Oral sleep-aiding composition containing ergothioneine and preparation method thereof

Abstract

The invention discloses an oral sleep-aiding composition containing ergothioneine and a preparation method of the oral sleep-aiding composition, and relates to the technical field of sleep-aiding compositions. The oral sleep-aiding composition containing the ergothioneine is prepared from the following components in parts by mass: 0.01 to 3 parts of the ergothioneine, 0.1 to 10 parts of melatonin, 10 to 40 parts of glycine, 2 to 15 parts of magnesium salt, 30 to 70 parts of a diluent, 1 to 10 parts of an adhesive, 0.5 to 5 parts of a lubricant, 2 to 10 parts of a disintegrating agent and 0.1 to 0.5 part of an antioxidant preservative. Through the synergistic compatibility of ergothioneine, melatonin, glycine and magnesium salt, a multi-dimensional action network of oxidation resistance, neuromodulation and receptor inhibition is formed, the limitation of single-component sleep aiding is broken through, and the sleeping efficiency and the sleep maintenance capability are remarkably improved. Based on the scientific proportion of endogenous substances (ergothioneine and glycine), the metabolic burden of traditional sleep-aiding components is avoided, and in combination with the design of a sustained-release preparation, the dose-dependent side effects are reduced, and the safety of long-term taking is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of sleep-aiding compositions, and in particular to an oral sleep-aiding composition containing ergothioneine and a preparation method thereof. Background Art

[0002] With the accelerating pace of modern life, sleep disorders have become a global health issue. According to the World Health Organization, approximately one-third of the world's population experiences varying degrees of sleep disorders, including difficulty falling asleep, light sleep, frequent awakenings, and early awakenings. Reduced sleep quality not only impacts daily work efficiency and quality of life but can also lead to psychological problems such as anxiety and depression, and even increase the risk of chronic diseases such as cardiovascular disease and immune dysfunction.

[0003] Ergothioneine (EGT) is a naturally occurring antioxidant that was first isolated from ergot fungi. Its chemical structure is β-glycerol thiamine. Studies in recent years have found that ergothioneine has powerful antioxidant, anti-inflammatory and mitochondrial protective effects. In terms of sleep regulation, ergothioneine can have a positive impact on sleep quality by scavenging free radicals, reducing oxidative stress damage, and improving nerve cell function. In addition, ergothioneine also has a certain neuroprotective effect, which can relieve nerve excitement caused by stress, fatigue and other factors, help regulate the central nervous system, promote natural sleep and maintain deep sleep.

[0004] Some existing sleep-aid products are mostly based on a single ingredient, such as melatonin and glycine. Although they have certain effects in improving sleep, they often have problems such as a single effect and limited effect. Melatonin mainly works by regulating circadian rhythms, but it is not very effective in maintaining sleep after falling asleep; although glycine can promote the release of GABA, its effect is weak when used alone. The synergistic effect of ergothioneine and other sleep-aiding ingredients has not yet been fully developed, and the market lacks compound sleep-aid products that scientifically combine ergothioneine with melatonin, glycine and other ingredients. Therefore, the development of an oral composition with ergothioneine as the core ingredient and combined with other sleep-aiding ingredients is of great significance for meeting the growing demand for sleep improvement. Summary of the Invention

[0005] The purpose of the present invention is to provide a sleep-aiding composition containing ergothioneine in response to the problems of single ingredients and limited effects of existing sleep-aiding products. The composition can effectively improve sleep quality with safety and reliability by rationally combining ergothioneine, melatonin, glycine, magnesium salts and other ingredients.

[0006] To achieve the above object, the technical solution adopted by the present invention is: an oral sleep-aiding composition containing ergothioneine, comprising the following components in parts by mass: 0.01-3 parts of ergothioneine, 0.1-10 parts of melatonin, 10-40 parts of glycine, 2-15 parts of magnesium salt, 30-70 parts of diluent, 1-10 parts of adhesive, 0.5-5 parts of lubricant, 2-10 parts of disintegrant, and 0.1-0.5 parts of antioxidant preservative;

[0007] The composition is in the form of a tablet, capsule or granule;

[0008] The antioxidant preservative has a structure shown in Formula 1:

[0009]

[0010] The Z1 is selected from: O, S, C(CH3)2.

[0011] Further, the structure of described thioneine is:

[0012] Furthermore, the magnesium salt is selected from at least one of magnesium glycinate, magnesium citrate or magnesium oxide.

[0013] Furthermore, the diluent is selected from at least one of microcrystalline cellulose, lactose or mannitol.

[0014] Furthermore, the binder is selected from at least one of hydroxypropyl methylcellulose, polyvinyl pyrrolidone or starch.

[0015] Furthermore, the lubricant is selected from at least one of magnesium stearate, silicon dioxide or talc.

[0016] Furthermore, the disintegrant is selected from at least one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose.

[0017] Furthermore, the antioxidant preservative is any one of the compounds shown in the following structures:

[0018]

[0019] Furthermore, the synthesis method of the antioxidant preservative is:

[0020]

[0021] Step 1: Raw materials 1 and 2 are synthesized by Williamson reaction to obtain intermediate 1;

[0022] In the second step, intermediate 1 is synthesized by boric acid to obtain intermediate 2;

[0023] In the third step, intermediate 2 and raw material 3 are synthesized through Suzuki coupling reaction to obtain antioxidant preservative.

[0024] A method for preparing an oral sleep-aiding composition containing ergothioneine comprises the following steps:

[0025] S1. The ergothioneine, melatonin, glycine, magnesium salt and antioxidant preservative are weighed, passed through an 80-200 mesh sieve, and premixed for 10-30 minutes to obtain a premix;

[0026] S2. Add the diluent and disintegrant to the premix in an amount of 50% to 70% of the total amount and continue mixing for 20-60 minutes to obtain a mixture;

[0027] S3. Adding a 5%-15% binder solution to the mixture, wet granulating, and drying to a moisture content of ≤3%;

[0028] S4. Add the remaining disintegrant and lubricant, mix thoroughly, and then compress into tablets or fill into capsules.

[0029] Furthermore, the drying temperature of the wet granulation is 40-60°C and the granulation pressure is 8-15 MPa;

[0030] The binder solution is a hydroxypropyl methylcellulose aqueous solution, and the amount used accounts for 3%-8% of the total weight of the particles.

[0031] Furthermore, the capsule is an enteric-coated capsule, using hydroxypropyl methylcellulose phthalate or acrylic resin as an enteric coating, and the coating weight gain is 3%-10%; the composition is packaged in a light-proof aluminum-plastic blister, and the storage conditions are temperature ≤25°C and relative humidity ≤60%.

[0032] The antioxidant preservative of the present invention contains multiple phenolic hydroxyl groups in its structure, which can neutralize free radicals by providing hydrogen atoms and block the oxidation chain reaction. 2+ 、Cu 2+ ), inhibiting the Fenton reaction. The aromatic ring and conjugated structure can stabilize the generated phenoloxy free radicals and prolong the antioxidant activity. The amino group can enhance the ability of the molecule to scavenge free radicals through hydrogen bonds or complexation. Chlorine atoms and hydrophobic groups enhance the lipid solubility of the molecule, penetrate the bacterial cell membrane, and interfere with membrane integrity. The ergothioneine described in the present invention specifically removes peroxynitrite anions and free radicals, protecting ingredients such as melatonin and glycine from oxidative degradation. Combined with melatonin, its half-life is extended; it cooperates with glycine and magnesium salts to reduce neuronal excitability, forming a multi-target sleep-aiding network.

[0033] Melatonin regulates circadian rhythms, and ergothioneine protects melatonin from oxidative inactivation while enhancing its receptor sensitivity. Glycine activates glycine receptors and inhibits spinal neurons; magnesium ions antagonize NMDA receptors, synergistically reducing central excitability and relieving muscle tension. The synergy between antioxidant preservatives and active ingredients protects ergothioneine, melatonin and other active ingredients that are sensitive to oxidation, ensuring the stability of the formulation and long-term storage effectiveness. Enteric coating (HPMCP / acrylic resin): avoids damage by gastric acid, targets intestinal release, and improves bioavailability. Disintegrant (cross-linked sodium carboxymethyl cellulose): regulates the disintegration rate of the tablet, ensures the sustained release of the active ingredient, and prolongs the duration of action. Lubricant (magnesium stearate): optimizes the tableting process to avoid uneven distribution of ingredients. Ergothioneine and glycine are both endogenous substances, reducing the metabolic burden on the liver and kidneys; magnesium salts supplement dietary magnesium deficiency and reduce the risk of side effects.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] 1. Multi-target synergistic enhancement: Through the synergistic combination of ergothioneine, melatonin, glycine and magnesium salts, a multi-dimensional action network of antioxidant, neuromodulation and receptor inhibition is formed, breaking through the limitations of a single ingredient in aiding sleep, and significantly improving the efficiency of falling asleep and the ability to maintain sleep.

[0036] 2. Significantly optimized stability: Specific antioxidant preservatives are combined with enteric coating technology to effectively protect active ingredients (such as ergothioneine and melatonin) from oxidative degradation and gastric acid damage, ensuring long-term storage stability and bioavailability of intestinal targeted release.

[0037] 3. Enhanced safety and tolerance: Based on the ratio of endogenous substances (ergothioneine and glycine), it avoids the metabolic burden of traditional sleep-inducing ingredients, combines with the design of sustained-release preparations, reduces dose-dependent side effects, and improves the safety of long-term use. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The invention discloses a method for synthesizing the antioxidant preservative. DETAILED DESCRIPTION

[0039] The following will clearly and completely describe the technical solution of the present invention in conjunction with the accompanying drawings. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0040] Synthesis example 1

[0041] Synthesis of antioxidant preservative 1:

[0042]

[0043] Step 1: Under a nitrogen atmosphere, 300 g of DMSO, 20 g of raw material 1, 46.68 g of raw material 2, 40.49 g of potassium phosphate trihydrate, 0.7 g of CuI and 0.09 g of pyridine-2-carboxylic acid were added to the reaction system, and the reaction was heated at 85° C. for 16 hours; after cooling, the reaction mixture was extracted with an ammonia solution and methyl tert-butyl ether, and the organic phase was washed five times with water and twice with a saturated NaCl solution; finally, the combined organic phase was dried over anhydrous magnesium sulfate, dried by spin drying, and passed through a silica gel column with a mixed solution of petroleum ether and ethyl acetate as the eluent, and dried by spin drying to obtain 39.30 g of intermediate 1.

[0044] Step 2: Under a nitrogen atmosphere, 39.30 g of intermediate 1 and 400 g of ultra-dry tetrahydrofuran were added to the reaction system, cooled to -70°C, 3.70 g of n-butyl lithium was added dropwise, and stirred for 1 hour after the addition was complete. Then, 15.98 g of triisopropyl borate was added dropwise, and the temperature was naturally raised to room temperature after the addition was complete. The reaction was carried out for 10 hours and the mixture was spin-dried to obtain 26.23 g of intermediate 2.

[0045] Step 3: Under a nitrogen atmosphere, 26.23 g of intermediate 2, 21.85 g of raw material 3, 11.01 g of anhydrous potassium carbonate, 1.38 g of tetrakis(triphenylphosphine)palladium, and 300 g of a mixed solution consisting of toluene, ethanol, and water (volume ratio 2:1:1) were added to the reaction system, heated to 75°C and refluxed for 10 hours. The heating was turned off, the mixture was cooled to room temperature, and the mixture was allowed to stand for separation. The aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed three times with water, dried, and subjected to column chromatography using a mixture of petroleum ether and ethyl acetate as an eluent to obtain 31.26 g of antioxidant preservative 1. MS [MS+H + ]:991.

[0046] Antioxidant preservative 1 1 HNMR (deuterated chloroform) is: δ9.64 (s, 1H), 8.87 (s, 1H), 8.76 (s, 1H), 8.03-7.94 (m, 3H), 7.83 (d, 1H), 7.65 (dd, 1H), 7.48-7.41 (m, 1H), 7.30-7.21 (m, 2H), 7.18-7.07 (m, 2H), 5.51-5.44 (m, 1H), 5.18 (m,1H),3.99(m,1H),3.88(m,1H),3.75(m,1H),3.60(s,1H),2.82-2.73(m,2H),2.56-2.47( m,1H),2.44-2.34(m,2H),2.32-2.18(m,2H),2.17-1.55(m,14H),1.17(d,3H),0.93(d,3H).

[0047] Synthesis Example 2-Synthesis Example 3

[0048] The antioxidant preservatives synthesized in Synthesis Examples 2-3 were prepared by referring to the synthesis method of Synthesis Example 1, replacing the raw material 1 therein, and the rest remained the same as Synthesis Example 1. The specific structure of raw material 1, the structure of antioxidant preservative and MS [MS+H + ]See the table below for data.

[0049]

[0050]

[0051] Example 1

[0052] Preparation of an oral sleep-aiding composition containing ergothioneine:

[0053] The ratio of raw materials by mass: 1.5 parts of ergothioneine, 6 parts of melatonin, 10 parts of magnesium glycinate, 30 parts of glycine, 55 parts of microcrystalline cellulose, 5 parts of hypromellose, 2 parts of magnesium stearate, 8 parts of cross-linked sodium carboxymethyl cellulose (5 parts of which are added in the premixing stage), and 0.3 part of antioxidant preservative 1 (product of Synthesis Example 1).

[0054] Raw material mass ratio: ergothioneine 1.5g, melatonin 6g, magnesium glycinate 10g, glycine 30g, microcrystalline cellulose 55g, hypromellose 5g, magnesium stearate 2g, cross-linked sodium carboxymethyl cellulose 8g (5g of which was added in the premixing stage), antioxidant preservative 1 (product of Synthesis Example 1) 0.3g.

[0055] Preparation method:

[0056] S1. Weigh ergothioneine, melatonin, magnesium glycinate, glycine and antioxidant preservative 1, pass them through a 100-mesh sieve, place them in a three-dimensional motion mixer, and premix them at 25 rpm for 20 minutes to obtain a premix.

[0057] S2. Add microcrystalline cellulose and croscarmellose sodium (5 g for the first time) to the premix, heat the mixer to 35 ± 2 °C, and mix at 18 Hz for 45 minutes to achieve a uniform material state.

[0058] S3. Prepare a 10% aqueous solution of hypromellose (dissolve 5 g of hypromellose in 50 mL of purified water) and spray it into the mixture. Granulate the mixture using a wet granulator at a pressure of 12 MPa. Place the resulting wet granules in a hot air circulating oven at 50°C and dry them to a moisture content of 2.8%.

[0059] S4. The dried granules are sieved through a 20-mesh sieve, and the remaining 3 g of cross-linked sodium carboxymethyl cellulose and magnesium stearate are added. The mixture is placed in a V-type mixer and mixed at a speed of 10 rpm for 15 minutes. A rotary tablet press (die diameter 8 mm) is used to press the tablet cores, with a tablet weight of 120 mg / tablet. Hydroxypropyl methylcellulose phthalate (HPMCP) coating solution (solid content 8%) is prepared, and an efficient coating pan is used for enteric coating. The inlet air temperature is controlled at 40°C, and the coating weight gain is 6%. The coated tablets are placed in light-proof aluminum-plastic blisters, 6 tablets per plate, and the outer packaging is sealed with an aluminum foil bag. The finished product is stored in a cool and dry environment with a temperature of 23±2°C and a relative humidity of 55±5%.

[0060] Example 2

[0061] A preparation method for an oral sleep-aiding composition containing ergothioneine, wherein the antioxidant preservative 1 is replaced by the product of Synthesis Example 2, and the rest is the same as Example 1.

[0062] Example 3

[0063] A preparation method for an oral sleep-aiding composition containing ergothioneine, wherein the antioxidant preservative 1 is replaced by the product of Synthesis Example 3, and the rest is the same as Example 1.

[0064] Example 4

[0065] A preparation method for an oral sleep-aiding composition containing ergothioneine, wherein the ergothioneine is replaced with 3 parts, and the rest is the same as in Example 1.

[0066] Comparative Example 1

[0067] The invention discloses a preparation method for an oral sleep-aiding composition containing ergothioneine, wherein the antioxidant preservative 1 is not added, and the rest of the preparation method is the same as that of Example 1.

[0068] Comparative Example 2

[0069] Preparation of an oral sleep-aiding composition containing ergothioneine, wherein the antioxidant preservative 1 is replaced with the comparative compound 1, and the rest remains the same as in Example 1.

[0070] Comparative compound 1:

[0071] Comparative Example 3

[0072] The invention discloses a preparation method for an oral sleep-aiding composition, wherein ergothioneine is not added, and the rest of the preparation method is the same as that of Example 1.

[0073] Performance testing:

[0074] 1. According to the enteric-coated tablet standard of the Chinese Pharmacopoeia, the dissolution rate of ergothioneine and melatonin in pH 6.8 phosphate buffer for 45 minutes was tested.

[0075] 2. Accelerated test (40°C / RH75%): Determine the degradation rates of ergothioneine and melatonin after 3 months.

[0076] 3. Sleep-aid test: Healthy adult SD rats (200±20 g) were selected and randomly divided into a control group (normal saline) and a drug-treated group (the composition prepared in the Examples and Comparative Examples, administered orally at 8 mg / kg body weight). The rats were given a single dose at a fixed time daily for 7 consecutive days. Thirty minutes after the last dose, a subthreshold dose of sodium pentobarbital (35 mg / kg) was injected intraperitoneally. The sleep onset rate within 15 minutes (loss of righting reflex >60 seconds) and sleep duration were recorded.

[0077]

[0078]

[0079] Compared to comparative example, the embodiment group containing specific structure antioxidant preservative all presents remarkable advantage in terms of active ingredient dissolution, storage stability and sleep-aiding effect.Wherein, the embodiment group using the antioxidant preservative of the present invention shows more excellent dissolution performance, lower active ingredient degradation rate and higher biological effect, and the comparative example group without adding or replacing preservative then presents the trend that dissolution efficiency declines, component stability weakens and sleep-aiding effect impairment.Meanwhile, the control group lacking thioneine is significantly weaker than complete formula group in sleep-aiding index, prompting that there is synergistic effect between each component.These trends show that the structural specificity of antioxidant preservative in the present composition, the core effect of thioneine and each component compatibility rationality have key influence on overall performance.

[0080] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. An oral sleep-aiding composition containing ergothioneine, characterized in that, The invention comprises the following components in parts by mass: 0.01-3 parts of ergothioneine, 0.1-10 parts of melatonin, 10-40 parts of glycine, 2-15 parts of magnesium salt, 30-70 parts of diluent, 1-10 parts of binder, 0.5-5 parts of lubricant, 2-10 parts of disintegrant, and 0.1-0.5 parts of antioxidant preservative; The composition is in the form of a tablet, capsule or granule; The antioxidant preservative has a structure shown in Formula 1: The Z1 is selected from: O, S, C(CH3)2.

2. according to a kind of oral sleep-aiding composition containing ergothioneine described in claim 1, it is characterized in that, The magnesium salt is selected from at least one of magnesium glycinate, magnesium citrate or magnesium oxide.

3. according to a kind of oral sleep-aiding composition containing ergothioneine described in claim 1, it is characterized in that, The diluent is selected from at least one of microcrystalline cellulose, lactose or mannitol.

4. according to a kind of oral sleep-aiding composition containing ergothioneine described in claim 1, it is characterized in that, The binder is selected from at least one of hydroxypropyl methylcellulose, polyvinyl pyrrolidone or starch.

5. according to a kind of oral sleep-aiding composition containing ergothioneine described in claim 1, it is characterized in that, The lubricant is selected from at least one of magnesium stearate, silicon dioxide or talc.

6. according to a kind of oral sleep-aiding composition containing ergothioneine described in claim 1, it is characterized in that, The disintegrant is selected from at least one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose.

7. according to a kind of oral sleep-aiding composition containing ergothioneine described in claim 1, it is characterized in that, The antioxidant preservative is any one of the compounds shown in the following structures:

8. A method for preparing an oral sleep-aiding composition containing ergothioneine according to any one of claims 1 to 7, characterized in that: The following steps are involved: S1. The ergothioneine, melatonin, glycine, magnesium salt and antioxidant preservative are weighed, passed through an 80-200 mesh sieve, and premixed for 10-30 minutes to obtain a premix; S2. Add the diluent and disintegrant to the premix in an amount of 50% to 70% of the total amount and continue mixing for 20-60 minutes to obtain a mixture; S3. Adding a 5%-15% binder solution to the mixture, wet granulating, and drying to a moisture content of ≤3%; S4. Add the remaining disintegrant and lubricant, mix thoroughly, and then compress into tablets or fill into capsules.

9. according to the preparation method of a kind of oral sleep-aiding composition containing ergothioneine described in claim 8, it is characterized in that, The drying temperature of the wet granulation is 40-60°C, and the granulation pressure is 8-15MPa; The binder solution is a hydroxypropyl methylcellulose aqueous solution, and the amount used accounts for 3%-8% of the total weight of the particles.

10. An oral sleep-aiding composition containing ergothioneine according to claim 1, characterized in that, The capsule is an enteric-coated capsule, which uses hydroxypropyl methylcellulose phthalate or acrylic resin as an enteric coating with a coating weight gain of 3%-10%. The composition is packaged in a light-proof aluminum-plastic blister and stored under the conditions of temperature ≤25°C and relative humidity ≤60%.

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