Composition for treating neurasthenia and preparation method and application thereof

Abstract

The invention provides a composition for treating neurasthenia as well as a preparation method and application thereof, and belongs to the technical field of medicines. The preparation method comprises the following steps: mixing an oxazepam derivative or physiologically acceptable salt thereof with traditional Chinese medicine polysaccharide, and adding other materials to prepare the sustained-release tablet. The composition for treating neurasthenia has the advantages that the medicine release time is prolonged, the patient compliance is obviously improved, the single administration dosage can be reduced by controlling the release rate, meanwhile, the composition is combined with the traditional Chinese medicine polysaccharide, the safety is better, the composition is milder and non-irritant, the composition is released in a targeted intestinal tract, the intestinal-brain axis is activated, the stability of the preparation is improved on the whole, and the application prospect is wide. Wide application prospects are realized.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a composition for treating neurasthenia, its preparation method, and its application. Background Technology

[0002] Neurasthenia is a condition characterized by decreased mental capacity and hypersensitivity to external stimuli due to excessive stress from work and life. Because no objective signs of organic damage sufficient to explain its symptoms can be found, neurasthenia is considered a functional disorder. Neurasthenia may cause insomnia. Mild neurasthenia patients may recover their vitality through biopsychosocial interventions. However, in clinical practice, drug treatment remains the first-line treatment for many patients.

[0003] Currently, the main medications used clinically to treat neurasthenia include benzodiazepines and antidepressants. While benzodiazepines can quickly relieve symptoms such as anxiety and insomnia, long-term use can easily lead to adverse reactions such as drug dependence, drug tolerance, and cognitive impairment. Although antidepressants are effective in improving patients' mood symptoms, their onset of action is slow, and some patients may experience side effects such as sexual dysfunction and weight gain, limiting their application in the treatment of neurasthenia.

[0004] In the field of Western medicine research and development, some novel drugs have also shown promising application prospects. For example, agomelatine, as a melatonin receptor agonist, can improve sleep quality, combat depression, regulate mood, and has mild adverse reactions. In addition, some drugs targeting neuroprotection and neurotrophic effects are under continuous development, such as neurotrophic factors and their analogues, which are expected to fundamentally improve the symptoms of neurasthenia patients by promoting the growth, repair, and functional recovery of nerve cells.

[0005] Compound medications offer unique advantages in treating neurasthenia, enhancing efficacy through synergistic effects across multiple targets and pathways. For example, some compound medications can simultaneously regulate neurotransmitters, improve cerebral blood flow, reduce neuroinflammation, and comprehensively improve patient symptoms. Currently, research on compound medications mainly focuses on traditional Chinese medicine compound prescriptions, integrated traditional Chinese and Western medicine compound prescriptions, and Western medicine compound prescriptions. Through modern pharmacological research and clinical trials, compound medications with clear efficacy and good safety profiles are being screened, providing more options for the treatment of neurasthenia.

[0006] Therefore, developing a mild, non-irritating composition with few side effects for the treatment of neurasthenia is promising. Summary of the Invention

[0007] The purpose of this invention is to propose a composition for treating neurasthenia, its preparation method, and its application. The composition prolongs the drug release time, significantly improving patient compliance. By controlling the release rate, the single dose can be reduced. Furthermore, when combined with traditional Chinese medicine polysaccharides, it offers better safety, is gentler and less irritating, targets intestinal release, activates the gut-brain axis, and improves the overall stability of the formulation, thus having broad application prospects.

[0008] The technical solution of this invention is implemented as follows: This invention provides a composition for treating neurasthenia, comprising a mixture of oxazepam derivatives or physiologically acceptable salts thereof and traditional Chinese medicine polysaccharides, with the addition of other materials to prepare a sustained-release tablet. The structural formula of the oxazepam derivative is shown in Formula I. Formula I; The herbal polysaccharide is prepared by mixing Gastrodia elata, Albizia julibrissin, Ziziphus jujuba var. spinosa, and Glycyrrhiza uralensis.

[0009] Preferably, the physiologically acceptable salts of the oxazepam derivatives are sodium salts, calcium salts, or arginine salts.

[0010] As a further improvement of the present invention, the preparation method of the oxazepam derivative is as follows: S1. Oxazepam and γ-aminobutyric acid were esterified under the action of a catalyst to obtain intermediate 1, with the following structure: ; S2. Intermediate 1 and succinic acid undergo a condensation reaction to obtain the product.

[0011] The synthesis route is as follows:

[0012] As a further improvement of the present invention, the molar ratio of oxazepam and γ-aminobutyric acid in step S1 is 1:1-1.2, the catalyst is p-toluenesulfonic acid or concentrated sulfuric acid, the temperature of the esterification reaction is 100-110℃, and the time is 4-6h.

[0013] As a further improvement of the present invention, the molar ratio of intermediate 1 and succinic acid in step S2 is 1:1-1.2, and N-hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide are also added, and the condensation reaction time is 10-15 h.

[0014] As a further improvement of the present invention, the preparation method of the traditional Chinese medicine polysaccharide is as follows: Gastrodia elata, Albizia julibrissin, Ziziphus jujuba var. spinosa, and Glycyrrhiza uralensis are mixed, pulverized, sieved, added to water, heated to boiling for extraction, cooled to room temperature, precipitated with ethanol, filtered, washed, and dried to obtain the traditional Chinese medicine polysaccharide.

[0015] As a further improvement of the present invention, the mass ratio of Gastrodia elata, Albizia julibrissin, Ziziphus jujuba var. spinosa, and Glycyrrhiza uralensis is 10-15:5-7:4-6:1-3; the heating and boiling extraction time is 3-5 hours; and ethanol is added until the ethanol content of the system is 70-80 wt%.

[0016] The present invention further protects a method for preparing the above-mentioned composition for treating neurasthenia, comprising the following steps: (1) Mix oxazepam derivatives or their physiologically acceptable salts, traditional Chinese medicine polysaccharides, sustained-release materials and fillers, granulate, and dry to obtain dry granules; (2) Mix the dry granules with the lubricant, compress the mixture into tablets, and obtain sustained-release tablets; (3) Coating the sustained-release tablets with a coating material to obtain a composition for treating neurasthenia.

[0017] As a further improvement of the present invention, the mass ratio of the oxazepam derivative or its physiologically acceptable salt, traditional Chinese medicine polysaccharide, sustained-release material, filler, and lubricant is 20-40:15-30:15-35:5-25:1-5.

[0018] As a further improvement of the present invention, the sustained-release material is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyvinylpyrrolidone, carbomer, and gum arabic; the filler is selected from at least one of lactose, microcrystalline cellulose, starch, mannitol, dextrin, and dicalcium phosphate; the lubricant is selected from at least one of talc, magnesium stearate, sodium fumarate stearate, stearic acid, and calcium stearate; and the coating material is selected from at least one of cellulose phthalate, cellulose acetate succinate, and polyvinyl acetate phthalate.

[0019] The present invention further protects the use of the above-mentioned composition for treating neurasthenia in the preparation of medicaments for treating neurasthenia, depression and insomnia.

[0020] The present invention has the following beneficial effects: Oxazepam is a short-acting benzodiazepine with anti-anxiety, anticonvulsant, sedative, hypnotic, and alcohol withdrawal symptoms-relieving effects. Due to its insolubility in water, its bioavailability is significantly reduced, and oral absorption is slow. In addition, it has a short half-life, is not easily accumulated, and has relatively low addictive potential; however, it also has some side effects, such as drowsiness, fatigue, ataxia, nystagmus, slurred speech, memory loss, disorientation, difficulty concentrating, and nausea. This invention utilizes the esterification reaction of γ-aminobutyric acid (GABA) with its hydroxyl group to construct a prodrug. After absorption in the intestine, the ester prodrug is hydrolyzed by esterases to release the parent drug, avoiding the shock effect caused by rapid peak blood concentration, reducing first-pass effect variability, and achieving targeted release in the intestine, thus improving absorption rate.

[0021] This invention further involves a condensation reaction between the amino group on the grafted γ-aminobutyric acid and succinic acid, introducing an easily metabolizable amide fragment. This allows the drug to be rapidly inactivated by plasma esterases after exerting its central effect, resulting in rapid onset of action, reduced residue, and improved efficacy to some extent. The optimized compound of this invention also exhibits significantly reduced side effects and can promote sleep by releasing γ-aminobutyric acid through decomposition. Furthermore, it demonstrates high safety, and the residual carboxyl group can be prepared into a physiologically acceptable salt, greatly improving the water solubility of the drug molecule, thereby enhancing bioavailability and drug stability.

[0022] This invention selects polysaccharides from traditional Chinese medicine as auxiliary components. On the one hand, they can form hydrogen bonds to further slow the release of active drugs, thereby reducing the frequency of medication and improving patient compliance. On the other hand, these polysaccharides significantly increase the levels of γ-aminobutyric acid, serotonin, and norepinephrine in the brain, while also increasing acetylcholine levels, resulting in a good sleep-promoting effect. Gastrodia elata polysaccharide can inhibit the excitatory toxicity caused by excessive glutamate induced by drugs, alleviating its damage to neurons. Albizia julibrissin and Ziziphus jujuba seed polysaccharides can inhibit inflammatory responses, enhance antioxidant stress, strengthen immune function, and promote emotional recovery. They are gentler, have no side effects, and are non-irritating, thus improving the overall safety of the medication.

[0023] The composition for treating neurasthenia prepared by this invention has a prolonged drug release time, which significantly improves patient compliance. By controlling the release rate, the single dose can be reduced. At the same time, when combined with traditional Chinese medicine polysaccharides, it has better safety, is gentler and less irritating, targets intestinal release, activates the gut-brain axis, and improves the overall stability of the formulation, thus having broad application prospects. Attached Figure Description

[0024] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0025] Figure 1 The mass spectrum of the oxazepam derivative prepared in Example 1; Figure 2 Infrared spectrum of the oxazepam derivative prepared in Example 1; Figure 3 The infrared spectrum is shown for the composition for treating neurasthenia prepared in Example 1. Detailed Implementation

[0026] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] Preparation Example 1: Oxazepam Derivatives The preparation method is as follows: S1. 0.1 mol oxazepam and 0.11 mol γ-aminobutyric acid were added to 200 mL of dimethyl sulfoxide, followed by 1 g of p-toluenesulfonic acid. The mixture was heated to 105 °C and stirred for 5 h. After washing with water and removing the solvent under reduced pressure, the mixture was recrystallized from ethanol, filtered, washed, and dried to obtain intermediate 1. ESI-MS calculated value: C 19 H 19 ClN3O3(M+H) + 371.12, measured value: 371.1, yield: 72%. NMR results: 1 H NMR (300MHz, CDCl3) δ7.9-8 (m, 3H), 7.6-7.64 (m, 2H), 7.5-7.53 (m, 3H), 7.29 (d, J =7.2Hz, 1H), 6.51 (s, 1H), 2.67 (m, 2H), 2.21 (t, 2H), 1.94-2.0 (m, 4H).

[0028] S2. 0.11 mol of succinic acid was added to 250 mL of ethanol, followed by 0.12 mol of N-hydroxysuccinimide and 0.12 mol of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The mixture was stirred and activated for 25 min. 0.1 mol of intermediate 1 was added, and the reaction was stirred at room temperature for 12 h. The mixture was washed with water, the solvent was removed under reduced pressure, and the mixture was recrystallized from acetone. The product was filtered, washed, and dried to obtain the final product. ESI-MS calculated value: C 23 H 23 ClN3O6(M+H) + 471.12, measured value: 471.1, yield: 69%. NMR results: 1 H NMR (300MHz, DMSO-d6) δ11.0 (br, 1H), 7.9-8.0 (br, 4H), 7.55-7.62 (m, 5H), 7.22 (d, J =7.0Hz, 1H), 6.57 (s, 1H), 3.22 (m, 2H), 2.47-2.52 (m, 4H), 2.29 (t, 2H), 1.91 (m, 2H). Figure 1 The mass spectrum of the prepared oxazepam derivative is shown. Figure 2The infrared spectrum of the prepared oxazepam derivative.

[0029] Preparation Example 2: Polysaccharides from Traditional Chinese Medicine The preparation method is as follows: 10g of Gastrodia elata, 5g of Albizia julibrissin, 4g of Ziziphus jujuba var. spinosa, and 1g of Glycyrrhiza uralensis are mixed, pulverized, passed through an 80-mesh sieve, added to 500mL of water, heated to boiling and extracted for 3h, cooled to room temperature, added ethanol until the ethanol content of the system is 70wt%, precipitated for 1h, filtered, washed, and dried to obtain the Chinese herbal polysaccharide.

[0030] Preparation Example 3: Polysaccharides from Traditional Chinese Medicine The preparation method is as follows: 15g of Gastrodia elata, 7g of Albizia julibrissin, 6g of Ziziphus jujuba var. spinosa, and 3g of Glycyrrhiza uralensis are mixed, pulverized, passed through an 80-mesh sieve, added to 500mL of water, heated to boiling and extracted for 5h, cooled to room temperature, added ethanol until the ethanol content of the system is 80wt%, precipitated for 1h, filtered, washed, and dried to obtain the Chinese herbal polysaccharide.

[0031] Preparation Example 4: Polysaccharides from Traditional Chinese Medicine The preparation method is as follows: 12g of Gastrodia elata, 6g of Albizia julibrissin, 5g of Ziziphus jujuba var. spinosa, and 2g of Glycyrrhiza uralensis are mixed, pulverized, passed through an 80-mesh sieve, added to 500mL of water, heated to boiling and extracted for 4h, cooled to room temperature, added ethanol until the ethanol content of the system is 75wt%, precipitated for 1h, filtered, washed, and dried to obtain the Chinese herbal polysaccharide. Example 1

[0032] This embodiment provides a method for preparing a composition for treating neurasthenia, comprising the following steps: (1) 20g of oxazepam derivative prepared in Preparation Example 1, 15g of traditional Chinese medicine polysaccharide prepared in Preparation Example 2, 15g of hydroxypropyl cellulose and 5g of starch were mixed, granulated and dried to obtain dry granules. (2) Mix the dry granules with 1g of calcium stearate, compress into tablets, and obtain sustained-release tablets; (3) Coating sustained-release tablets with polyvinyl acetate phthalate to obtain a composition for treating neurasthenia. Figure 3 Infrared spectrum of the prepared composition for treating neurasthenia. Example 2

[0033] This embodiment provides a method for preparing a composition for treating neurasthenia, comprising the following steps: (1) 40g of oxazepam derivative prepared in Preparation Example 1, 30g of traditional Chinese medicine polysaccharide prepared in Preparation Example 3, 35g of hydroxypropyl cellulose and 25g of mannitol were mixed, granulated and dried to obtain dry granules; (2) Mix the dry granules with 5g of sodium fumarate stearate, compress into tablets, and obtain sustained-release tablets; (3) Coating sustained-release tablets with polyvinyl acetate phthalate to obtain a composition for treating neurasthenia. Example 3

[0034] This embodiment provides a method for preparing a composition for treating neurasthenia, comprising the following steps: (1) Mix 30g of oxazepam derivative prepared in Preparation Example 1, 20g of traditional Chinese medicine polysaccharide prepared in Preparation Example 4, 25g of hydroxypropyl cellulose, and 15g of microcrystalline cellulose, granulate, and dry to obtain dry granules; (2) Mix the dry granules with 3g of magnesium stearate, compress into tablets, and obtain sustained-release tablets; (3) Coating sustained-release tablets with polyvinyl acetate phthalate to obtain a composition for treating neurasthenia.

[0035] Comparative Example 1 The difference from Example 3 is that the oxazepam derivative was replaced by an equal mass of intermediate 1 obtained from Preparation Example 1.

[0036] Comparative Example 2 The difference from Example 3 is that the oxazepam derivative was replaced with an equal mass of oxazepam.

[0037] Comparative Example 3 The difference compared to Example 3 is that no traditional Chinese medicine polysaccharides were added.

[0038] Includes the following steps: (1) Mix 30g of the oxazepam derivative prepared in Preparation Example 1, 45g of hydroxypropyl cellulose and 15g of microcrystalline cellulose, granulate and dry to obtain dry granules; (2) Mix the dry granules with 3g of magnesium stearate, compress into tablets, and obtain sustained-release tablets; (3) Coating sustained-release tablets with polyvinyl acetate phthalate to obtain a composition for treating neurasthenia.

[0039] Comparative Example 4 The difference compared to Example 3 is that no sustained-release material was added.

[0040] Includes the following steps: (1) Mix 30g of oxazepam derivative prepared in Preparation Example 1, 45g of traditional Chinese medicine polysaccharide prepared in Preparation Example 4, and 15g of microcrystalline cellulose, granulate, and dry to obtain dry granules; (2) Mix the dry granules with 3g of magnesium stearate, compress the mixture into tablets; (3) Coating tablets with polyvinyl acetate phthalate to obtain a composition for treating neurasthenia.

[0041] Comparative Example 5 The difference compared to Example 3 is that no oxazepam derivative was added.

[0042] Includes the following steps: (1) Mix 50g of the Chinese herbal polysaccharide prepared in Preparation Example 4, 25g of hydroxypropyl cellulose and 15g of microcrystalline cellulose, granulate and dry to obtain dry granules; (2) Mix the dry granules with 3g of magnesium stearate, compress into tablets, and obtain sustained-release tablets; (3) Coating sustained-release tablets with polyvinyl acetate phthalate to obtain a composition for treating neurasthenia.

[0043] Test Example 1 Male SD rats weighing 160-200g were housed in an environment with a temperature of (23±2)℃ and humidity of (55±5%), with a circadian rhythm of 12h and free access to food and water. Following the standard operating procedures for SD rat husbandry, the environment should be kept clean, dust-free, and well-ventilated to prevent respiratory diseases caused by SD rats' sensitivities to airborne dust, ammonia, hydrogen sulfide, etc. An acclimatization period of one week was implemented.

[0044] Rats were divided into a normal group, a model group, Example 1-3 groups, and Comparative Example 1-5 groups, with 10 rats in each group. Except for the normal group, rats in the other groups underwent modeling. Each day for 28 days, one of the following seven mild stimuli was randomly selected and administered to the rats: ① Swimming in 0℃ ice water for 5 minutes; ② Reversed day-night cycle for 24 hours; ③ Fasting and water restriction for 24 hours; ④ Tail clamping for 1 minute; ⑤ Swimming in 45℃ hot water for 5 minutes; ⑥ Tilting the cage at a 45-degree angle. ° 24h; ⑦ humid environment for 24h. After modeling, rats were subjected to sucrose preference test and forced swimming test to determine that successful modeling could be achieved in 28 days.

[0045] Except for the model group, before each stress stimulus, rats in Examples 1-3 and Comparative Examples 1-5 were administered the corresponding prepared composition for treating neurasthenia by gavage at a dose of 5 mg / kg body weight for 4 consecutive weeks. The model group and the normal group were given the same amount of water. The experimental results are shown in Table 1.

[0046] 1. Sucrose Preference Consumption Test After 5 weeks of treatment, rats were acclimatized to a 1% sucrose solution. Each rat was housed individually and provided with two bottles of the 1% sucrose solution. After 24 hours, one of the solutions was replaced with purified water, and this process was repeated for another 24 hours. Then, the rats were fasted and deprived of water for 12 hours, allowing them to freely choose between the two solutions (one 1% sucrose solution and one purified water). After 1 hour, the two solutions were swapped. Two hours later, the weight of each solution was measured, and the sucrose preference rate was calculated.

[0047] Sucrose preference rate = (Sucrose water consumption / (Sucrose water consumption + Water consumption)) × 100% 2. Forced swimming test A transparent cylinder with a diameter of 25 cm was used, filled with water to a depth of 35 cm at a temperature of (25±1)℃. During the experiment, each rat was allowed to swim for 15 minutes before being returned to its cage. 24 hours later, the rats were placed individually in the cylinder to swim again, and the time each rat remained still within 5 minutes was recorded.

[0048] Table 1

[0049] Note: * indicates P<0.05 compared with the control group; # indicates P<0.05 compared with the normal group.

[0050] As shown in the table above, the compositions for treating neurasthenia prepared in Examples 1-3 of this invention can significantly increase the sucrose preference rate and reduce the resting time in rats.

[0051] Test Example 2 SPF-grade Kunming mice weighing 18-23g were randomly divided into a control group, Example 1-3 groups, and Comparative Example 1-5 groups, with 10 mice in each group. The mice were administered the prepared neurasthenia treatment composition at a dose of 7mg / kg body weight via gavage. The model group and the normal group were given the same amount of water. Administered once daily. During the experiment, the animals had free access to food and water, and their activity and growth were observed daily. The experiment was conducted 14 days after gavage. The results are shown in Table 2.

[0052] 1. Pentobarbital sodium sleep duration prolongation test Thirty minutes after the last gavage, mice in each group were intraperitoneally injected with 45 mg / (kg·bw) of sodium pentobarbital. The disappearance of the righting reflex was used as an indicator of sleep onset, and the average sleep time of each group was recorded.

[0053] 2. Sodium barbiturate sleep latency test Twenty minutes after completing the pentobarbital sodium sleep time extension test, mice in each group were intraperitoneally injected with 250 mg / (kg·bw) of barbital sodium. The disappearance of the righting reflex was used as the basis to observe whether the test drug could shorten the sleep latency of barbital sodium.

[0054] Table 2

[0055] Note: * indicates P<0.05 compared to the control group.

[0056] As can be seen from the table above, the compositions for treating neurasthenia prepared in Examples 1-3 of the present invention can significantly prolong sleep time and shorten sleep latency.

[0057] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A composition for treating neurasthenia, characterized by comprising, The application discloses a preparation method of a sustained-release tablet for treating neurasthenia, and belongs to the technical field of medicine. Formula I; The traditional Chinese medicine polysaccharide is prepared by mixing Gastrodia elata, Albizia julibrissin, Spondias axillaris and Glycyrrhiza uralensis.

2. The composition for treating neurasthenia according to claim 1, wherein The preparation method of the oxazepam derivative is as follows: S1. esterification of oxazepam and gamma-aminobutyric acid in the presence of a catalyst to obtain intermediate 1, which has the following structure: ； S2. condensation of intermediate 1 and succinic acid to obtain the product.

3. The composition for treating neurasthenia according to claim 2, wherein In step S1, the molar ratio of oxazepam to gamma-aminobutyric acid is 1:1-1.2, the catalyst is p-toluenesulfonic acid or concentrated sulfuric acid, the esterification temperature is 100-110 DEG C, and the esterification time is 4-6 hours.

4. The composition for treating neurasthenia according to claim 2, wherein In step S2, the molar ratio of intermediate 1 to succinic acid is 1:1-1.2, and N-hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide are added, and the condensation time is 10-15 hours.

5. The composition for treating neurasthenia according to claim 1, wherein The preparation method of the traditional Chinese medicine polysaccharide is as follows: Gastrodia elata, Albizia julibrissin, Spondias axillaris and Glycyrrhiza uralensis are mixed, crushed, sieved, added into water, heated and boiled to extract, cooled to room temperature, precipitated by adding ethanol, filtered, washed and dried to obtain the traditional Chinese medicine polysaccharide.

6. The composition for treating neurasthenia according to claim 5, wherein The mass ratio of Gastrodia elata, Albizia julibrissin, Spondias axillaris and Glycyrrhiza uralensis is 10-15:5-7:4-6:1-3, the heating and boiling extraction time is 3-5 hours, and the ethanol content in the system is 70-80 wt%.

7. A process for the preparation of a composition for the treatment of neurasthenia as claimed in any one of claims 1 to 6, characterized in that, The method comprises the following steps: (1) mixing the oxazepam derivative or the physiologically acceptable salt thereof, the traditional Chinese medicine polysaccharide, a sustained-release material and a filler, granulating, drying to obtain dry granules; (2) mixing the dry granules with a lubricant, tabletting to obtain the sustained-release tablet; (3) coating the sustained-release tablet with a coating material to obtain the composition for treating neurasthenia.

8. The production method according to claim 7, characterized by, The mass ratio of the oxazepam derivative or the physiologically acceptable salt thereof, the traditional Chinese medicine polysaccharide, the sustained-release material, the filler and the lubricant is 20-40:15-30:15-35:5-25:1-5.

9. The preparation method according to claim 7, characterized in that, The sustained-release material is at least one selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, carbomer and gum arabic; the filler is at least one selected from lactose, microcrystalline cellulose, starch, mannitol, dextrin and calcium hydrogen phosphate; the lubricant is at least one selected from talc, magnesium stearate, sodium stearyl fumarate, stearic acid and calcium stearate; and the coating material is at least one selected from cellulose phthalate, cellulose acetate succinate and polyvinyl acetate phthalate.

10. The composition for treating neurasthenia according to any one of claims 1-6 in the preparation of a medicine for resisting neurasthenia, resisting depression and insomnia.

Images