CN116172979A - Melatonin slow-release pellets and preparation method thereof - Google Patents

Melatonin slow-release pellets and preparation method thereof Download PDF

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Publication number
CN116172979A
CN116172979A CN202310174278.XA CN202310174278A CN116172979A CN 116172979 A CN116172979 A CN 116172979A CN 202310174278 A CN202310174278 A CN 202310174278A CN 116172979 A CN116172979 A CN 116172979A
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melatonin
solution
release
shellac
hydroxypropyl methylcellulose
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黄旻
冯利萍
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Zhejiang Beiling Biomedical Co ltd
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Zhejiang Beiling Biomedical Co ltd
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    • 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
    • A61K9/5089—Processes
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to the field of pharmaceutical health-care food preparations, in particular to a melatonin slow-release pellet and a preparation method thereof. The melatonin slow release pellet sequentially comprises a pellet core, a drug-containing layer and a coating layer from inside to outside; the pill core is mannitol pill core; the medicine-containing layer comprises melatonin, sodium dodecyl sulfate and hydroxypropyl methylcellulose; the coating layer comprises shellac; in the raw materials of the melatonin sustained-release pellets, the mass ratio of melatonin to hydroxypropyl methylcellulose is 1:0.8-1, the mass ratio of melatonin to sodium dodecyl sulfate is 1:0.1-0.3, and the mass ratio of mannitol pellet cores to shellac is 1:0.03-0.06. The invention can control the melatonin release speed at a more ideal level, can avoid influencing the daytime state while ensuring the night sleep quality, and has no burst release and time lag phenomena, thereby being capable of rapidly taking effect after taking medicine and reducing toxic and side effects.

Description

Melatonin slow-release pellets and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical health-care food preparations, in particular to a melatonin slow-release pellet and a preparation method thereof.
Background
Melatonin is an amine hormone secreted by glands of pine nut in human body, has various important physiological functions of regulating circadian rhythm, immunity, endocrine and the like, has a promoting effect on sleep, can regulate sleep and conscious period of people, deepens sleep, improves sleep quality and improves the functional state of the whole body. Compared with other hypnotics, melatonin has no addiction and obvious side effects, and is favored by patients and doctors once being pushed out.
The half-life period of melatonin is short, and the metabolism speed of the oral tablet in the body is high, so that if the melatonin is directly taken, the effective concentration is difficult to maintain for a long time, and the melatonin is prepared into a slow release preparation, so that the melatonin is slowly released, the irritation of high-concentration medicines to gastrointestinal tracts can be avoided, the melatonin in blood can be maintained at a relatively stable concentration for a certain time, and the action time of the melatonin is prolonged. However, the existing melatonin slow release preparation is difficult to realize ideal release speed, the release speed is too high, so that the action time is short, the sleeping quality at night is difficult to ensure, and the release speed is too low, so that more melatonin still exists in the body after sleeping is finished, and the working and living states at daytime are influenced; in addition, the melatonin sustained release tablet also has burst release phenomenon, and generates larger toxic and side effects.
For example, patent CN200910234697.8 discloses a sustained release preparation containing melatonin and a preparation method thereof, which can solve the problem of sudden release of a general sustained release tablet, but the release amount of the sustained release preparation is only about 20% in 1h after taking the tablet, so that the sleep-aiding effect is difficult to be quickly exerted, the accumulated release amount after 5h is less than 80%, more medicine is still not released, the patient is difficult to be gradually awake in proper time, and the burden is easily caused to the work and life of the patient in daytime.
Disclosure of Invention
The invention provides a melatonin slow-release pellet and a preparation method thereof, aiming at solving the technical problem that the existing melatonin slow-release preparation is not ideal in release speed. The melatonin slow-release pellets can control the melatonin release speed to be at a relatively ideal level, can avoid influencing the daytime state while ensuring the night sleep quality, and have no burst release and time lag phenomena, so that the melatonin slow-release pellets can take effect rapidly after taking medicine and reduce toxic and side effects.
The specific technical scheme of the invention is as follows:
in a first aspect, the invention provides a melatonin sustained release pellet, which sequentially comprises a pellet core, a drug-containing layer and a coating layer from inside to outside; the pill core is mannitol pill core; the medicine-containing layer comprises melatonin, dodecyl sulfate and hydroxypropyl methylcellulose; the coating layer comprises shellac; the melatonin slow-release pellets comprise the following raw materials in parts by weight: 1.0 to 1.5 parts of melatonin, 0.1 to 0.3 part of dodecyl sulfate, 90 to 95 parts of mannitol pill core, 1.0 to 1.5 parts of hydroxypropyl methyl cellulose and 2.7 to 5.5 parts of shellac; in the raw materials, the mass ratio of the melatonin to the hydroxypropyl methylcellulose is 1:0.8-1, the mass ratio of the melatonin to the dodecyl sulfate is 1:0.1-0.3, and the mass ratio of the mannitol pill core to the shellac is 1:0.03-0.06.
The invention can control the release rate of melatonin to be at ideal level by comprehensively controlling the composition components and the dosage of each component of the melatonin sustained-release pellet, so that the release rate of melatonin after taking for 5 hours reaches 85-100%, the condition that the release rate is too fast to ensure sleeping quality at night and the release is too slow to influence the daytime can be avoided, meanwhile, the release rate of melatonin is stable, the blood concentration in a human body is stable, the sudden release phenomenon and the time lag phenomenon (the release rate after taking for 1 hour can reach more than 30%) are avoided, and the melatonin sustained-release pellet can take effect rapidly and has small toxic and side effects. In addition, the melatonin slow-release pellets have larger distribution area on the surface of the gastrointestinal tract, which is beneficial to reducing the irritation of the medicine to the gastrointestinal tract and improving the bioavailability of the medicine.
The composition components and the dosage of each component of the melatonin sustained-release pellet can influence the release of melatonin, and all factors must be comprehensively controlled to realize ideal release speed on the whole, wherein any one of the factors is improperly controlled, so that the release speed is possibly too high or too low, or the phenomenon of sudden release or time lag occurs. For example:
(1) Dodecyl sulfate is added into the medicine-containing layer, and the dosage is controlled:
when the melatonin powder is adopted for granulation, the problem of uneven distribution of melatonin on the mannitol pill core exists. However, if the granules are granulated by spraying the melatonin solution onto the mannitol cores, the melatonin cannot be dissolved by water, and some organic solvents (such as ethanol) can dissolve the melatonin to a certain extent, but the problem of uneven melatonin dispersion still exists. Therefore, the specific anionic surfactant dodecyl benzene sulfonate is added into the drug-containing layer aiming at the molecular structure of the melatonin, so that the melatonin can be more uniformly dispersed in the solution by utilizing acting forces such as hydrogen bonds, and further the distribution of the melatonin in the drug-containing layer is more uniform, thereby being beneficial to better controlling the release speed of the melatonin, enabling the melatonin to take effect quickly after taking the drug, ensuring sleeping quality at night and avoiding influencing the daytime state.
When the amount of the dodecyl sulfate to be used is too small, melatonin cannot be uniformly dispersed, which is disadvantageous in controlling the release rate of melatonin to a desired level. Furthermore, the present team found that when the amount of dodecyl sulfate relative to melatonin was too large, the rate of melatonin release was too fast.
(2) Adding hydroxypropyl methyl cellulose into the medicine-containing layer, and controlling the dosage of the hydroxypropyl methyl cellulose:
in the process of applying (i.e., dosing) a mixed solution containing melatonin and dodecyl sulfate onto a pellet core, particularly when the process is performed in a centrifugal granulator, the phenomenon of separation of the pellet core from the solution tends to occur, which makes it difficult for melatonin to be effectively bound to the pellet core, and eventually results in too low drug loading in the melatonin sustained release pellets. In order to solve the problem, the hydroxypropyl methylcellulose is added into the drug-containing layer, and hydrogen bonds can be formed between the hydroxypropyl methylcellulose and the mannitol pill core and between the hydroxypropyl methylcellulose and the melatonin, so that the melatonin is favorably and rapidly combined with the mannitol pill core in the preparation process.
In addition, the hydroxypropyl methylcellulose is selected as the binder between melatonin and the pill core, and has the following effects: the hydroxypropyl methylcellulose has certain water solubility, and can be dissolved after being contacted with enough water so as to release the melatonin adhered on the pill core, so that the hydroxypropyl methylcellulose is used as an adhesive, and the melatonin is not stably adhered on the pill core after entering a human body for a period of time, so that the release speed of the melatonin is too slow. In addition, in the selection of the binder, even though the binder is soluble, different binders have different solubilities and dissolution rates, and the disintegration rates in the body are also different, and thus the release rate of melatonin is related to the selection of the binder.
In addition, when the dosage of the hydroxypropyl methylcellulose relative to the melatonin is too small, the problem that the drug loading rate in the melatonin sustained-release pellets is too small due to the separation of the pellet core and the solution in the drug loading process is difficult to effectively solve. When the amount of hydroxypropyl methylcellulose is too large relative to melatonin, the release rate of melatonin in the body is too slow.
(3) Shellac is selected as the coating material and its dosage is controlled:
the choice of coating material and the amount of the coating material can influence the speed of melatonin penetrating through the coating layer, and simultaneously can influence the contact speed of moisture penetrating through the coating layer and hydroxypropyl methylcellulose in the drug-carrying layer, so that the speed of the hydroxypropyl methylcellulose disintegrating and releasing melatonin is influenced. The shellac is selected as the coating material, the mass ratio of the shellac to the pill core is controlled within a range, and the release speed of melatonin can be controlled to be at an ideal level after the shellac is matched with other components.
Preferably, the hydroxypropyl methylcellulose has a methoxy group content of 19-24% and a hydroxypropoxy group content of 4-12%.
For hydroxypropyl methylcellulose that is soluble in water, wherein methoxy (i.e. -OCH 3 ) And hydroxypropoxy (i.e. -OCH) 2 (OH)CH 3 ) The content of (2) affects its solubility and dissolution rate, and thus its rate of disintegration in the body, and ultimately the rate of melatonin release. The invention is realized by selecting hydroxypropyl methyl fiberThe composition is used as adhesive, and the content of methoxy and hydroxypropyl groups is controlled to be in the range of 19-24% and 4-12%, respectively, and can realize ideal melatonin release speed by being matched with other components.
Preferably, the melatonin sustained release pellets have a melatonin content of 0.8-1.3 wt%.
Preferably, the particle size of the melatonin slow-release pellets is 0.6-0.8 mm.
In a second aspect, the invention provides a preparation method of the melatonin sustained release pellets, which comprises the following steps:
(1) Weighing all raw materials according to parts by weight for standby;
(2) Dissolving melatonin in an organic solvent A to prepare a melatonin solution; dissolving dodecyl sulfate in water to obtain dodecyl sulfate solution;
(3) Uniformly mixing a melatonin solution and a dodecyl sulfate solution to prepare a mixed solution A;
(4) Dissolving hydroxypropyl methylcellulose in an organic solvent B to prepare hydroxypropyl methylcellulose solution;
(5) Uniformly mixing the mixed solution A and the hydroxypropyl methyl cellulose solution to prepare a mixed solution B;
(6) Spraying the mixed solution B onto mannitol pill cores by adopting a spraying and medicine feeding mode to obtain pill cores;
(7) Dissolving shellac in an organic solvent C to prepare shellac solution;
(8) Coating the pill core with shellac solution to obtain melatonin sustained release pill.
Preferably, the organic solvent a, the organic solvent B and the organic solvent C are all ethanol.
According to the invention, the hydroxypropyl methylcellulose is selected as the adhesive, and because the melatonin and the hydroxypropyl methylcellulose can be both dissolved in the ethanol water solution under the action of the dodecyl sulfate, the melatonin and the hydroxypropyl methylcellulose can not be separated or agglomerated from the solution after the mixed solution B is prepared, and can be uniformly dispersed, so that the melatonin and the adhesive can be uniformly distributed in the drug-containing layer, and the drug release speed of the melatonin sustained-release pellets is more stable.
Preferably, in the step (2), the concentration of the melatonin solution is 1.0 to 1.5wt% and the concentration of the dodecyl sulfate solution is 0.1 to 0.3wt%; in the step (4), the concentration of the hydroxypropyl methylcellulose solution is 1.0-1.5wt%; in the step (7), the concentration of the shellac solution is 4.5-5.5 wt%.
Preferably, in the step (6), spraying and dosing are performed in a centrifugal granulator, the temperature is controlled to be 45-50 ℃, and the rotating speed is controlled to be 20-150 r/min.
Further, in the step (6), air blowing is carried out while spraying and medicine feeding, the air blowing frequency is controlled to be 10-20 Hz, and the air pressure in the centrifugal granulator is controlled to be 0.2-0.7 MPa.
Preferably, in the step (8), the temperature is controlled to be 45-50 ℃ during the coating process.
Preferably, in the step (8), after coating, screening is performed to screen melatonin sustained release pellets with the particle size of 0.6-0.8 mm.
Compared with the prior art, the invention has the following advantages:
(1) In the melatonin slow-release pellet, the composition components and the dosage of each component are comprehensively controlled, so that the release speed of melatonin can be controlled at an ideal level, the sleeping quality at night is ensured, the influence on the state at daytime is avoided, and the phenomena of burst release and time lag are avoided, thereby rapidly taking effect after taking medicine and reducing toxic and side effects;
(2) In the melatonin sustained release pellets, the substitution degree of methoxy and hydroxypropyl groups in the hydroxypropyl methylcellulose is controlled, so that the melatonin sustained release pellets are beneficial to avoiding too high or too low release speed.
Drawings
Fig. 1 is a cumulative release profile of melatonin sustained release pellets of example 1.
Detailed Description
The invention is further described below with reference to examples.
General examples
The melatonin slow release pellet sequentially comprises a pellet core, a drug-containing layer and a coating layer from inside to outside; the pill core is mannitol pill core; the medicine-containing layer comprises melatonin, dodecyl sulfate and hydroxypropyl methylcellulose; the coating layer comprises shellac; the melatonin slow-release pellets comprise the following raw materials in parts by weight: 1.0 to 1.5 parts of melatonin, 0.1 to 0.3 part of dodecyl sulfate, 90 to 95 parts of mannitol pill core, 1.0 to 1.5 parts of hydroxypropyl methyl cellulose and 2.7 to 5.5 parts of shellac; in the raw materials, the mass ratio of the melatonin to the hydroxypropyl methylcellulose is 1:0.8-1, the mass ratio of the melatonin to the dodecyl sulfate is 1:0.1-0.3, and the mass ratio of the mannitol pill core to the shellac is 1:0.03-0.06.
As a specific embodiment, the hydroxypropyl methylcellulose has a methoxy group content of 19-24% and a hydroxypropoxy group content of 4-12%.
As a specific embodiment, the content of ethoxy in the shellac is 48-49.5%.
As a specific embodiment, the melatonin sustained release pellet has a melatonin content of 0.8-1.3 wt%.
As a specific embodiment, the particle size of the melatonin sustained release pellets is 0.6-0.8 mm.
The preparation method of the melatonin sustained release pellets comprises the following steps:
(1) Weighing all raw materials according to parts by weight for standby;
(2) Dissolving melatonin in an organic solvent A to prepare a melatonin solution; dissolving dodecyl sulfate in water to obtain dodecyl sulfate solution;
(3) Uniformly mixing a melatonin solution and a dodecyl sulfate solution to prepare a mixed solution A;
(4) Dissolving hydroxypropyl methylcellulose in an organic solvent B to prepare hydroxypropyl methylcellulose solution;
(5) Uniformly mixing the mixed solution A and the hydroxypropyl methyl cellulose solution to prepare a mixed solution B;
(6) Spraying the mixed solution B onto mannitol pill cores by adopting a spraying and medicine feeding mode to obtain pill cores;
(7) Dissolving shellac in an organic solvent C to prepare shellac solution;
(8) Coating the pill core with shellac solution to obtain melatonin sustained release pill.
As a specific embodiment, the organic solvent a, the organic solvent B, and the organic solvent C are all ethanol.
As a specific embodiment, in the step (2), the concentration of the melatonin solution is 1.0 to 1.5wt% and the concentration of the dodecyl sulfate solution is 0.1 to 0.3wt%; in the step (4), the concentration of the hydroxypropyl methylcellulose solution is 1.0-1.5wt%; in the step (7), the concentration of the shellac solution is 4.5-5.5 wt%.
In the step (6), spraying and spraying are performed in a centrifugal granulator, air blowing is performed while spraying and spraying, the air blowing frequency is controlled to be 10-20 Hz, the air pressure in the centrifugal granulator is controlled to be 0.2-0.7 MPa, the temperature is controlled to be 45-50 ℃, and the rotating speed is controlled to be 20-150 r/min.
As a specific embodiment, in the step (8), the temperature is controlled to be 45-50 ℃ in the coating process.
In step (8), after coating, the melatonin slow-release pellets with the particle size of 0.6-0.8 mm are screened out by screening.
Example 1
The melatonin slow release pill sequentially comprises a pill core, a medicine-containing layer and a coating layer from inside to outside, wherein the raw materials and the dosage of the layers are shown in table 1.
TABLE 1
Figure BDA0004100374610000061
The melatonin slow release pellets are prepared by the following steps:
(1) Weighing all raw materials according to parts by weight for standby;
(2) Adding melatonin into ethanol, controlling the temperature to be 47.5+/-2.5 ℃, and heating and dissolving to prepare a melatonin solution with the concentration of 1.2 weight percent; dissolving sodium dodecyl sulfate in water to prepare sodium dodecyl sulfate solution with the concentration of 0.2 wt%;
(3) Uniformly mixing melatonin solution and sodium dodecyl sulfate solution to prepare a mixed solution A;
(4) Dissolving hydroxypropyl methylcellulose in ethanol, controlling the temperature to 47.5+/-2.5 ℃, and heating to dissolve to prepare a hydroxypropyl methylcellulose solution with the concentration of 1.2 weight percent;
(5) Uniformly mixing the mixed solution A and the hydroxypropyl methyl cellulose solution to prepare a mixed solution B;
(6) Starting air blast in a centrifugal granulator, setting the air blast frequency to be 15Hz, setting the air pressure in the centrifugal granulator to be 0.5MPa and the temperature to be 50 ℃, putting mannitol pill cores into the centrifugal granulator, setting the rotating speed to be 100r/min, spraying the mixed solution B onto the mannitol pill cores in a spraying and medicine feeding mode, and discharging to obtain pill cores;
(7) Dissolving shellac in ethanol to obtain shellac solution with concentration of 5wt%;
(8) And (3) putting the pill cores into a multifunctional coating machine, setting the temperature to be 40 ℃, coating the pill cores by using shellac solution, and then screening according to the target particle size of 0.6-0.8 mm to obtain the melatonin slow-release pellets.
Example 2
The melatonin slow release pill sequentially comprises a pill core, a medicine-containing layer and a coating layer from inside to outside, wherein the raw materials and the dosage of each layer are shown in table 2.
TABLE 2
Figure BDA0004100374610000071
The melatonin slow release pellets are prepared by the following steps:
(1) Weighing all raw materials according to parts by weight for standby;
(2) Adding melatonin into ethanol, controlling the temperature to be 47.5+/-2.5 ℃, and heating and dissolving to prepare a melatonin solution with the concentration of 1.0 weight percent; dissolving sodium dodecyl sulfate in water to prepare sodium dodecyl sulfate solution with the concentration of 0.3wt%;
(3) Uniformly mixing melatonin solution and sodium dodecyl sulfate solution to prepare a mixed solution A;
(4) Dissolving hydroxypropyl methylcellulose in ethanol, controlling the temperature to 47.5+/-2.5 ℃, and heating to dissolve to prepare a hydroxypropyl methylcellulose solution with the concentration of 1.0 wt%;
(5) Uniformly mixing the mixed solution A and the hydroxypropyl methyl cellulose solution to prepare a mixed solution B;
(6) Starting air blast in a centrifugal granulator, setting the air blast frequency to be 20Hz, setting the air pressure in the centrifugal granulator to be 0.7MPa and the temperature to be 45 ℃, putting mannitol pill cores into the centrifugal granulator, setting the rotating speed to be 150r/min, spraying the mixed solution B onto the mannitol pill cores in a spraying and medicine feeding mode, and discharging to obtain pill cores;
(7) Dissolving shellac in ethanol to prepare shellac solution with the concentration of 4.5 wt%;
(8) And (3) putting the pill cores into a multifunctional coating machine, setting the temperature to be 50 ℃, coating the pill cores by using shellac solution, and then screening according to the target particle size of 0.6-0.8 mm to obtain the melatonin slow-release pellets.
Example 3
The melatonin slow release pill sequentially comprises a pill core, a medicine-containing layer and a coating layer from inside to outside, wherein the raw materials and the dosage of each layer are shown in table 3.
TABLE 3 Table 3
Figure BDA0004100374610000072
The melatonin slow release pellets are prepared by the following steps:
(1) Weighing all raw materials according to parts by weight for standby;
(2) Adding melatonin into ethanol, controlling the temperature to be 47.5+/-2.5 ℃, and heating and dissolving to prepare a melatonin solution with the concentration of 1.5 weight percent; dissolving sodium dodecyl sulfate in water to prepare sodium dodecyl sulfate solution with the concentration of 0.1 wt%;
(3) Uniformly mixing melatonin solution and sodium dodecyl sulfate solution to prepare a mixed solution A;
(4) Dissolving hydroxypropyl methylcellulose in ethanol, controlling the temperature to 47.5+/-2.5 ℃, and heating to dissolve to prepare a hydroxypropyl methylcellulose solution with the concentration of 1.5 weight percent;
(5) Uniformly mixing the mixed solution A and the hydroxypropyl methyl cellulose solution to prepare a mixed solution B;
(6) Starting air blast in a centrifugal granulator, setting the air blast frequency to be 10Hz, setting the air pressure in the centrifugal granulator to be 0.2MPa and the temperature to be 45 ℃, putting mannitol pill cores into the centrifugal granulator, setting the rotating speed to be 20r/min, spraying the mixed solution B onto the mannitol pill cores in a spraying and medicine feeding mode, and discharging to obtain pill cores;
(7) Dissolving shellac in ethanol to obtain shellac solution with concentration of 5.5 wt%;
(8) And (3) putting the pill cores into a multifunctional coating machine, setting the temperature to be 50 ℃, coating the pill cores by using shellac solution, and then screening according to the target particle size of 0.6-0.8 mm to obtain the melatonin slow-release pellets.
Example 4
The melatonin slow release pill sequentially comprises a pill core, a medicine-containing layer and a coating layer from inside to outside, wherein the raw materials and the dosage of each layer are shown in table 4.
TABLE 4 Table 4
Figure BDA0004100374610000081
The melatonin slow release pellets are prepared by the following steps:
(1) Weighing all raw materials according to parts by weight for standby;
(2) Adding melatonin into ethanol, controlling the temperature to be 47.5+/-2.5 ℃, and heating and dissolving to prepare a melatonin solution with the concentration of 1.2 weight percent; dissolving sodium dodecyl sulfate in water to prepare sodium dodecyl sulfate solution with the concentration of 0.2 wt%;
(3) Uniformly mixing melatonin solution and sodium dodecyl sulfate solution to prepare a mixed solution A;
(4) Dissolving hydroxypropyl methylcellulose in ethanol, controlling the temperature to 47.5+/-2.5 ℃, and heating to dissolve to prepare a hydroxypropyl methylcellulose solution with the concentration of 1.2 weight percent;
(5) Uniformly mixing the mixed solution A and the hydroxypropyl methyl cellulose solution to prepare a mixed solution B;
(6) Starting air blast in a centrifugal granulator, setting the air blast frequency to be 15Hz, setting the air pressure in the centrifugal granulator to be 0.5MPa and the temperature to be 50 ℃, putting mannitol pill cores into the centrifugal granulator, setting the rotating speed to be 100r/min, spraying the mixed solution B onto the mannitol pill cores in a spraying and medicine feeding mode, and discharging to obtain pill cores;
(7) Dissolving shellac in ethanol to obtain shellac solution with concentration of 5wt%;
(8) And (3) putting the pill cores into a multifunctional coating machine, setting the temperature to be 50 ℃, coating the pill cores by using shellac solution, and then screening according to the target particle size of 0.6-0.8 mm to obtain the melatonin slow-release pellets.
Example 5
The melatonin slow release pill sequentially comprises a pill core, a medicine-containing layer and a coating layer from inside to outside, wherein the raw materials and the dosage of each layer are shown in table 5.
TABLE 5
Figure BDA0004100374610000091
The melatonin slow release pellets are prepared by the following steps:
(1) Weighing all raw materials according to parts by weight for standby;
(2) Adding melatonin into ethanol, controlling the temperature to be 47.5+/-2.5 ℃, and heating and dissolving to prepare a melatonin solution with the concentration of 1.2 weight percent; dissolving sodium dodecyl sulfate in water to prepare sodium dodecyl sulfate solution with the concentration of 0.2 wt%;
(3) Uniformly mixing melatonin solution and sodium dodecyl sulfate solution to prepare a mixed solution A;
(4) Dissolving hydroxypropyl methylcellulose in ethanol, controlling the temperature to 47.5+/-2.5 ℃, and heating to dissolve to prepare a hydroxypropyl methylcellulose solution with the concentration of 1.2 weight percent;
(5) Uniformly mixing the mixed solution A and the hydroxypropyl methyl cellulose solution to prepare a mixed solution B;
(6) Starting air blast in a centrifugal granulator, setting the air blast frequency to be 15Hz, setting the air pressure in the centrifugal granulator to be 0.5MPa and the temperature to be 50 ℃, putting mannitol pill cores into the centrifugal granulator, setting the rotating speed to be 100r/min, spraying the mixed solution B onto the mannitol pill cores in a spraying and medicine feeding mode, and discharging to obtain pill cores;
(7) Dissolving shellac in ethanol to obtain shellac solution with concentration of 5wt%;
(8) And (3) putting the pill cores into a multifunctional coating machine, setting the temperature to be 50 ℃, coating the pill cores by using shellac solution, and then screening according to the target particle size of 0.6-0.8 mm to obtain the melatonin slow-release pellets.
Comparative example 1
The melatonin slow release pill sequentially comprises a pill core, a medicine-containing layer and a coating layer from inside to outside, wherein the raw materials and the dosage of each layer are shown in table 6.
TABLE 6
Figure BDA0004100374610000101
The melatonin slow release pellets are prepared by the following steps:
(1) Weighing all raw materials according to parts by weight for standby;
(2) Adding melatonin into ethanol, controlling the temperature to be 47.5+/-2.5 ℃, and heating and dissolving to prepare a melatonin solution with the concentration of 1.2 weight percent;
(3) Dissolving hydroxypropyl methylcellulose in ethanol, controlling the temperature to 47.5+/-2.5 ℃, and heating to dissolve to prepare a hydroxypropyl methylcellulose solution with the concentration of 1.2 weight percent;
(4) Uniformly mixing a melatonin solution and a hydroxypropyl methyl cellulose solution to prepare a mixed solution B;
(5) Starting air blast in a centrifugal granulator, setting the air blast frequency to be 15Hz, setting the air pressure in the centrifugal granulator to be 0.5MPa and the temperature to be 50 ℃, putting mannitol pill cores into the centrifugal granulator, setting the rotating speed to be 100r/min, spraying the mixed solution B onto the mannitol pill cores in a spraying and medicine feeding mode, and discharging to obtain pill cores;
(6) Dissolving shellac in ethanol to obtain shellac solution with concentration of 5wt%;
(7) And (3) putting the pill cores into a multifunctional coating machine, setting the temperature to be 50 ℃, coating the pill cores by using shellac solution, and then screening according to the target particle size of 0.6-0.8 mm to obtain the melatonin slow-release pellets.
Comparative examples 2 to 6
Comparative examples 2 to 6 were different from example 1 only in that the raw material amounts were changed according to Table 7, and the production process was the same as example 1.
TABLE 7
Figure BDA0004100374610000102
Figure BDA0004100374610000111
Comparative example 7
The melatonin slow release pill sequentially comprises a pill core, a medicine-containing layer and a coating layer from inside to outside, wherein the raw materials and the dosage of the layers are shown in table 8.
TABLE 8
Figure BDA0004100374610000112
The melatonin slow release pellets are prepared by the following steps:
(1) Weighing all raw materials according to parts by weight for standby;
(2) Adding melatonin into ethanol, controlling the temperature to be 47.5+/-2.5 ℃, and heating and dissolving to prepare a melatonin solution with the concentration of 1.2 weight percent; dissolving sodium dodecyl sulfate in water to prepare sodium dodecyl sulfate solution with the concentration of 0.2 wt%;
(3) Uniformly mixing melatonin solution and sodium dodecyl sulfate solution to prepare a mixed solution A;
(4) Dissolving hydroxypropyl methylcellulose in ethanol, controlling the temperature to 47.5+/-2.5 ℃, and heating to dissolve to prepare a hydroxypropyl methylcellulose solution with the concentration of 1.2 weight percent;
(5) Uniformly mixing the mixed solution A and the hydroxypropyl methyl cellulose solution to prepare a mixed solution B;
(6) Starting air blast in a centrifugal granulator, setting the air blast frequency to be 15Hz, setting the air pressure in the centrifugal granulator to be 0.5MPa and the temperature to be 50 ℃, putting mannitol pill cores into the centrifugal granulator, setting the rotating speed to be 100r/min, spraying the mixed solution B onto the mannitol pill cores in a spraying and medicine feeding mode, and discharging to obtain pill cores;
(7) Dissolving ethyl cellulose in ethanol to prepare an ethyl cellulose solution with the concentration of 5 weight percent;
(8) And (3) putting the pill cores into a multifunctional coating machine, setting the temperature to be 50 ℃, coating the pill cores by using shellac solution, and then screening according to the target particle size of 0.6-0.8 mm to obtain the melatonin slow-release pellets.
Test case
The melatonin sustained release pellets prepared in each of examples and comparative examples were taken, the melatonin content (mass percent) therein was measured, and the release rate of melatonin, i.e., the cumulative release rate of melatonin at 1h, 3h and 5h, was measured, and the results are shown in table 9, and the cumulative release rate profile of melatonin in example 1 is shown in fig. 1.
TABLE 9
Figure BDA0004100374610000121
From fig. 1 and table 9, it can be seen that:
(1) In the embodiments 1 to 3, the release rate of melatonin in 0 to 3 hours is stable, the release rate after 1 hour can reach 32 to 35 percent, the release rate after 5 hours can reach 85 to 100 percent, and the phenomena of abrupt release and time lag do not exist, so that the melatonin slow release pellets have ideal release rate, can take effect rapidly after being taken, can avoid the problems that the release is too fast, the sleeping quality at night is difficult to ensure, and the release is too slow, so that the daytime state is influenced.
(2) With respect to sodium lauryl sulfate:
compared with example 1, the release rate of comparative example 1 is slower, the release rate after 1 hour can only reach 29.89%, and more melatonin is still not released after 5 hours. The explanation is through adding sodium dodecyl sulfate in the medicine-containing layer, can control the release rate of melatonin better, make it can take effect fast after taking medicine to when guaranteeing night sleep quality, avoid producing the influence to daytime's state. The method is characterized in that the dispersibility of the melatonin in the ethanol is poor, and after the ethanol solution of the melatonin is mixed with the sodium dodecyl sulfate, the sodium dodecyl sulfate can promote the melatonin to be uniformly dispersed in the ethanol-water mixed solvent, so that the melatonin is uniformly distributed in the medicine-containing layer.
The amount of sodium dodecyl sulfate used in comparative example 2 was too large compared to example 1, and the melatonin release rate was too high. The result shows that when the dosage of the sodium dodecyl sulfate in the medicine-containing layer is too large, the medicine release speed of the melatonin slow release pellets is too high, and the sleeping quality is difficult to ensure for a long time at night.
(3) Regarding hydroxypropyl methylcellulose:
the hydroxypropyl methylcellulose methoxy content used in example 4 was lower, the hydroxypropyl oxy content was higher, the hydroxypropyl methylcellulose methoxy content used in example 5 was higher, and the melatonin release rates in examples 4 and 5 were not ideal as compared to example 1. It is explained that when the content of methoxy and hydroxypropoxy groups in hydroxypropyl methylcellulose is controlled improperly, melatonin is released too fast or too slow, which makes it difficult to ensure the quality of sleeping at night or affects the state of the daytime. This is because the methoxy and hydroxypropoxy content of hydroxypropyl methylcellulose affects its solubility and dissolution rate, and thus its rate of disintegration in the body, ultimately affecting the rate of melatonin release.
Compared with example 1, the amount of hydroxypropyl methylcellulose in comparative example 3 was too small, and the melatonin content in the melatonin sustained release pellets was too small, because when a mixed solution containing melatonin and sodium dodecyl sulfate was applied to the pellet core in a centrifugal granulator, the amount of hydroxypropyl methylcellulose was too small, which resulted in difficulty in solving the problem of too small drug loading in the melatonin sustained release pellets due to separation of the pellet core from the solution.
Compared with example 1, the dosage of hydroxypropyl methylcellulose in comparative example 4 is too large, the melatonin release rate is too slow, the release rate is too low within 1h, and more melatonin is not released after 5h, because the dissolution of excessive hydroxypropyl methylcellulose is slow, and the rate of disintegration and release of melatonin is slow.
(4) Regarding shellac:
in example 1 and comparative example 7, shellac and ethylcellulose were used as the coating materials, respectively, the melatonin release rate of comparative example 7 was not good, since the choice of the coating material would affect the rate of melatonin permeation through the coating, and also the rate of moisture permeation through the coating and hydroxypropyl methylcellulose contact in the drug-loaded layer, and thus the rate of melatonin release by disintegration of hydroxypropyl methylcellulose.
Compared with example 1, the dosage of shellac in comparative example 5 was too small, the melatonin release rate was too high, the release rate reached 85.63% after 3 hours, and it was difficult to ensure the night sleep quality, because the rate of melatonin permeation through the coating layer was high, and the rate of moisture permeation through the coating layer and the rate of contact with hydroxypropyl methylcellulose in the drug-loaded layer was high, resulting in a high rate of release of melatonin by hydroxypropyl methylcellulose disintegration.
Compared with example 1, the shellac of comparative example 6 was too high in dosage, and the melatonin release rate was too slow, and the release rate was too low within 1 hour, and more melatonin was not released after 5 hours, because the melatonin penetrated the coating layer at a slower rate, and the hydroxypropyl methylcellulose was disintegrated at a slower rate by water penetration through the coating layer.
The raw materials and equipment used in the invention are common raw materials and equipment in the field unless specified otherwise; the methods used in the present invention are conventional in the art unless otherwise specified.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and any simple modification, variation and equivalent transformation of the above embodiment according to the technical substance of the present invention still fall within the scope of the technical solution of the present invention.

Claims (10)

1. The melatonin sustained release pellet is characterized by sequentially comprising a pellet core, a drug-containing layer and a coating layer from inside to outside; the pill core is mannitol pill core; the medicine-containing layer comprises melatonin, sodium dodecyl sulfate and hydroxypropyl methylcellulose; the coating layer comprises shellac; the melatonin slow-release pellets comprise the following raw materials in parts by weight: 1.0-1.5 parts of melatonin, 0.1-0.3 part of dodecyl sulfate, 90-95 parts of mannitol pill cores, 1.0-1.5 parts of hydroxypropyl methyl cellulose and 2.7-5.5 parts of shellac; in the raw materials, the mass ratio of the melatonin to the hydroxypropyl methylcellulose is 1:0.8-1, the mass ratio of the melatonin to the dodecyl sulfate is 1:0.1-0.3, and the mass ratio of the mannitol pill core to the shellac is 1:0.03-0.06.
2. The melatonin sustained release pellet of claim 1 wherein the hydroxypropyl methylcellulose has a methoxy content of 19-24% and a hydroxypropoxy content of 4-12%.
3. The melatonin sustained-release pellet of claim 1, wherein the melatonin content in the melatonin sustained-release pellet is 0.8-1.3 wt%.
4. The melatonin sustained release pellet of claim 1, wherein the melatonin sustained release pellet has a particle size of 0.6-0.8 mm.
5. A method for preparing the melatonin sustained release pellets of any one of claims 1-4, comprising the steps of:
(1) Weighing all raw materials according to parts by weight for standby;
(2) Dissolving melatonin in an organic solvent A to prepare a melatonin solution; dissolving dodecyl sulfate in water to obtain dodecyl sulfate solution;
(3) Uniformly mixing a melatonin solution and a dodecyl sulfate solution to prepare a mixed solution A;
(4) Dissolving hydroxypropyl methylcellulose in an organic solvent B to prepare hydroxypropyl methylcellulose solution;
(5) Uniformly mixing the mixed solution A and the hydroxypropyl methyl cellulose solution to prepare a mixed solution B;
(6) Spraying the mixed solution B onto mannitol pill cores by adopting a spraying and medicine feeding mode to obtain pill cores;
(7) Dissolving shellac in an organic solvent C to prepare shellac solution;
(8) Coating the pill core with shellac solution to obtain melatonin sustained release pill.
6. The method of claim 5, wherein the organic solvent A, the organic solvent B and the organic solvent C are ethanol.
7. The method according to claim 5, wherein in the step (2), the concentration of the melatonin solution is 1.0 to 1.5wt%, and the concentration of the dodecyl sulfate solution is 0.1 to 0.3wt%; in the step (4), the concentration of the hydroxypropyl methylcellulose solution is 1.0-1.5wt%; in the step (7), the concentration of the shellac solution is 4.5-5.5wt%.
8. The preparation method according to claim 5, wherein in the step (6), spraying and applying are performed in a centrifugal granulator, the temperature is controlled to be 40-50 ℃, and the rotating speed is controlled to be 20-150 r/min.
9. The method according to claim 5 or 8, wherein in the step (6), air blowing is performed while spraying, the frequency of the air blowing is controlled to be 10-20 hz, and the air pressure in the centrifugal granulator is controlled to be 0.2-0.7 mpa.
10. The method according to claim 5, wherein in the step (8), the temperature is controlled to be 40-50 ℃ during the coating.
CN202310174278.XA 2023-02-15 2023-02-15 Melatonin slow-release pellets and preparation method thereof Pending CN116172979A (en)

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