Melatonin orally disintegrating tablet and preparation method thereof

Abstract

The invention relates to a melatonin orally disintegrating tablet and a preparation method thereof.The melatonin orally disintegrating tablet comprises raw materials including melatonin and vitamin B6 and auxiliary materials including an adhesive, a forming agent, a flavoring agent, an emulsifier and edible essence, the melatonin orally disintegrating tablet is prepared through the working procedures of mixing, dissolving, emulsifying and degassing, filling, freeze-drying and packaging, and the melatonin orally disintegrating tablet has the advantages that the melatonin orally disintegrating tablet is suitable for oral administration; the raw materials and the auxiliary materials meet the requirements of filing health-care food regulations, the disintegration time limit is as fast as 10 seconds, the absorption is fast, the effect taking time is fast, the first-pass effect of the liver is avoided, the bioavailability of the product is improved, the storage and the transportation are convenient, and the application prospect is very good.

Description

Technical Field

[0001] The invention relates to the preparation of a melatonin orodisintegrating tablet, belonging to the field of health food. Background Art

[0002] The China Sleep Research Society and other institutions released the "2022 China National Healthy Sleep White Paper". Statistics show that in 2021, more than 300 million Chinese people have sleep disorders, and the incidence of insomnia in adults is as high as 38.2%.

[0003] Melatonin, commonly known as "sleep hormone", is a biological hormone that exists under the human cortex. It has many benefits, such as regulating the body's biological clock, promoting sleep, improving immunity, and delaying aging. The level of melatonin in the human body decreases year by year after the age of 35, and drops to an extremely low level at the age of 80, and the difference between day and night tends to disappear. Because melatonin is a strong endogenous free radical scavenger, it can resist oxidation and prevent cell aging. Some young women use melatonin as a beauty product for a long time; its secretion is restricted by light, and a small amount of supplementation can guide natural sleep, so some people use it as a sleeping pill; related studies have also shown that melatonin can pass through the blood-brain barrier to delay the occurrence of Alzheimer's disease.

[0004] In March 2021, the State Administration for Market Regulation issued a document to include melatonin in the raw material catalog of health food filing products, and stipulated the dosage forms and excipients allowed for use. It is currently the only raw material for filing products that are allowed to claim to improve sleep function, with a daily dose of 1-3 mg. Tablets and capsules are usually available on the market. Due to the large first-pass effect of melatonin, short plasma half-life (20-30 minutes), and poor bioavailability (15%), the effect of improving sleep is greatly reduced. Patent CN 105982070 discloses a melatonin oral fast-dissolving film and a preparation method thereof, and patent CN 114831983 discloses a melatonin oral sublingual fast-dissolving composition and a preparation method thereof. Both methods disclose methods for preparing fast-dissolving films of melatonin, and obtain melatonin dosage forms that are easy to disintegrate. However, some of the excipients used are not in the catalog allowed for use by the State Administration for Market Regulation, and the product cannot be filed for listing, which limits the use of the product. Therefore, it is very important to develop a melatonin dosage form that is easy to take, has high bioavailability, and complies with regulations. Summary of the invention

[0005] The purpose of the present invention is to provide a melatonin orally disintegrating tablet and a preparation method thereof.

[0006] The melatonin orally disintegrating tablet provided by the present invention comprises raw materials including melatonin and vitamin B6, and auxiliary materials including a binder, a molding agent, a flavoring agent, an emulsifier, and an edible flavor.

[0007] The melatonin content of the orally disintegrating melatonin tablet is 1-3 mg / tablet, and the vitamin B6 content is 0.5-10 mg / tablet.

[0008] The binder of the orally disintegrating melatonin tablet includes one or more of gelatin, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and edible corn starch, and the added amount is 1%-10% of the tablet weight, preferably 2%-4% of gelatin.

[0009] The molding agent of the orally disintegrating melatonin tablet is one or more of sorbitol, mannitol, oligofructose and lactose, and the added amount is 50%-80% of the tablet weight, preferably a combination of mannitol and oligofructose, and the ratio of mannitol to oligofructose is 2:1-0.5:1.

[0010] The flavoring agent of the melatonin orally disintegrating tablet is one or more of citric acid, white sugar and edible glucose, and the added amount is 2%-30%.

[0011] The emulsifier of the melatonin orally disintegrating tablet is polyoxyethylene sorbitan monooleate, and the added amount is 0.1%-1%.

[0012] The edible flavor of the melatonin orally disintegrating tablet is a food flavor that complies with GB 30616, and the flavors include but are not limited to milk flavor, lavender flavor, banana flavor, and grape flavor, and the added amount is 0.2%-5%.

[0013] The method for preparing the melatonin orally disintegrating tablet of the present invention comprises the following steps: (1) Mixing: weigh the raw and auxiliary materials according to the formula and mix them evenly; (2) Dissolving: Add 4-8 times of purified water to the mixed materials in step 1), heat at 40-60°C and stir to dissolve; (3) Emulsification and degassing: emulsify the above-mentioned liquid in a shear emulsifier for 10-20 minutes, and vacuum degas the emulsified liquid for 20-30 minutes; (4) Filling: quantitatively fill the liquid into the bubble eyes of the aluminum-plastic blister plate; (5) Freeze drying: pre-freeze the liquid in the blister at -40°C to -80°C for 10 to 30 minutes, and then freeze-dry in a freeze dryer to obtain melatonin orally disintegrating tablets; (6) Packaging: Take the blister plate out of the freeze dryer and seal it with film under a relative humidity of 10%-40%. Beneficial effects of the present invention:

[0014] 1. The present invention adopts freeze-drying technology to prepare a melatonin orodisintegrating tablet, which is taken orally and has a disintegration time of as fast as 10 seconds, thus avoiding the first-pass effect of the liver and improving the bioavailability of the product.

[0015] 2. The raw and auxiliary materials used in the present invention meet the technical requirements of registered health foods. Compared with commercially available products, the present invention is easy to take, quickly absorbed, requires a reduced dosage, and has a faster onset of effect.

[0016] 3. The melatonin orodisintegrating tablets prepared by the freeze-drying technology of the present invention are packaged in blister packing, which is convenient for storage and transportation. DETAILED DESCRIPTION

[0017] In order to further illustrate the present invention, the melatonin orally disintegrating tablet and the preparation method thereof provided by the present invention are described in detail below in conjunction with examples, but they should not be construed as limiting the scope of protection of the present invention.

[0018] Example 1 Product Formula Preparation method: 1) Mixing: weigh melatonin, vitamin B6, gelatin, mannitol, oligofructose, white sugar, polyoxyethylene sorbitan monooleate, and milk flavor according to the formula and mix for 10 minutes; 2) Dissolution: Add the mixed materials into purified water, heat to 50°C, and stir to dissolve; 3) Emulsification and degassing: Place the above-mentioned liquid in a shear emulsifier and emulsify at 10,000 rpm for 10 minutes. The emulsified liquid is vacuum degassed for 20 minutes. 4) Filling: Fill the liquid into the blister of the aluminum-plastic blister plate at 300 mg / hole; 5) Freeze drying: pre-freeze the liquid in the blister at -80°C for 10 minutes, and then freeze-dry it in a freeze dryer to obtain the melatonin orally disintegrating tablets; 6) Packaging: Take the blister plate out of the freeze dryer, seal it with film under a relative humidity of 10%-40%, and mark the sample as S1.

[0019] Example 2 Product Formula Preparation method: 1) Mixing: weigh melatonin, vitamin B6, gelatin, mannitol, lactose, citric acid, polyoxyethylene sorbitan monooleate, and lavender essence according to the formula and mix for 10 minutes; 2) Dissolution: Add the mixed materials into purified water, heat to 60°C, and stir to dissolve; 3) Emulsification and degassing: Place the above-mentioned liquid in a shear emulsifier and emulsify at 10,000 rpm for 20 minutes. The emulsified liquid is vacuum degassed for 30 minutes. 4) Filling: Fill the liquid into the blister of the aluminum-plastic blister plate at 360 mg / hole; 5) Freeze drying: pre-freeze the liquid in the blister at -40°C for 30 minutes, and then freeze-dry it in a freeze dryer to obtain the melatonin orally disintegrating tablets; 6) Packaging: Take the blister plate out of the freeze dryer, seal it with film under a relative humidity of 10%-40%, and mark the sample as S2.

[0020] Example 3 Product Formula Preparation method: 1) Mixing: weigh melatonin, vitamin B6, sodium carboxymethyl cellulose, mannitol, sorbitol, edible glucose, polyoxyethylene sorbitan monooleate, and grape flavor according to the formula and mix for 10 minutes; 2) Dissolution: Add the mixed materials into purified water, heat to 40°C, and stir to dissolve; 3) Emulsification and degassing: Place the above-mentioned liquid in a shear emulsifier and emulsify at 10,000 rpm for 20 minutes. The emulsified liquid is vacuum degassed for 30 minutes. 4) Filling: Fill the liquid into the blister of the aluminum-plastic blister plate at 200 mg / hole; 5) Freeze drying: pre-freeze the liquid in the blister at -60°C for 20 minutes, and then freeze-dry it in a freeze dryer to obtain melatonin orally disintegrating tablets; 6) Packaging: Take the blister plate out of the freeze dryer, seal it with film under a relative humidity of 10%-40%, and mark the sample as S3.

[0021] Example 4 Product Formula Preparation method: 1) Mixing: weigh melatonin, vitamin B6, corn starch, mannitol, oligofructose, white sugar, polyoxyethylene sorbitan monooleate, and banana flavor according to the formula and mix for 10 minutes; 2) Dissolution: Add the mixed materials into purified water, heat to 50°C, and stir to dissolve; 3) Emulsification and degassing: Place the above-mentioned liquid in a shear emulsifier and emulsify at 10,000 rpm for 15 minutes. The emulsified liquid is vacuum degassed for 25 minutes. 4) Filling: Fill the liquid into the blister of the aluminum-plastic blister plate at 240 mg / hole; 5) Freeze drying: pre-freeze the liquid in the blister at -50°C for 25 minutes, and then freeze-dry it in a freeze dryer to obtain melatonin orally disintegrating tablets; 6) Packaging: Take the blister plate out of the freeze dryer, seal it with film under a relative humidity of 10%-40%, and mark the sample as S4.

[0022] Comparison example Product Formula Preparation method: 1) Mixing: Weigh melatonin, vitamin B6, sorbitol, magnesium stearate, and milk flavor according to the formula and mix for 10 minutes; 2) Tablet pressing: Place the mixed materials in a tablet press for tablet pressing, control the loading amount to 250 mg / tablet, and obtain melatonin tablet reference substance sample A0.

[0023] Experimental example Disintegration time determination According to the provisions of Item 0921 of the General Rules of Part IV of the Pharmacopoeia of the People's Republic of China, the samples obtained in the examples were tested according to the orodisintegrating tablet method, and the control samples were tested according to the ordinary tablet method. The results are as follows: It can be seen from the data in the table that the disintegration time of the four orally disintegrating tablet samples prepared in the present invention is less than 60 seconds, and the fastest one is sample S1, which has a disintegration time limit of 10 seconds.

[0024] Product trial feedback According to the disintegration time results, sample S1 and reference product A0 were selected for trial verification. A total of 46 volunteers aged 18-60 were recruited. The control group took reference product A0, a total of 16 people; the test group took sample S1, a total of 30 people; the taste, time to fall asleep, sleep duration, and sleep quality were evaluated, and the feedback results are as follows: From the feedback results of the test takers in the table, it can be seen that the melatonin orodisintegrating tablet samples prepared by the present invention have high taste acceptance, and the time to fall asleep is faster than that of ordinary tablet products. The number of people who fall asleep within 10 minutes accounts for 70%, the number of people whose sleep time is extended by more than 30 minutes accounts for 80%, and the sleep quality improvement rate reaches 93.3%; the taste acceptance of ordinary tablets is general, and most people fall asleep within 30 minutes after taking the medicine, and the number of people whose sleep time is extended by more than 30 minutes accounts for 62.5%, and the sleep quality improvement rate is 81.25%. Considering that the melatonin orodisintegrating tablets of this trial have a melatonin content of 1 mg per tablet, while the melatonin content of each tablet of the control group is 3 mg, it shows that the melatonin orodisintegrating tablets prepared by the present invention have good taste, fast absorption, fast onset time, and higher bioavailability.

Claims

1. A melatonin orodisintegrating tablet, characterized in that: The raw materials include melatonin and vitamin B6, and the auxiliary materials include adhesives, forming agents, flavoring agents, emulsifiers, and edible flavors.

2. The orodisintegrating melatonin tablet according to claim 1, wherein the content of melatonin is 1-3 mg / tablet, and the content of vitamin B6 is 0.5-10 mg / tablet.

3. The binder of the orally disintegrating melatonin tablet according to claim 1 comprises one or more of gelatin, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and edible corn starch, and the added amount is 1%-10% of the tablet weight, preferably 2%-4% of gelatin.

4. The forming agent of the melatonin orally disintegrating tablet according to claim 1 is one or more of sorbitol, mannitol, oligofructose, and lactose, and the added amount is 50%-80% of the tablet weight, preferably a combination of mannitol and oligofructose, and the ratio of mannitol to oligofructose is 2:1-0.5:

1.

5. The flavoring agent of the melatonin orally disintegrating tablet according to claim 1 is one or more of citric acid, white sugar, and edible glucose, and the added amount is 2%-30%.

6. The emulsifier of the melatonin orally disintegrating tablet according to claim 1 is polyoxyethylene sorbitan monooleate, and the added amount is 0.1%-1%.

7. The edible flavor of the melatonin orally disintegrating tablet according to claim 1 is a food flavor that complies with GB 30616, and the flavors include but are not limited to milk flavor, lavender flavor, banana flavor, and grape flavor, and the added amount is 0.2%-5%.

8. The method for preparing the orally disintegrating melatonin tablet according to claim 1, comprising the following steps: (1) Mixing: weigh the raw and auxiliary materials according to the formula and mix them evenly; (2) Dissolving: Add 4-8 times of purified water to the mixed materials in step 1), heat at 40-60°C and stir to dissolve; (3) Emulsification and degassing: emulsify the above-mentioned liquid in a shear emulsifier for 10-20 minutes, and vacuum degas the emulsified liquid for 20-30 minutes; (4) Filling: quantitatively fill the liquid into the bubble eyes of the aluminum-plastic blister plate; (5) Freeze drying: pre-freeze the liquid in the blister at -40°C to -80°C for 10 to 30 minutes, and then freeze-dry in a freeze dryer to obtain melatonin orally disintegrating tablets; (6) Packaging: Take the blister plate out of the freeze dryer and seal it with film under a relative humidity of 10%-40%.