CN117815226A - Melatonin anhydrous swallow granule and preparation method thereof - Google Patents

Abstract

The invention provides melatonin anhydrous swallow particles, which comprise drug-carrying micropills and taste-modifying particles, wherein the drug-carrying micropills comprise pill cores and smooth layers from inside to outside. The pill-containing core comprises microcrystalline cellulose pill core, melatonin, hypromellose, polysorbate 80 and purified water; the smooth layer comprises hydroxypropyl methylcellulose, carbomer, talcum powder, titanium dioxide, sucralose and ethanol; the taste-modifying particles comprise sorbitol, sodium carboxymethyl cellulose, aspartame, citric acid, fruit essence, magnesium stearate and ethanol; the core of the pill can also contain gamma-aminobutyric acid and/or L-magnesium threonate. The melatonin anhydrous swallow granule provided by the invention is convenient to take, can obviously improve the sleep quality of the elderly, does not contain sugar in the preparation, and can be taken by the diabetic elderly.

Description

Melatonin anhydrous swallow granule and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical preparations, relates to a novel dosage form of melatonin, and in particular relates to a melatonin anhydrous swallow granule and a preparation method thereof.

Background

Melatonin (Melatonin) is also known as pine cone hormone, commonly known as human brain platinum, has a chemical structural formula of N-ethyl-5-methoxy tryptamine, and is a hormone with antioxidant activity secreted by animals and plants. Researches prove that melatonin controls the biological clock of a human body, and the melatonin in the body is reduced year by year along with the increase of the age, so that a series of aging symptoms such as insomnia, dreaminess, amnesia and the like appear. In recent years, the biological functions of melatonin, especially the health care functions as dietary supplements are widely studied at home and abroad, and the melatonin has various physiological functions of promoting sleep, resisting aging, preventing and treating senile dementia, regulating immunity, preventing senile cataract, macular degeneration and retinal detachment, regulating organism biological clock to promote sleep, reducing cholesterol to relieve atherosclerosis, resisting tumor and the like. Therefore, the melatonin is supplemented from outside the body, so that the level of the in-vivo black-cord fading can be maintained in a young state, the circadian rhythm is regulated and recovered, the sleep can be deepened, the sleep quality is improved, more importantly, the functional state of the whole body is improved, the life quality is improved, and the aging process is delayed. Melatonin is a currently accepted health food which can replace 'stable' without side effects and addiction.

Gamma-aminobutyric acid (GABA) is an amino acid that is widely found in vertebrates, plants, and microorganisms. Gamma-aminobutyric acid is an important central nervous system inhibitory neurotransmitter, which has good water solubility and thermal stability. It has been confirmed that GABA, which is a small molecular weight non-protein amino acid, is safe for eating and can be used for the production of foods such as beverages. Research shows that the intake of a certain amount of GABA has the physiological effects of improving the sleep quality of organisms, reducing blood pressure and the like.

Magnesium L-threonate is a binary compound of L-threonic acid and magnesium ions. L-threonic acid is a degradation product of vitamin C, and simple edible salts of L-threonic acid can promote the absorption and utilization of vitamin C in the human body. Numerous studies have shown that magnesium L-threonate contributes to age-related memory loss, mood disorders, neuroinflammation, and enhances cognitive function. Proper amounts of magnesium supplements have been shown to improve mood, enhance stress resistance, increase attention and concentration, increase energy levels, and improve sleep quality. The national health buddhist in 2016 issues No. 8 bulletin, and the L-threonic acid magnesium is listed as a new variety of food nutrition enhancer for enhancing magnesium element in food.

With the age, the pine cone gradually shrinks, the secreted melatonin is correspondingly reduced, particularly after the age of 35 years, the self-secreted melatonin in the body is obviously reduced by 10-15% every 10 years on average, sleep disorder and a series of dysfunctions are caused, and the reduced melatonin level and the reduced sleep are one of important marks of human brain aging. Therefore, the melatonin is supplemented from outside the body, so that the melatonin level in the body can be maintained in a young state, the circadian rhythm is regulated and recovered, the sleep can be deepened, the sleep quality is improved, more importantly, the functional state of the whole body is improved, the life quality is improved, and the aging process is delayed.

Most of the existing melatonin products are administered in the form of tablets and capsules, and few oral liquid or gel candy forms exist. The usage rate of auxiliary materials in tablets, soft capsules, oral liquid and gel candies is relatively high, so that the product shape is relatively high, and the taking difficulty is increased for people with dyspepsia in the gastrointestinal tract of the elderly, children.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a melatonin preparation which is convenient to take, can well improve sleep quality and cognitive ability, a melatonin particle which can be swallowed without water and a preparation method thereof.

In order to achieve the above purpose, the present invention adopts the following technical scheme:

a melatonin anhydrous swallow granule comprises drug-loaded micropill and corrective granule, wherein the drug-loaded micropill comprises a drug-containing pill core and a smooth layer from inside to outside.

The pill core comprises microcrystalline cellulose pill core, melatonin, hypromellose, polysorbate 80 and purified water; wherein the microcrystalline cellulose pellet core is by weight: melatonin: hypromellose: polysorbate 80: purified water = 150-500:1-5:5-10:2-8:200-600;

preferably, the microcrystalline cellulose pellet core, by weight: melatonin: hypromellose: polysorbate 80: purified water = 200-400:1-4:8-10:3-6:300-500;

more preferably, the microcrystalline cellulose pellet core, by weight: melatonin: hypromellose: polysorbate 80: purified water = 300:3:9:5:400;

the smooth layer comprises hypromellose, carbomer, talcum powder, titanium dioxide, sucralose and ethanol; wherein, by weight, the hypromellose: carbomer: talc powder: titanium dioxide: sucralose: ethanol=2-10:1-5:10-30:5-20:40-100:100-300;

preferably, hypromellose, by weight: carbomer: talc powder: titanium dioxide: sucralose: ethanol=3-8:2-4:15-25:8-16:60-80:150-250;

more preferably, hypromellose, by weight: carbomer: talc powder: titanium dioxide: sucralose: ethanol=5:3:20:12:70:200;

the above-mentioned taste-modifying granule contains sorbitol, sodium carboxymethyl cellulose, aspartame, citric acid, fruit essence, magnesium stearate and ethanol, the said fruit essence is selected from orange essence, apple essence, etc., wherein, by weight, sorbitol: sodium carboxymethyl cellulose: aspartame: citric acid: fruit essence: magnesium stearate=400-800:5-20:1-5:0-10:10-30:1-8, proper amount of ethanol;

preferably, sorbitol, by weight: sodium carboxymethyl cellulose; aspartame; citric acid: fruit essence: magnesium stearate = 500-700:8-15:1-4:4-8:15-25:3-6;

more preferably, sorbitol, by weight: sodium carboxymethyl cellulose; aspartame; citric acid: fruit essence: magnesium stearate = 600:13:3:6:10:4;

the mass percentage of the pill-containing core and the smooth layer in the drug-carrying micropill is 60-90 percent, 10-40 percent;

the mass ratio of the drug-carrying pellets to the taste-modifying particles in the anhydrous swallow particles is 1:0.5-3;

in some embodiments, the melatonin anhydrous swallow granule further comprises gamma-aminobutyric acid, wherein the mass ratio of melatonin to gamma-aminobutyric acid is 1-5:20-60, preferably the mass ratio of melatonin to gamma-aminobutyric acid is 3:50;

in some embodiments, the melatonin anhydrous swallow granule further comprises magnesium L-threonate, wherein the mass ratio of melatonin, gamma-aminobutyric acid, and magnesium L-threonate is 1-5:20-60:100-500, preferably the mass ratio of melatonin, gamma-aminobutyric acid, and magnesium L-threonate is 3:50:300;

the invention also provides a preparation method of the melatonin anhydrous swallow granule, which comprises the following steps:

preparation of the pill-containing core: dissolving the hydroxypropyl methylcellulose with the prescription amount in purified water, fully stirring and dissolving, sequentially adding melatonin and polysorbate 80, and stirring to prepare uniform suspension; taking microcrystalline cellulose pill core as medicine-carrying base pill, adopting fluidized bed bottom spray to make suspension medicine-feeding procedure, controlling material temperature at 30-50deg.C in medicine-feeding process, continuously drying micropill after medicine-feeding is completed, and controlling micropill water content below 3% (weight).

Preparation of a smooth layer: adding the prescription amount of hypromellose, carbomer, talcum powder, titanium dioxide and sucralose into ethanol to prepare uniform smooth layer coating suspension; and (3) coating the pill-containing cores by adopting a fluidized bed medicine feeding procedure, wherein the material temperature is controlled to be 30-50 ℃ in the medicine feeding process, and the coated medicine-carrying pellets are obtained.

Preparation of taste-modifying particles: adding the sorbitol, aspartame, citric acid and fruit essence with the prescription amount into a wet granulator, fully mixing the materials, adding a proper amount of ethanol in an atomized form under the stirring state, granulating for a certain time, and performing wet granulation; drying by using a fluidized bed, and sieving with a 20-mesh sieve for dry granulation; and adding sodium carboxymethylcellulose and magnesium stearate in a prescription proportion into the particles according to the yield of the materials, and uniformly mixing to obtain the taste-correcting particles.

Mixing the drug-loaded pellets with the taste-modifying particles: mixing the drug-loaded pellets and the taste-correction particles according to a certain proportion to obtain the melatonin anhydrous swallow particles.

In some embodiments, a prescribed amount of gamma-aminobutyric acid may also be added during the preparation of the medicated pill core;

in some embodiments, the prescribed amount of magnesium L-threonate can be added during the preparation of the pill-containing core;

the invention adopts microcrystalline cellulose pellets, sucralose, aspartame and other sweeteners, and the prescription does not contain sugar, so that the diabetic elderly can take the drug with safety.

According to the invention, the gamma-aminobutyric acid is added on the basis of the melatonin, so that the gamma-aminobutyric acid can produce a synergistic effect with the melatonin, and the sleeping quality is further improved.

According to the invention, based on melatonin and gamma-aminobutyric acid, the L-magnesium threonate is added, so that the L-magnesium threonate is beneficial to memory loss, mood disorder and neuroinflammation related to age, and the cognitive function is enhanced, and the addition of the L-magnesium threonate is beneficial to further improving sleep quality.

The melatonin anhydrous swallow granule overcomes the defect that the conventional preparation needs to be taken with water or is taken after being infused with water, can be taken without water, has fragrant and sweet taste, and improves the compliance of a user.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Example 1

Prescription:

the preparation process comprises the following steps:

preparation of the pill-containing core: dissolving the prescription amount of hypromellose in purified water, fully stirring and dissolving, sequentially adding melatonin and polysorbate 80, and stirring to prepare uniform suspension; taking microcrystalline cellulose pill core as medicine-carrying base pill, adopting fluidized bed to make suspension medicine-feeding process, controlling material temperature at 30-50deg.C in the medicine-feeding process, continuously drying micropill after medicine-feeding is completed, and controlling water content of micropill below 3% (weight).

Preparation of a smooth layer: adding hypromellose, carbomer, talcum powder, titanium dioxide and sucralose into ethanol to prepare uniform smooth layer coating suspension; and (3) coating the pill-containing cores by adopting a fluidized bed medicine feeding procedure, wherein the material temperature is controlled to be 30-50 ℃ in the medicine feeding process, and the coated medicine-carrying pellets are obtained.

Preparation of taste-modifying particles: adding the prescription amount of sorbitol, aspartame, citric acid and orange essence into a wet granulator, fully mixing the materials, adding a proper amount of ethanol in an atomized form under the stirring state, granulating for a certain time, and performing wet granulation; drying by using a fluidized bed, and sieving with a 20-mesh sieve for dry granulation; and adding sodium carboxymethyl cellulose and magnesium stearate into the particles according to the yield of the materials, and uniformly mixing to obtain the taste-correcting particles.

Mixing the drug-loaded pellets with the taste-modifying particles: mixing the drug-loaded pellets and the taste-correction particles according to the mass ratio of 1:1 to obtain the melatonin anhydrous swallow particles.

Example 2

Prescription:

the preparation process is the same as in example 1, except that the drug-loaded pellets and the taste-modifying particles are mixed according to a mass ratio of 1:2, and the melatonin anhydrous swallow particles are obtained.

Example 3

Prescription:

the preparation process is the same as in example 1, except that the drug-loaded pellets and the taste-modifying particles are mixed according to the mass ratio of 2:1, and the melatonin anhydrous swallow particles are obtained.

Example 4

Prescription:

the preparation process is the same as in example 1, and the melatonin anhydrous swallow granule is obtained by mixing the drug-carrying pellets and the taste-modifying granules according to the mass ratio of 1:3.

Example 5

The recipe was as in example 4 except that 50g of gamma-aminobutyric acid was added to the core of the pellets, and the preparation process was as in example 1 except that 50g of gamma-aminobutyric acid was added simultaneously with melatonin.

Example 6

The recipe was as in example 5 except that the amount of gamma-aminobutyric acid added was 20g, and the preparation process was as in example 5.

Example 7

The recipe was as in example 5 except that the amount of gamma-aminobutyric acid added was 60g, and the preparation process was as in example 5.

Example 8

The recipe is the same as in example 5 except that the active ingredient L-magnesium threonate is added into the core of the pill, the amount of the L-magnesium threonate is 300g, the preparation process is the same as in example 5 except that melatonin and gamma-aminobutyric acid are added, 300g of the L-magnesium threonate is added at the same time, and finally the drug-carrying pellets and the taste-modifying particles are mixed according to the mass ratio of 2:1, so that the melatonin anhydrous swallow particles are obtained.

Example 9

The recipe was as in example 8 except that the amount of magnesium L-threonate added was 100g, and the preparation process was the same as in example 8.

Example 10

The recipe was as in example 8 except that the amount of magnesium L-threonate added was 500g, and the preparation process was the same as in example 8.

Experiment of the effect of the preparation

Experiment 1 experiment of the effect of no-water swallowing

Taking 5g of melatonin anhydrous swallow granules prepared in examples 1-10, selecting 20 healthy adult men and women with ages of 25-40 as an evaluator, recording time of complete dissolution of the granules in the mouth and taste evaluation after taking, and recording that complete dissolution and smooth swallowing of the granules in the mouth are qualified after 2min, and that complete dissolution of the granules in the mouth is unqualified after 2 min; the taste evaluation criteria were: a score of 5 represents that the particles are smooth and sweet in taste; a score of 4 represents that the particles were smooth, slightly off-flavor but acceptable; the 3 points represent slightly rough particles, and the taste of the particles is fragrant and sweet; score 2 represents slightly coarser particles, slightly off-flavored but acceptable; a score of 1 represents slightly coarser particles, which are unacceptable in taste; a score of 0 represents a coarse particle and an unacceptable taste. The specific evaluation results are shown in Table 1.

TABLE 1 results of experiment on the effect of no-water swallowing

Through a swallowing test, the anhydrous swallowing particles prepared by the invention can be rapidly disintegrated and dissolved in the mouth, and can be swallowed without water; the anhydrous swallow granule prepared by the invention has smooth and sweet taste, and improves the compliance of patients.

Experiment 2 dissolution test

The melatonin anhydrous swallow particles prepared in the embodiments 1-10 of the invention are taken as test objects for dissolution experiments, and the specific experimental steps are as follows:

referring to the third method of the fourth general rule of the edition 2020 of Chinese pharmacopoeia, phosphate buffer with pH of 6.8 is taken as a dissolution medium, a sample is added into the dissolution medium under the conditions of 37 ℃ and 250ml volume and 50 revolutions per minute, sampling time points are respectively 5, 10, 15 and 20 minutes, filtration is carried out after sampling, the subsequent filtrate is taken as a solution of a test sample, and the dissolution rate is measured by adopting a high performance liquid chromatography, wherein the specific result is shown in Table 2.

TABLE 2 dissolution test results

As can be seen from the data in the table, the average dissolution rate of the anhydrous swallow granule of the invention is 58-96.5% in 5-20min, and the anhydrous swallow granule of the invention can meet the requirements of stable and rapid release of melatonin in the body, is favorable for quick effect of the medicament, and ensures that a patient can enter a sleep state quickly.

Experiment 3 Effect of formulation on sodium pentobarbital induced sleep time in mice

The ICR mice were taken for 110 experiments, and each experiment was adapted for 1 week. Mice were randomly divided into 11 groups, blank control group and experiments 1-10 groups, respectively. Mice of each experimental group were given a parenteral injection of pentobarbital sodium (45 mg/kg,10 mL/kg) for 30min after intragastric administration, and the administration time was recorded. The blank group was not dosed, and the rest was identical to the experimental group. Then placing the mouse in an independent space at about 25 ℃ to observe the sleep state of the mouse, wherein the fact that the mouse cannot spontaneously turn over in a supine position for 60 seconds is recorded as the time for the disappearance of the regular reflection; the mice placed in the supine position can be automatically turned over and repeated three times within 60 seconds, and the recovery time is recorded as the recovery time of the turning over and the positive reflection of the mice. And respectively calculating sleep latency and sleep duration, wherein the sleep latency is from the time of intraperitoneal injection to the time of specular reflection disappearance, and the sleep duration is from the time of specular reflection disappearance to the time of specular reflection restoration. The specific experimental results are shown in Table 3.

Table 3 effect of formulation on sodium pentobarbital on sleep time in mice

From the results, the experimental groups 1-10 can obviously shorten the sleep latency of the mice and increase the sleep duration of the mice, and the comparison of the experimental groups 1-4, the experimental groups 5-7 and the experimental groups 8-10 can show that the gamma-aminobutyric acid and the L-magnesium threonate can cooperate with the action of melatonin, thereby prolonging the sleep time of the mice and being beneficial to further improving the sleep quality.

Finally, it should be noted that: the foregoing description is only illustrative of the preferred embodiments of the present invention, and although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described, or equivalents may be substituted for elements thereof, and any modifications, equivalents, improvements or changes may be made without departing from the spirit and principles of the present invention.

Claims (17)

1. The melatonin anhydrous swallow granule is characterized by comprising drug-carrying micropills and taste-modifying particles, wherein the drug-carrying micropills comprise a drug-containing pill core and a smooth layer from inside to outside. The pill-containing core comprises microcrystalline cellulose pill core, melatonin, hypromellose, polysorbate 80 and purified water; the smooth layer comprises hydroxypropyl methylcellulose, carbomer, talcum powder, titanium dioxide, sucralose and ethanol.

2. A melatonin anhydrous swallowable granule according to claim 1, wherein said taste-modifying granule comprises sorbitol, sodium carboxymethyl cellulose, aspartame, citric acid, fruit flavors selected from the group consisting of orange flavors, apple flavors, etc., wherein sorbitol is by weight: sodium carboxymethyl cellulose: aspartame: citric acid: fruit essence: magnesium stearate=400-800:5-20:1-5:0-10:10-30:1-8, proper amount of ethanol.

3. A melatonin anhydrous swallowable granule according to claim 1, wherein, in said flavored granule, sorbitol is by weight: sodium carboxymethyl cellulose: aspartame: citric acid: fruit essence: magnesium stearate=500-700:8-15:1-4:4-8:15-25:3-6.

4. A melatonin anhydrous swallowable granule according to claim 1, wherein, in said flavored granule, sorbitol is by weight: sodium carboxymethyl cellulose; aspartame; citric acid: fruit essence: magnesium stearate: ethanol=600:13:3:6:10:4.

5. A melatonin anhydrous swallowable granule according to claim 1, wherein, in the capsule core, microcrystalline cellulose capsule core is by weight: melatonin: hypromellose: polysorbate 80: purified water = 150-500:1-5:5-10:2-8:200-600.

6. A melatonin anhydrous swallowable granule according to claim 1, wherein, in the capsule core, microcrystalline cellulose capsule core is by weight: melatonin: hypromellose: polysorbate 80: purified water = 200-400:1-4:8-10:3-6:300-500.

7. A melatonin anhydrous swallowable granule according to claim 1, wherein, in the capsule core, microcrystalline cellulose capsule core is by weight: melatonin: hypromellose: polysorbate 80: purified water = 300:3:9:5:400.

8. A melatonin anhydrous swallowable granule according to claim 1, wherein, in the smooth layer, by weight, hypromellose: carbomer: talc powder: titanium dioxide: sucralose: ethanol=2-10:1-5:10-30:5-20:40-100:100-300.

9. A melatonin anhydrous swallowable granule according to claim 1, wherein, in the smooth layer, by weight, hypromellose: carbomer: talc powder: titanium dioxide: sucralose: ethanol=3-8:2-4:15-25:8-16:60-80:150-250.

10. A melatonin anhydrous swallowable granule according to claim 1, wherein, in the smooth layer, by weight, hypromellose: carbomer: talc powder: titanium dioxide: sucralose: ethanol=5:3:20:12:70:200.

11. A melatonin anhydrous swallowable granule according to claim 1, further comprising gamma-aminobutyric acid in the core, wherein the mass ratio of melatonin to gamma-aminobutyric acid is 1-5:20-60.

12. A melatonin anhydrous swallowable granule according to claim 11, wherein the mass ratio of melatonin to gamma-aminobutyric acid is 3:50.

13. A melatonin anhydrous swallowable granule according to claim 11, further comprising magnesium L-threonate in the core of the pill, wherein the mass ratio of melatonin, gamma-aminobutyric acid and magnesium L-threonate is in the range of 1-5:20-60:100-500.

14. A melatonin anhydrous swallowable granule according to claim 13, wherein the mass ratio of melatonin, gamma-aminobutyric acid and magnesium L-threonate is 3:50:300.

15. The melatonin anhydrous swallow granule according to claim 1, wherein the drug-loaded pellets comprise 60-90% by mass of the drug-containing core and 10-40% by mass of the smoothing layer.

16. A melatonin anhydrous swallowable granule according to claim 1, wherein the mass ratio of drug-carrying pellets to taste-modifying particles in the anhydrous swallowable granule is 1:0.5-3.

17. A method for preparing melatonin anhydrous swallow granules, which is characterized by comprising the following steps:

preparation of the pill-containing core: dissolving the hydroxypropyl methylcellulose with the prescription amount in purified water, fully stirring and dissolving, sequentially adding melatonin and polysorbate 80, and stirring to prepare uniform suspension; taking microcrystalline cellulose pill core (preferably with particle size of 0.3-0.6 mm) as drug-carrying base pill, spraying at fluidized bed bottom to carry out suspension feeding process, controlling material temperature at 30-50deg.C during feeding process, and drying the pellet after feeding, wherein the water content of the pellet is controlled below 3% (weight).

Preparation of a smooth layer: adding the prescription amount of hypromellose, carbomer, talcum powder, titanium dioxide and sucralose into ethanol to prepare uniform smooth layer coating suspension; and (3) coating the pill-containing cores by adopting a fluidized bed medicine feeding procedure, wherein the material temperature is controlled to be 30-50 ℃ in the medicine feeding process, and the coated medicine-carrying pellets are obtained.

Preparation of taste-modifying particles: adding the sorbitol, aspartame, citric acid and fruit essence with the prescription amount into a wet granulator, fully mixing the materials, adding a proper amount of ethanol in an atomized form under the stirring state, granulating for a certain time, and performing wet granulation; drying by using a fluidized bed, and sieving with a 20-mesh sieve for dry granulation; and adding sodium carboxymethylcellulose and magnesium stearate in a prescription proportion into the particles according to the yield of the materials, and uniformly mixing to obtain the taste-correcting particles.

Mixing the drug-loaded pellets with the taste-modifying particles: mixing the drug-loaded pellets and the taste-correction particles according to a certain proportion to obtain the melatonin anhydrous swallow particles.