 6 Or gamma-aminobutyric acid.
In the present invention, the melatonin is mixed with vitamin B 6 The mass ratio of melatonin to gamma-aminobutyric acid is 1: 1.
The melatonin sublingual buccal instant composition provided by the invention preferably comprises vitamin B 6 0 to 5 parts.
The melatonin sublingual oral instant composition provided by the invention preferably comprises 0-5 parts of gamma-aminobutyric acid.
The melatonin sublingual buccal instant composition provided by the invention preferably comprises 20-35 parts of a film-forming agent, more preferably 23-30 parts, and most preferably 26.5-28.5 parts.
In the present invention, the film forming agent comprises preferably one or more of pullulan, chitosan, sodium alginate, hyaluronic acid, sodium carboxymethylcellulose, hypromellose, hyprolose and pectin. When the film forming agent is preferably a mixture, the mass ratio of each substance in the mixture is not particularly limited, and the mixture can be used in any proportion.
The melatonin sublingual buccal instant composition provided by the invention preferably comprises 6-32 parts of a disintegrating agent, more preferably 7-22 parts, and most preferably 10-11 parts.
In the present invention, the disintegrant preferably further comprises one or more of corn starch, pregelatinized starch, soluble starch, crospovidone, sodium carboxymethyl starch, and sodium cross-linked carboxymethyl starch.
In the invention, the disintegrating agent preferably comprises 4-20 parts of calcium carbonate and 0-18 parts of other kinds of disintegrating agents, more preferably comprises 6-17 parts of calcium carbonate, 0-15 parts of other kinds of disintegrating agents, most preferably comprises 7-14 parts of calcium carbonate, and 0-8 parts of other kinds of disintegrating agents, wherein the other kinds of disintegrating agents comprise one or more of corn starch, pregelatinized starch, soluble starch, crospovidone, sodium carboxymethyl starch and sodium cross-linked carboxymethyl starch.
In the invention, the mass percentage of the disintegrating agent in the melatonin sublingual oral cavity instant composition is preferably 20-30%.
The melatonin sublingual buccal instant composition provided by the invention preferably comprises 0.8-1.8 parts of plasticizer, more preferably 1.0-1.5 parts, and most preferably 1.2-1.3 parts, wherein the plasticizer is used for increasing the film shaping.
In the present invention, the plasticizer preferably includes one or more of glycerin, polyethylene glycol, and propylene glycol. When the plasticizer is preferably a mixture, the mass ratio of each substance in the mixture is not particularly limited in the present invention, and a mixture in any ratio may be used.
The melatonin sublingual oral cavity instant composition provided by the invention preferably comprises 0.7-1.8 parts of surfactant, more preferably 1.8-1.3 parts, and most preferably 1.0-1.1 parts, wherein the surfactant enables melatonin to be uniformly and stably distributed.
The melatonin sublingual buccal instant composition provided by the invention preferably comprises 0.3-1.5 parts of saliva stimulating agent, more preferably 0.5-1.2 parts, and most preferably 0.7-0.8 part.
In the present invention, the saliva stimulating agent preferably includes one or more of malic acid, ascorbic acid, citric acid, lactic acid and tartaric acid, and stimulates saliva secretion to accelerate disintegration release. When the saliva stimulating agent is preferably a mixture, the mass ratio of each substance in the mixture is not particularly limited, and the mixture may be used in any ratio.
In the invention, the saliva stimulant is used for promoting a human body to secrete a large amount of saliva, so that the quick disintegration and release of the sublingual buccal instant product are facilitated, and the disintegration time is further shortened.
The melatonin sublingual oral instant composition provided by the invention preferably comprises 0.2-1.0 part of a flavoring agent, more preferably 0.3-0.8 part, and most preferably 0.55-0.6 part.
In the present invention, the taste-modifying agent preferably comprises one or more of stevioside, mogroside, ammonium glycyrrhizinate, sucralose, cyclamate, aspartame, alitame, acesulfame potassium and neotame, and the taste-modifying agent effects taste modification. When the flavoring agent is preferably a mixture, the mass ratio of each substance in the mixture is not particularly limited, and the mixture can be used in any proportion.
In the present invention, the melatonin sublingual buccal instant composition is preferably a tablet.
In the invention, the thickness of each melatonin sublingual oral cavity instant composition is preferably 12-80 μm.
The invention also provides a preparation method of the melatonin sublingual oral cavity instant composition, which comprises the following steps:
mixing the film forming agent, the flavoring agent, the saliva stimulant, part of the surfactant and water to obtain a mixed solution;
mixing a disintegrating agent with water to obtain a disintegrating agent solution;
mixing the mixed solution and the disintegrant solution to obtain a mixture;
mixing melatonin, the rest surfactant and a solvent to obtain a solution containing melatonin;
and mixing the mixture, the melatonin-containing solution and the plasticizer, and drying to obtain the melatonin sublingual oral cavity instant composition.
The invention mixes film forming agent, corrective, saliva stimulant, partial surface active agent and water to obtain mixed liquid.
In the invention, the part of the surfactant is preferably 50-70% of the mass of the surfactant.
In the present invention, the mixing is preferably stirring.
The invention mixes disintegrating agent and water to obtain disintegrating agent solution. In the present invention, the temperature of the water is preferably 60 ℃.
After the mixed solution and the disintegrant solution are obtained, the mixed solution and the disintegrant solution are mixed to obtain a mixture.
In the present invention, the mixing is preferably performed in a water bath at 60 to 70 ℃.
After the mixture is obtained, the melatonin, the residual surfactant and the solvent are mixed to obtain the solution containing the melatonin.
In the present invention, the solvent is preferably water or an ethanol solution.
In the present invention, the temperature of the solvent is preferably 60 to 70 ℃.
After the mixture and the solution containing the melatonin are obtained, the mixture, the solution containing the melatonin and the plasticizer are mixed and dried to obtain the melatonin sublingual oral cavity instant composition.
In the invention, the mixing is preferably ultrasonic mixing for 15-20 min, and the mixing has the effect of uniform dissolution and dispersion.
After the mixing is finished, the melatonin sublingual oral cavity instant composition is preferably prepared by quickly laying a plate after standing and degassing for two hours, drying the plate in a 60 ℃ oven until the film is completely removed, and then cutting the plate into a film.
In order to further illustrate the present invention, the following examples are provided to describe the sublingual buccal instant melatonin compositions and the preparation thereof in detail, but they should not be construed as limiting the scope of the present invention.
Detection of disintegration time in inventive examples 1 to 7 and comparative examples 1 to 2 (in vitro evaluation): taking a proper amount of distilled water with the temperature of 37 ℃ in a watch glass, putting the melatonin sublingual oral instant composition to be detected into the water, starting timing, recording the disintegration time of the film by using a stopwatch, and repeatedly measuring for three times.
Example 1
The formula comprises the following components in percentage by weight:
3 parts of melatonin, 28.5 parts of pullulan, 1.3 parts of glycerol, 11 parts of calcium carbonate, 1.0 part of sucrose ester, 0.8 part of malic acid, 0.45 part of stevioside and 0.1 part of sucralose.
The preparation method comprises the following steps:
weighing the materials in batches according to the formula for later use.
Adding water into pullulan, sucralose, stevioside, malic acid and 50 wt% sucrose ester, stirring and dissolving, and stirring to obtain a mixed solution 1 for later use;
dissolving calcium carbonate in water at 60 ℃, stirring, mixing with the mixed solution 1, and dissolving in water at 60 ℃ until the solution is uniform to obtain a mixed solution 2 for later use;
dissolving melatonin and the rest sucrose ester with water at 60 deg.C, and stirring to obtain melatonin solution.
Adding glycerol and melatonin liquid into the mixed solution 2, ultrasonically mixing for 15min, standing, degassing for two hours, quickly paving the mixed solution, drying in an oven at 60 ℃ for 2 hours until the mixed solution is completely stripped, and cutting into films with the specification of 2cm multiplied by 2.5cm to obtain the melatonin sublingual instant composition.
Evaluation: the melatonin oral instant film is uniform in color, appropriate in drug loading, uniform in content, good in taste, certain in toughness and 8-13 s in disintegration time.
Example 2 (increase of calcium carbonate and malic acid to a certain amount, the disintegration time of the product was rather prolonged)
3 parts of melatonin, 31.5 parts of pullulan, 1.4 parts of glycerol, 17 parts of calcium carbonate, 1.0 part of sucrose ester, 1.35 parts of malic acid, 0.75 part of stevioside and 0.1 part of sucralose.
The preparation method comprises the following steps:
weighing the materials in batches according to the formula for later use.
Adding water into pullulan, sucralose, stevioside, malic acid and 60 wt% sucrose ester, stirring and dissolving, and stirring to obtain a mixed solution 1 for later use;
dissolving calcium carbonate in water at 70 ℃, stirring, mixing with the mixed solution 1, and dissolving in water at 70 ℃ until the solution is uniform to obtain a mixed solution 2 for later use;
dissolving melatonin and the rest sucrose ester with water at 60 deg.C, and stirring to obtain melatonin solution.
Adding glycerol and melatonin liquid into the mixed solution 2, ultrasonically mixing for 20min, standing, degassing for two hours, quickly paving the mixed solution, drying in an oven at 60 ℃ for 2 hours until the mixed solution is completely stripped, and cutting into films with the specification of 2cm multiplied by 2.5cm to obtain the melatonin sublingual instant composition.
Evaluation: the melatonin oral instant film is uniform in color, appropriate in drug loading, uniform in content, good in taste, certain in toughness and 23-30 s in disintegration time.
Example 3 (Change of disintegrant to calcium carbonate + pregelatinized starch, appropriate disintegration time of product)
3 parts of melatonin, 26.5 parts of pullulan, 1.2 parts of glycerol, 7 parts of calcium carbonate, 4 parts of pregelatinized starch, 1.0 part of sucrose ester, 0.6 part of malic acid, 0.40 part of stevioside and 0.1 part of sucralose.
Weighing the materials in batches according to the formula for later use.
Adding water into pullulan, sucralose, stevioside, malic acid and 60 wt% sucrose ester, stirring and dissolving, and stirring to obtain a mixed solution 1 for later use;
dissolving calcium carbonate and pregelatinized starch in 70 deg.C water, stirring, mixing with the above mixed solution 1, and dissolving in 70 deg.C water to obtain mixed solution 2;
dissolving melatonin and the rest sucrose ester with water at 70 deg.C, and stirring to obtain melatonin solution.
Adding glycerol and melatonin liquid into the mixed solution 2, ultrasonically mixing for 20min, standing, degassing for two hours, quickly paving the mixed solution, drying in an oven at 60 ℃ for 2 hours until the mixed solution is completely stripped, and cutting into films with the specification of 2cm multiplied by 2.5cm to obtain the melatonin sublingual instant composition.
Evaluation: the melatonin oral instant film is uniform in color, appropriate in drug loading, uniform in content, good in taste and certain in toughness, and the disintegration time is 13-18 s.
Example 4 (replacement of disintegrant with less calcium carbonate + pregelatinized starch, extended disintegration time of product)
3 parts of melatonin, 26.5 parts of pullulan, 1.2 parts of glycerol, 4 parts of calcium carbonate, 6 parts of pregelatinized starch, 1.1 parts of sucrose ester, 0.4 part of malic acid, 0.30 part of stevioside and 0.1 part of sucralose.
Weighing the materials in batches according to the formula for later use.
Adding water into pullulan, sucralose, stevioside, malic acid and 60 wt% sucrose ester, stirring and dissolving, and stirring to obtain a mixed solution 1 for later use;
dissolving calcium carbonate and pregelatinized starch in 60 deg.C water, stirring, mixing with the above mixed solution 1, and dissolving in 60 deg.C water to obtain mixed solution 2;
dissolving melatonin and the rest sucrose ester with water at 60 deg.C, and stirring to obtain melatonin solution.
Adding glycerol and melatonin liquid into the mixed solution 2, ultrasonically mixing for 20min, standing, degassing for two hours, quickly paving the mixed solution, drying in an oven at 60 ℃ for 2 hours until the mixed solution is completely stripped, and cutting into films with the specification of 2cm multiplied by 2.5cm to obtain the melatonin sublingual instant composition.
Evaluation: the melatonin oral instant film is uniform in color, appropriate in drug loading, uniform in content, good in taste, certain in toughness and capable of disintegrating for 25-29 s.
Example 5
5 parts of melatonin, 29.5 parts of pullulan, 1.3 parts of glycerol, 11 parts of calcium carbonate, 1.2 parts of sucrose ester, 0.8 part of malic acid, 0.40 part of aspartame and 0.1 part of sucralose.
Weighing the materials in batches according to the formula for later use.
Adding water into pullulan, sucralose, aspartame, malic acid and 60 wt% sucrose ester, stirring for dissolving, and stirring to obtain a mixed solution 1 for later use;
dissolving calcium carbonate in water at 70 ℃, stirring, mixing with the mixed solution 1, and dissolving in water at 70 ℃ until the solution is uniform to obtain a mixed solution 2 for later use;
dissolving melatonin and the rest sucrose ester with 70% ethanol, and stirring to obtain melatonin solution.
Adding glycerol and melatonin liquid into the mixed solution 2, ultrasonically mixing for 20min, standing, degassing for two hours, quickly paving the mixed solution, drying in an oven at 60 ℃ for 2 hours until the mixed solution is completely stripped, and cutting into films with the specification of 2cm multiplied by 2.5cm to obtain the melatonin sublingual instant composition.
Evaluation: the melatonin oral instant film is uniform in color, appropriate in drug loading, uniform in content, good in taste, certain in toughness and 8-16 s in disintegration time.
Example 6 (Small format formulation)
1 part of melatonin, 23 parts of pullulan, 1 part of glycerol, 8 parts of calcium carbonate, 0.8 part of sucrose ester, 0.6 part of malic acid, 0.2 part of stevioside, 0.1 part of acesulfame and 0.1 part of sucralose.
Weighing the materials in batches according to the formula for later use.
Adding water into pullulan polysaccharide, sucralose, stevioside, acesulfame, malic acid and 50 wt% of sucrose ester, stirring for dissolving, and stirring to obtain a mixed solution 1 for later use;
dissolving calcium carbonate in water at 70 ℃, stirring, mixing with the mixed solution 1, and dissolving in water at 70 ℃ until the solution is uniform to obtain a mixed solution 2 for later use;
dissolving melatonin and the rest sucrose ester with water at 70 deg.C, and stirring to obtain melatonin solution.
Adding glycerol and melatonin liquid into the mixed solution 2, ultrasonically mixing for 15min, standing, degassing for two hours, quickly paving the mixed solution, drying in an oven at 60 ℃ for 2 hours until the mixed solution is completely stripped, and cutting into films with the specification of 2cm multiplied by 2.5cm to obtain the melatonin sublingual instant composition.
Evaluation: the melatonin oral instant film is uniform in color, appropriate in drug loading, uniform in content, good in taste, certain in toughness and 5-10 s in disintegration time.
Example 7 (formulation of compounded essential ingredients with modified film-forming agent)
5 parts of melatonin and vitamin B 6 5 parts of hydroxypropyl methyl30 parts of cellulose, 1.5 parts of glycerol, 14 parts of calcium carbonate, 1.3 parts of sucrose ester, 1.2 parts of malic acid, 0.65 part of aspartame and 0.15 part of sucralose.
Weighing the materials in batches according to the formula for later use.
Adding water into hydroxypropyl methyl cellulose and 60 wt% of sucrose ester, stirring for dissolving, and stirring to obtain a mixed solution 1 for later use;
dissolving calcium carbonate in water at 70 ℃, stirring, mixing with the mixed solution 1, sucralose, aspartame and malic acid, and dissolving in water at 70 ℃ until the solution is uniform to obtain a mixed solution 2 for later use;
dissolving melatonin and the rest sucrose ester with 70% ethanol, and stirring to obtain melatonin solution.
Adding glycerol and melatonin liquid into the mixed solution 2, ultrasonically mixing for 20min, standing, degassing for two hours, quickly paving the mixed solution, drying in an oven at 60 ℃ for 2 hours until the mixed solution is completely stripped, and cutting into films with the specification of 2cm multiplied by 2.5cm to obtain the melatonin sublingual instant composition.
Evaluation: the melatonin oral instant film is uniform in color, appropriate in drug loading, uniform in content, good in taste, certain in toughness and 14-20 s in disintegration time.
Comparative example 1 (replacement of disintegrant with calcium carbonate-free addition, extended disintegration time of product)
3 parts of melatonin, 28.5 parts of pullulan, 1.2 parts of glycerol, 1 part of crospovidone, 9 parts of corn starch, 2.0 parts of sucrose ester, 0.7 part of malic acid, 0.6 part of stevioside and 0.1 part of sucralose.
Weighing the materials in batches according to the formula for later use.
Dissolving pullulan polysaccharide, sucralose, stevioside, malic acid, crospovidone, corn starch and 60 wt% sucrose ester in water under stirring, dissolving in water at 60 deg.C until the solution is uniform, and stirring to obtain mixed solution 1;
dissolving melatonin and the rest sucrose ester with water at 60 deg.C, and stirring to obtain melatonin solution.
Adding glycerol and melatonin liquid into the mixed solution 1, ultrasonically mixing for 18min, standing, degassing for two hours, quickly paving, drying in a 60 ℃ oven for about 2 hours until completely removing the membrane, and cutting into membranes with the specification of 2cm multiplied by 2.5cm to obtain the melatonin sublingual instant composition.
Evaluation: the melatonin oral instant film is uniform in color, appropriate in drug loading, uniform in content, good in taste and certain in toughness, and the disintegration time is 36-43 seconds.
Comparative example 2 (no saliva stimulating agent, product disintegration time significantly extended)
As in example 1, except that no saliva stimulating agent was added.
Evaluation: the product has the advantages of uniform color, proper drug loading, uniform content, good taste, certain toughness and disintegration time of 18-24 s.
Comparative disintegration time data melatonin sublingual buccal fast dissolving compositions were used as the product from example 1.
(1) The disintegration time limit of the melatonin common dosage form is compared, data are obtained from experimental measurement, and the result is shown in table 1.
TABLE 1 comparison of disintegration time limits of melatonin formulations commonly used
Figure BDA0003666331830000111
(2) The disintegration time of different oral instant films were compared and the data was derived from experimental measurements with results shown in table 2.
TABLE 2 comparison of disintegration time limits of different oral fast dissolving films
Figure BDA0003666331830000112
Figure BDA0003666331830000121
Test food investigation result of melatonin sublingual oral cavity instant composition
Test subject
The selected population of 18-60 years old, half of men and half of women, actually recruited 35 volunteers and 29 effective data.
Test drugs
The melatonin sublingual oral instant composition prepared in the embodiment 1 of the invention is orally taken.
Test results
Dissolving time of melatonin oral instant film in oral cavity
The dissolution time of the melatonin sublingual oral cavity instant composition in the oral cavity was determined (in vivo assay) and is shown in table 3.
The melatonin sublingual buccal instant composition was placed under the tongue, the timer was started, and the disintegration time of the film was recorded using a stopwatch.
TABLE 3 dissolution time statistics of melatonin sublingual oral instant compositions in the oral cavity
Options for Small counter Ratio of
≤5s 6 20.69％
5～10s 14 48.27％
10～20s 7 24.14％
20～30s 1 3.45％
More than 30s 1 3.45％
The statistics of the time to sleep after oral administration of the melatonin sublingual oral instant composition are shown in table 4.
TABLE 4 statistics of time to sleep after oral administration of melatonin sublingual oral instant compositions
Figure BDA0003666331830000122
Figure BDA0003666331830000131
The results of the questionnaire on whether the sleeping time after the test feeding was prolonged or not are shown in table 5.
TABLE 5 questionnaire survey results of whether sleep time was prolonged after tasting
Options for Small counter Ratio of
That is, the time to wake up at night is reduced and overall sleep is extended 22 75.86％
No, no particularly significant improvement 6 20.69％
Other cases 1 3.45％
The results of the questionnaire survey on the improvement of sleep quality after the test feeding are shown in table 6.
TABLE 6 questionnaire survey results on sleep quality improvement after test feeding
Options for Small counter Ratio of
That is, after use, sleep more fragrant 22 75.86％
No, and not too much change 6 20.69％
Other cases 1 3.45％
The results of the questionnaire awakened the next day after use are shown in table 7.
TABLE 7 questionnaire results of waking the next day after use
Options for Small counter Ratio of
Sufficient sleep and full spirit 17 58.62％
Want to sleep again 5 17.24％
Without feeling too big 6 20.69％
Other cases 1 3.45％
Tables 3-7 illustrate the test data: through data analysis of a test population, the dissolving time of the melatonin sublingual oral cavity instant composition disclosed by the invention in the oral cavity is shorter and can reach below 5s at the fastest speed; the time for the volunteers to fall asleep is short after the medicine is taken; 75.86% believe that the total sleep time is prolonged and that the user sleeps more fragrant after use.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be construed as the protection scope of the present invention.

Claims (10)

1. The melatonin sublingual buccal instant composition is characterized by comprising the following components in parts by mass: 1-5 parts of melatonin, 15-40 parts of a film forming agent, 4-38 parts of a disintegrating agent, 0.5-2.0 parts of a plasticizer, 0.5-2.0 parts of a surfactant, 0.1-2.0 parts of a saliva stimulant and 0.1-1.5 parts of a flavoring agent, wherein the disintegrating agent contains calcium carbonate.
2. The melatonin sublingual oral composition of claim 1, wherein the film-forming agent comprises one or more of pullulan, chitosan, sodium alginate, hyaluronic acid, sodium carboxymethylcellulose, hypromellose, hyprolose, and pectin.
3. The melatonin sublingual buccal instant composition of claim 1, wherein the disintegrant further comprises one or more of corn starch, pregelatinized starch, soluble starch, crospovidone, sodium carboxymethyl starch, and sodium cross-linked carboxymethyl starch.
4. The melatonin sublingual buccal instant composition of claim 1, wherein the plasticizer comprises one or more of glycerol, polyethylene glycol, and propylene glycol.
5. The melatonin sublingual buccal instant composition of claim 1, wherein the surfactant comprises a sucrose ester.
6. The melatonin sublingual buccal instant composition of claim 1, wherein the saliva stimulating agent comprises one or more of malic acid, ascorbic acid, citric acid, lactic acid, and tartaric acid.
7. The melatonin sublingual buccal instant composition of claim 1 wherein the flavoring agent comprises one or more of steviol glycoside, mogroside, ammonium glycyrrhizinate, sucralose, cyclamate, aspartame, alitame, acesulfame potassium, and neotame.
8. The melatonin sublingual buccal instant composition of any one of claims 1-7, further comprising vitamin B 6 Or gamma-aminobutyric acid.
9. The melatonin sublingual buccal instant composition of claim 8, wherein the melatonin is admixed with vitamin B 6 The mass ratio of the melatonin to the gamma-aminobutyric acid is 2:1, and the mass ratio of the melatonin to the gamma-aminobutyric acid is 1: 1.
10. The method of preparing a melatonin sublingual buccal instant composition as claimed in any one of claims 1 to 9, comprising the steps of:
mixing the film forming agent, the flavoring agent, the saliva stimulant, part of the surfactant and water to obtain a mixed solution;
mixing a disintegrating agent with water to obtain a disintegrating agent solution;
mixing the mixed solution and the disintegrant solution to obtain a mixture;
mixing melatonin, the rest surfactant and a solvent to obtain a solution containing melatonin;
and mixing the mixture, the melatonin-containing solution and the plasticizer, and drying to obtain the melatonin sublingual oral cavity instant composition.
CN202210593022.8A 2022-05-27 2022-05-27 Melatonin sublingual oral cavity instant composition and preparation method thereof Pending CN114831983A (en)

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Publication number Priority date Publication date Assignee Title
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