Melatonin granules and preparation method thereof

Abstract

The invention relates to melatonin granules and a preparation method thereof. The preparation method of the melatonin granule comprises the following steps: S1, preparing melatonin and a wetting agent into a melatonin solution, and mixing the melatonin solution with dextrin to obtain a granule precursor; s2, mixing the particle precursor with a wetting agent, then mixing with mannitol, and drying to obtain the melatonin granules, the mass ratio of the melatonin to the dextrin in the step S1 to the mannitol in the step S2 is 1: (45-175): (225-355). According to the preparation method disclosed by the invention, the hardening proportion in the process of preparing the melatonin granules is low, and the obtained melatonin granules are good in disintegration effect, short in oral cavity disintegration time and good in buccal experience.

Description

Technical Field

[0001] The present invention relates to the technical field of health food, and more specifically, to a melatonin granule and a preparation method thereof. Background Art

[0002] Melatonin has a molecular formula of C 13 H 16 N2O2, chemical name is N-acetyl-5-methoxytryptamine. It plays an important role in regulating human growth, reproduction and metabolism, and has the effects of sedation, hypnosis, immune enhancement, life extension and tumor inhibition. The varieties and dosage forms currently available in the market at home and abroad are: ordinary tablets, capsules, and general sustained-release tablets.

[0003] Melatonin, as a sleep-promoting drug with good safety, can effectively solve the sleep problems caused by neurodevelopmental disorders in children. At the same time, taking melatonin to help sleep is a good choice for the physiological or pathological insomnia symptoms caused by age in the elderly. However, children and the elderly have difficulties in swallowing or compliance when taking the drug. Therefore, there is a certain market demand for the development of a melatonin preparation suitable for children and the elderly.

[0004] In order to solve the above problems, researchers are committed to the development of orally disintegrating melatonin preparations, which currently mainly include orally disintegrating tablets and granules. For example, the Chinese patent entitled "A melatonin orally disintegrating tablet and its preparation method" provides orally disintegrating tablets. However, tablets still have a noticeable foreign body sensation when taken, so granules have become a better choice. Orally disintegrating melatonin granules are generally prepared according to the following process: (1) Melatonin and excipients are mixed evenly to obtain a dry material; (2) A wetting agent is added to the dry material, mixed evenly to form a soft material, and then the soft material is made into wet granules; (3) The wet granules are heated at 60-80°C to remove the wetting agent and excess water to obtain dry granules; (4) The dry granules are sieved to remove lumps and fine powder to obtain melatonin granules.

[0005] Orally disintegrating granules are mainly disintegrated by a small amount of saliva in the oral cavity. In order to make melatonin granules disintegrate quickly in the oral cavity, the prior art often adds excipients such as sucrose and xylitol that can be quickly dissolved in the oral cavity. However, the direct addition of such excipients creates another problem: such excipients are easily soluble in the wetting agent during the preparation process. During the drying process, as the wetting agent evaporates due to heat, such excipients tend to adhere to more particles and form agglomerates, that is, the agglomeration ratio increases, which in turn leads to a decrease in the yield rate of the granules.

[0006] Therefore, it is necessary to solve the problem that the current melatonin orally disintegrating granules cannot simultaneously take into account the fast disintegration speed and the low proportion of hardening during the preparation process. Summary of the invention

[0007] The primary purpose of the present invention is to overcome the problem that the existing melatonin orally disintegrating granules cannot simultaneously take into account the fast disintegration speed and the low hardening ratio during the preparation process, and to provide a method for preparing melatonin granules.

[0008] A further object of the present invention is to provide a melatonin granule.

[0009] The above-mentioned object of the present invention is achieved by the following technical solutions:

[0010] A method for preparing melatonin granules comprises the following steps:

[0011] S1. First, melatonin and a wetting agent are prepared into a melatonin solution, and then the melatonin solution is mixed with dextrin to obtain a granule precursor;

[0012] S2. The granule precursor and the wetting agent are mixed, and then mixed with mannitol and dried to obtain melatonin granules;

[0013] The mass ratio of melatonin, dextrin and mannitol in step S1 is 1:

[0014] (45~175):(225~355).

[0015] Dextrin and mannitol are commonly used excipients in health foods, among which dextrin is generally used as a suspending agent, adhesive or diluent, and mannitol is generally used as a sweetener or tonic.

[0016] The inventors have found that in the process of wet granulation, dextrin is first added to form a granule precursor, and then mannitol is added, and the mass ratio of the two is adjusted, which can not only reduce the hardening ratio of melatonin granules in the preparation process, thereby improving the yield rate, but also the disintegration speed of the obtained melatonin granules is fast. The reason is: firstly mixing the melatonin solution with a certain amount of dextrin can form a stable and uniform granule precursor, which can effectively avoid the bonding effect of mannitol on the granules caused by the volatilization of the wetting agent in the subsequent drying process, thereby greatly reducing the degree of hardening in the granulation process; at the same time, the bonding effect of mannitol itself on the granules is also small, which is also conducive to maintaining a low hardening ratio; the granule core of the obtained melatonin granules is mainly dextrin, and the outer layer of the granules is mainly mannitol, mannitol itself is easily soluble in water (or saliva), and the mannitol solution formed by mannitol and a small amount of water (or saliva) has a good dissolution-promoting effect on dextrin, thereby ensuring the rapid disintegration of the melatonin granules.

[0017] Therefore, the proportion of hardening during the preparation of melatonin granules by the preparation method of the present invention is low, and the obtained melatonin granules have good disintegration effect, short oral disintegration time, and good buccal disintegration experience.

[0018] The amount of dextrin and mannitol and the order in which they are added are critical. If dextrin is not added or the amount of dextrin added is too little and the amount of mannitol is too much, the hardening ratio of the preparation process of melatonin granules will be high, and too much mannitol will cause the melatonin granules to be too compact and have a long disintegration time; if mannitol is not added or the amount of mannitol added is too little and the amount of dextrin is too much, the disintegration time of the melatonin granules will be long, and there will be a clear sense of gravel when taking it. If dextrin and mannitol are not added in a sequential order during the wet granulation process, the hardening ratio of the preparation process is high, and the disintegration effect of the melatonin granules is poor. If other alcohols (such as xylitol) or sucrose are used instead of mannitol, or other sugars (such as tapioca starch) are used instead of dextrin, the hardening ratio of the preparation process is high, and the disintegration effect of the melatonin granules is poor.

[0019] In the present invention, the mass ratio of melatonin to dextrin in step S1 can be 1:45, 1:50, 1:80, 1:100, 1:120, 1:150 or 1:175; the mass ratio of melatonin in step S1 and mannitol in step S2 can be 1:225, 1:250, 1:280, 1:300, 1:320 or 1:355.

[0020] Preferably, in step S1, the mass ratio of melatonin to wetting agent is 1:(3-6).

[0021] Preferably, before the mixing in step S1, a step of mixing the melatonin solution with other auxiliary materials is also included.

[0022] The present invention can add other corresponding auxiliary materials according to other requirements of the product (such as appearance, taste, etc.).

[0023] More preferably, the other auxiliary materials are at least one of pigment, vitamin or citric acid. The pigment is a natural pigment; and the vitamin is vitamin B6.

[0024] More preferably, the dosage of other auxiliary materials is: 0.8-1.2 weight parts of pigment per 1 weight part of melatonin; 2-4 weight parts of vitamins per 1 weight part of melatonin; 8-12 weight parts of citric acid per 1 weight part of melatonin.

[0025] More preferably, the other auxiliary materials are mixed with the melatonin solution in the form of a solution.

[0026] Further preferably, the preparation process of the solution of the other auxiliary materials is: mixing the other auxiliary materials with the wetting agent; the mass ratio of the other auxiliary materials to the wetting agent is 1:(1.5-8); the wetting agent is an ethanol aqueous solution with a volume concentration of 75-85%. Specifically, the mass ratio of the pigment to the wetting agent is 1:(6-8), the mass ratio of the vitamin to the wetting agent is 1:(3-6), and the mass ratio of citric acid to the wetting agent is 1:(1.5-2.5).

[0027] Preferably, the mixing conditions in step S1 are: a rotation speed of 20 to 50 rpm and a time of 20 to 40 seconds.

[0028] Preferably, the dosage ratio of the particle precursor to the wetting agent in step S2 is 1:(0.15-0.2).

[0029] More preferably, the mass ratio of the granule precursor to the wetting agent in step S2 is 1:(0.15-0.175). Within this range, the agglomeration ratio is lower during the preparation of melatonin granules, and the disintegration effect is better.

[0030] Preferably, the wetting agent in step S1 and step S2 is an ethanol aqueous solution with a volume concentration of 75-85% (the volume concentration of ethanol is 75-85%).

[0031] More preferably, the wetting agent in step S1 and step S2 is an ethanol aqueous solution with a volume concentration of 80-85%. Within this range, the agglomeration ratio in the preparation process of melatonin granules is lower and the disintegration effect is better.

[0032] Preferably, the conditions for mixing the particle precursor and the wetting agent in step S2 are: a rotation speed of 20 to 50 rpm and a time of 10 to 60 seconds.

[0033] Preferably, the conditions for mixing with mannitol in step S2 are: a rotation speed of 20 to 50 rpm and a time of 20 to 40 seconds.

[0034] Preferably, the drying temperature in step S2 is 70-75° C. and the drying time is 15-30 min.

[0035] Preferably, after drying in step S2, a screening step is also included.

[0036] More preferably, after the sieving, a step of adding essence for mixing is further included. The amount of the essence is: 1 to 2 parts by weight of essence per 1 part by weight of melatonin.

[0037] Preferably, the melatonin granules are brewed melatonin granules or orally disintegrating melatonin granules (orally disintegrating melatonin granules).

[0038] A melatonin granule is prepared by the above preparation method.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] The preparation method of the present invention has a low hardening ratio during the preparation of melatonin granules, and the obtained melatonin granules have good disintegration effect, short oral disintegration time, and good buccal disintegration experience. DETAILED DESCRIPTION

[0041] In order to more clearly and completely describe the technical solution of the present invention, the present invention is further described in detail through specific embodiments below. It should be understood that the specific embodiments described herein are only used to explain the present invention, and are not used to limit the present invention. Various changes can be made within the scope of the rights of the present invention.

[0042] Example 1

[0043] This embodiment provides a method for preparing melatonin granules, comprising the following steps:

[0044] 1) Weigh the raw material components, including: 550 parts by weight of mannitol, 409 parts by weight of dextrin, 2.4 parts by weight of melatonin, 7.5 parts by weight of vitamin B6, 24.6 parts by weight of citric acid, 4 parts by weight of edible flavor, and 2.5 parts by weight of natural pigment.

[0045] 2) Add citric acid to 80% ethanol solution (the mass ratio of citric acid to ethanol solution is 1:2) (ethanol solution refers to ethanol aqueous solution, the same below), and continue stirring until completely dissolved to obtain a citric acid solution; add natural pigment to 80% ethanol solution (the mass ratio of natural pigment to ethanol solution is 9:70), and continue stirring until completely dissolved to obtain a natural pigment solution; add vitamin B6 to 80% ethanol solution (the mass ratio of vitamin B6 to ethanol solution is 1:5), stir for about 20 seconds until the material is evenly dispersed, and obtain a vitamin B6 solution.

[0046] 3) Add melatonin to 80% ethanol solution (the mass ratio of melatonin to ethanol solution is 1:5), and stir for about 20 seconds until the materials are evenly dispersed to obtain a melatonin solution.

[0047] 4) First, add dextrin into a mixing granulator; then combine the melatonin solution, vitamin B6 solution, citric acid solution and natural pigment solution, stir for 5 seconds, quickly add them into the mixing granulator, mix for 30 seconds at a speed of 35 rpm, and obtain a granule precursor.

[0048] 5) Add 80% ethanol solution to the mixing granulator, the mass ratio of the particle precursor to the 80% ethanol solution is 1:0.175, mix for 30 seconds at a speed of 35 rpm; then add mannitol, mix for 30 seconds at a speed of 35 rpm to make a soft material.

[0049] 6) Pour the soft material into a granulator pre-installed with a 24-mesh screen and shake it for granulation, then put it into a boiling dryer, set the inlet air temperature to 70°C, and dry it for 20 minutes; then pre-install a 16-60 mesh screen on an oscillating sieve, sieve the whole grains to obtain granules, mix the edible flavor with the granules by the equal-increment method, put them into a total mixer, mix (15 Hz / min, total mixing 16 minutes), and obtain melatonin granules.

[0050] Example 2

[0051] This embodiment provides a method for preparing melatonin granules, which is basically the same as that of embodiment 1, except that: the weighing amounts of the raw material components in step 1) are as follows: 600 parts by weight of mannitol, 359 parts by weight of dextrin, 2.4 parts by weight of melatonin, 7.5 parts by weight of vitamin B6, 24.6 parts by weight of citric acid, 4 parts by weight of edible flavor, and 2.5 parts by weight of natural pigment. That is, the weighing amounts of mannitol and dextrin are different.

[0052] Example 3

[0053] This embodiment provides a method for preparing melatonin granules, which is basically the same as that of embodiment 1, except that: the weighing amounts of the raw material components in step 1) are as follows: 850 parts by weight of mannitol, 109 parts by weight of dextrin, 2.4 parts by weight of melatonin, 7.5 parts by weight of vitamin B6, 24.6 parts by weight of citric acid, 4 parts by weight of edible flavor, and 2.5 parts by weight of natural pigment. That is, the weighing amounts of mannitol and dextrin are different.

[0054] Example 4

[0055] This embodiment provides a method for preparing melatonin granules, which is basically the same as that of Embodiment 1, except that: in step 3), the mass ratio of melatonin to ethanol solution is 1:4.

[0056] Example 5

[0057] This embodiment provides a method for preparing melatonin granules, which is basically the same as that of Embodiment 1, except that in step 5), the mass ratio of the granule precursor to the ethanol solution is 1:0.15.

[0058] Example 6

[0059] This embodiment provides a method for preparing melatonin granules, which is basically the same as that of Embodiment 1, except that in step 5), the mass ratio of the granule precursor to the ethanol solution is 1:0.2.

[0060] Example 7

[0061] This embodiment provides a method for preparing melatonin granules, which is basically the same as that of Embodiment 1, except that the 80% ethanol solution used in each step is replaced by a 75% ethanol solution.

[0062] Example 8

[0063] This embodiment provides a method for preparing melatonin granules, which is basically the same as that of Embodiment 1, except that the 80% ethanol solution used in each step is replaced by an 85% ethanol solution.

[0064] Comparative Example 1

[0065] This comparative example provides a method for preparing melatonin granules, which is basically the same as Example 1, except that: the weighing amounts of the raw material components in step 1) are as follows: 900 parts by weight of mannitol, 59 parts by weight of dextrin, 2.4 parts by weight of melatonin, 7.5 parts by weight of vitamin B6, 24.6 parts by weight of citric acid, 4 parts by weight of edible flavor, and 2.5 parts by weight of natural pigment. That is, the weighing amounts of mannitol and dextrin are different.

[0066] Comparative Example 2

[0067] This comparative example provides a method for preparing melatonin granules, comprising the following steps:

[0068] 1) Weighing the raw material components, including: 550 parts by weight of mannitol, 409 parts by weight of dextrin, 2.4 parts by weight of melatonin, 7.5 parts by weight of vitamin B6, 24.6 parts by weight of citric acid, 4 parts by weight of edible flavor, and 2.5 parts by weight of natural pigment;

[0069] 2) Add citric acid to 80% ethanol solution (the mass ratio of citric acid to ethanol solution is 1:2) (ethanol solution refers to ethanol aqueous solution, the same below), and continue stirring until completely dissolved to obtain a citric acid solution; add natural pigment to 80% ethanol solution (the mass ratio of natural pigment to ethanol solution is 9:70), and continue stirring until completely dissolved to obtain a natural pigment solution; add vitamin B6 to 80% ethanol solution (the mass ratio of vitamin B6 to ethanol solution is 1:5), stir for about 20 seconds until the material is evenly dispersed, and obtain a vitamin B6 solution.

[0070] 3) Add melatonin to 80% ethanol solution (the mass ratio of melatonin to ethanol solution is 1:5), and stir for about 20 seconds until the materials are evenly dispersed to obtain a melatonin solution.

[0071] 4) First, add dextrin and mannitol into a mixing granulator; then combine the melatonin solution, vitamin B6 solution, citric acid solution and natural pigment solution, stir for 5 seconds, and quickly add them into the mixing granulator, mix for 30 seconds at a speed of 35 rpm to obtain a granule precursor.

[0072] 5) Add 80% ethanol solution to the mixing granulator, the mass ratio of the particle precursor to the 80% ethanol solution is 1:0.175, mix for 60 seconds at a speed of 35 rpm to make a soft material.

[0073] 6) Pour the soft material into a granulator pre-installed with a 24-mesh screen and shake it for granulation, then put it into a boiling dryer, set the inlet air temperature to 70°C, and dry it for 20 minutes; then pre-install a 16-60 mesh screen on an oscillating sieve, sieve the whole grains to obtain granules, mix the edible flavor with the granules by the equal-increment method, put them into a total mixer, mix (15 Hz / min, total mixing 16 minutes), and obtain melatonin granules.

[0074] Comparative Example 3

[0075] This comparative example provides a method for preparing melatonin granules, comprising the following steps:

[0076] 1) Weighing the raw material components, including: 550 parts by weight of mannitol, 409 parts by weight of dextrin, 2.4 parts by weight of melatonin, 7.5 parts by weight of vitamin B6, 24.6 parts by weight of citric acid, 4 parts by weight of edible flavor, and 2.5 parts by weight of natural pigment;

[0077] 2) Add citric acid to 80% ethanol solution (the mass ratio of citric acid to ethanol solution is 1:2) (ethanol solution refers to ethanol aqueous solution, the same below), and continue stirring until completely dissolved to obtain a citric acid solution; add natural pigment to 80% ethanol solution (the mass ratio of natural pigment to ethanol solution is 9:70), and continue stirring until completely dissolved to obtain a natural pigment solution; add vitamin B6 to 80% ethanol solution (the mass ratio of vitamin B6 to ethanol solution is 1:5), stir for about 20 seconds until the material is evenly dispersed, and obtain a vitamin B6 solution.

[0078] 3) Add melatonin to 80% ethanol solution (the mass ratio of melatonin to ethanol solution is 1:5), and stir for about 20 seconds until the materials are evenly dispersed to obtain a melatonin solution.

[0079] 4) First, add mannitol into the mixing granulator; then combine the melatonin solution, vitamin B6 solution, citric acid solution and natural pigment solution, stir for 5 seconds, quickly add them into the mixing granulator, mix for 30 seconds at a speed of 35 rpm, and obtain a granule precursor.

[0080] 5) Add 80% ethanol solution to the mixing granulator, with the ratio of the particle precursor to the 80% ethanol solution being 1:0.175, and mix for 30 seconds at a speed of 35 rpm; then add dextrin, mix for 30 seconds at a speed of 35 rpm to make a soft material.

[0081] 6) Pour the soft material into a granulator pre-installed with a 24-mesh screen and shake it for granulation, then put it into a boiling dryer, set the inlet air temperature to 70°C, and dry it for 20 minutes; then pre-install a 16-60 mesh screen on an oscillating sieve, sieve the whole grains to obtain granules, mix the edible flavor with the granules by the equal-increment method, put them into a total mixer, mix (15 Hz / min, total mixing 16 minutes), and obtain melatonin granules.

[0082] Comparative Example 4

[0083] This comparative example provides a method for preparing melatonin granules, which is basically the same as Example 1, except that the mannitol in Example 1 is replaced by xylitol.

[0084] Comparative Example 5

[0085] This comparative example provides a method for preparing melatonin granules, which is basically the same as that of Example 1, except that the dextrin in Example 1 is replaced by cassava starch.

[0086] Performance Testing

[0087] 1. Hardening ratio: Calculate the total weight W1 of all solid materials (i.e., the raw materials in step 1) in the formulations of Examples 1-8 and Comparative Examples 1-5, and record the weight W2 of the materials that cannot pass through the 16-mesh screen in step 6) according to the respective preparation methods. Hardening ratio = W2 / W1×100%

[0088] 2. Disintegration time: Take 1g of each product of Examples 1-8 and Comparative Examples 1-5, add them to beakers respectively, add 100ml of 70°C warm water to the beaker, start a stopwatch at the same time, and observe the time required for all the particles at the bottom of the beaker to disintegrate, which is the disintegration time. It is generally believed that in this test, when the disintegration time of this test is within 20 seconds, the sensory disintegration time during oral disintegration is short, and the experience is good; when the disintegration time of this test is more than 20 seconds, the sensory disintegration time during oral disintegration is long, and the experience is not good.

[0089] The performance test results of each embodiment and comparative example are as follows:

[0090] Table 1

[0091]

[0092]

[0093] From Table 1, we can see that:

[0094] The hardening ratios of the preparation methods of Examples 1 to 8 were all below 9.0%, and the disintegration times in the disintegration test were all within 19 seconds, indicating that the hardening ratio of melatonin granules prepared by the preparation method of the present invention was low, and the prepared melatonin granules had good disintegration effect, short oral disintegration time, and good buccal disintegration experience.

[0095] The dosage of mannitol and dextrin in Comparative Example 1 is not appropriate, the hardening ratio of the preparation method is high, and the disintegration time of the melatonin granules is long. In Comparative Example 2, dextrin and mannitol are added to the mixing granulator at the same time, the hardening ratio of the preparation method is high, and the disintegration time of the melatonin granules is long. In Comparative Example 3, mannitol is added first, and then dextrin is added. The hardening ratio of the preparation method is high, and the disintegration time of the melatonin granules is long. In Comparative Example 4, xylitol is used instead of mannitol, and the hardening ratio of the preparation method is high, and the disintegration time of the melatonin granules is long. In Comparative Example 5, cassava starch is used instead of dextrin, and the hardening ratio of the preparation method is high, and the disintegration time of the melatonin granules is long.

[0096] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing melatonin granules, characterized in that: The steps include: S1. First, melatonin and a wetting agent are prepared into a melatonin solution, and then the melatonin solution is mixed with dextrin to obtain a granule precursor; S2. The granule precursor and the wetting agent are mixed, and then mixed with mannitol and dried to obtain melatonin granules; The mass ratio of melatonin, dextrin and mannitol in step S1 is 1: (45～175):(225～355)。 2. The preparation method according to claim 1, characterized in that: The mass ratio of melatonin to wetting agent in step S1 is 1:(3-6).

3. The preparation method according to claim 1, characterized in that: Before the mixing in step S1, the method further includes the step of mixing the melatonin solution with other auxiliary materials.

4. The preparation method according to claim 3, characterized in that: The other auxiliary materials are at least one of pigments, vitamins or citric acid.

5. The preparation method according to claim 3, characterized in that: The other auxiliary materials are mixed with the melatonin solution in the form of solution.

6. The preparation method according to claim 1, characterized in that: The mixing conditions in step S1 are: a rotation speed of 20 to 50 rpm and a time of 20 to 40 seconds.

7. The preparation method according to claim 1, characterized in that: The mass ratio of the particle precursor to the wetting agent in step S2 is 1:(0.15-0.2).

8. The preparation method according to claim 1, characterized in that: The wetting agent in step S1 and step S2 is an ethanol aqueous solution with a volume concentration of 75-85%.

9. The preparation method according to claim 1, characterized in that: The melatonin granules are brewed melatonin granules or orally disintegrating melatonin granules.

10. A melatonin granule, characterized in that: It is prepared by the preparation method according to any one of claims 1 to 9.

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