Composition containing zolpidem tartrate and trazodone hydrochloride as well as preparation and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a composition containing zolpidem tartrate and trazodone hydrochloride as well as a preparation and application of the composition, the trazodone hydrochloride can treat sleep disorders under the condition of single use and can remarkably treat the sleep disorders when being combined with zolpidem tartrate, and pharmacological experiments find that the trazodone hydrochloride can be used for treating the sleep disorders. The sleep latency can be remarkably shortened and the sleep time can be prolonged by combined medication; the content of 5HT and NE in blood is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a composition containing zolpidem tartrate and trazodone hydrochloride, its preparations, and applications. Background Art

[0002] Zolpidem tartrate is a non-benzodiazepine, γ-aminobutyric acid A-benzodiazepine receptor agonist, with the chemical formula C 23 H 27 N3O7 and its structural formula is as follows:

[0003]

[0004] Zolpidem tartrate can selectively antagonize the γ-aminobutyric acid A complex receptor and promote the action of GABA, and has a strong sedative and hypnotic effect. Clinically, it is mainly used for hypnosis. It takes effect 30 minutes after taking the medicine, and its half-life in the blood is about 2.5 hours. Compared with benzodiazepine drugs, zolpidem has less residual effects, less tolerance and dependence are produced after long-term use, and almost no rebound insomnia is caused. It is the first choice for non-benzodiazepine treatment of insomnia.

[0005] Currently, the commercially available ordinary preparations of zolpidem tartrate include: ordinary tablets, capsules, sublingual tablets, oral sprays, and solutions, etc. Chinese Patent CN117357493A, a zolpidem tartrate orally disintegrating sustained-release tablet and its preparation method. The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a zolpidem tartrate orally disintegrating sustained-release tablet and its preparation method. Chinese Patent CN1334729A discloses a controlled-release dosage form containing zolpidem or its salt, which can release zolpidem according to a biphasic dissolution profile at a predetermined time; CN103230381B discloses a zolpidem tartrate time-controlled pulsatile release pellet, which can have a time lag and then release rapidly within a certain time. Chinese Patent CN115429768A, a zolpidem tartrate time-controlled release tablet. The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a zolpidem tartrate time-controlled release tablet and its preparation method.

[0006] Trazodone hydrochloride, chemical name: 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one monohydrochloride, molecular formula: C 19 H 22 C l N5O·HCl and its structural formula is as follows:

[0007]

[0008] The commercially available trazodone hydrochloride is mainly tablets. In the prior art, Chinese Patent CN105708796A discloses a sustained-release preparation of an oral solution containing trazodone hydrochloride and its preparation method. The sustained-release preparation is a suspension-type oral solution that achieves slow release within 24 hours, which is convenient and easy for patients to swallow. Chinese Patent CN116549406B discloses a trazodone hydrochloride sustained-release tablet. The preparation contains trazodone hydrochloride, a filler, a sustained-release material, a binder, and a lubricant, wherein the sustained-release material includes carnauba wax and polyethylene oxide. The advantage is that the tablet weight is small and easy to swallow, making it more suitable for clinical use. Chinese Patent CN117919178A discloses a liposome composition, its preparation method, and a pharmaceutical preparation containing the same. The active drug is one or two of trazodone hydrochloride and trazodone. The cumulative release degree of the liposome composition in an aqueous medium at 36 - 38 °C is less than 15% within 24 hours, less than 35% within 10 days, and greater than 95% within 40 days. This solves the problem of sudden drug release and improves bioavailability and medication safety.

[0009] In the prior art, there is no preparation of trazodone hydrochloride and zolpidem tartrate into a preparation, or the use of the two prepared into a preparation. Summary of the Invention

[0010] To overcome the deficiencies of the prior art, the present invention provides a composition of trazodone hydrochloride and zolpidem tartrate, and the composition is prepared into tablets. Pharmacological experiments have confirmed that the mutual utilization of the two components significantly shortens the sleep latency and prolongs the sleeping time of rats.

[0011] Specifically, the technical solution of the present invention is realized as follows:

[0012] The application of trazodone hydrochloride in the preparation of a drug for treating sleep disorders. It was accidentally found in clinical experiments that individual patients would feedback that the drug had this function after taking it.

[0013] A pharmaceutical composition for improving sleep disorders, the pharmaceutical composition is composed of zolpidem tartrate and trazodone hydrochloride, and the mass ratio is 0.5 - 1:2.5 - 12.5.

[0014] The pharmaceutical composition is composed of zolpidem tartrate and trazodone hydrochloride, and the mass ratio is 0.5 - 1:5 - 10, and further preferably 1:10.

[0015] Furthermore, in a preferred embodiment of the present invention, the pharmaceutical composition is prepared into a solid oral preparation, and the dose of trazodone hydrochloride in each unit preparation is 50 - 100 mg, and the dose of zolpidem tartrate is 5 - 10 mg.

[0016] Further, in a preferred embodiment of the present invention, the pharmaceutical composition is prepared into a solid oral preparation, and the dose of trazodone hydrochloride in each unit preparation is 50 mg or 100 mg, and the dose of zolpidem tartrate is 10 mg or 5 mg.

[0017] Further, in a preferred embodiment of the present invention, the pharmaceutical composition is prepared into a solid oral preparation, and the dose of trazodone hydrochloride in each unit preparation is 75 mg, and the dose of zolpidem tartrate is 7.5 mg.

[0018] Zolpidem tartrate plays a hypnotic role but does not promote deep sleep. A small dose of trazodone hydrochloride (less than 150 mg) improves sleep, adjusts the sleep structure, and promotes deep sleep. A large dose of trazodone regulates mood and has antidepressant effects. Therefore, when the two are combined, a small dose of trazodone (50 - 100 mg) + zolpidem tartrate (5 - 10 mg) complements each other to play the role of improving sleep.

[0019] It should be noted that according to the common general knowledge in the field of pharmaceutical preparations, those skilled in the art can prepare the above-mentioned drug active ingredients and pharmaceutical excipients into solid oral preparations according to conventional processes, such as tablets (including orally disintegrating tablets, dispersible tablets, sustained-release tablets, etc.), capsules, and granules. Further, the pharmaceutical composition is a solid oral preparation, including tablets, capsules, or granules.

[0020] For example, in the preparation of the preparation of the present invention, the key laboratory of Shandong New ****** Pharmaceutical Co., Ltd. was specifically commissioned to complete it. Specifically calculated by weight ratio, the tablet is prepared from the following raw materials: the dose of trazodone hydrochloride is 25 - 125 parts, the dose of zolpidem tartrate is 5 - 10 parts, microcrystalline cellulose PH101 133 - 220 parts, sorbitol 138 - 238 parts, low-substituted hydroxypropyl cellulose 22 parts, polyvinylpyrrolidone K30 10.5 parts, magnesium stearate 3.5 parts, coating powder 16 parts, and an appropriate amount of water; within the above range, tablets meeting the requirements of the 2020 edition of the Chinese Pharmacopoeia can be prepared.

[0021] Further preferably, in order to reflect the preparation effect of the tablet and meet the requirements for marketing, the tablet is prepared from the following raw materials: the dose of trazodone hydrochloride is 50 - 100 parts, the dose of zolpidem tartrate is 5 - 10 parts, microcrystalline cellulose PH101 200 - 220 parts, sorbitol 138 - 168 parts, low-substituted hydroxypropyl cellulose 22 parts, polyvinylpyrrolidone K30 10.5 parts, magnesium stearate 3.5 parts, coating powder 16 parts, and an appropriate amount of water.

[0022] Meanwhile, the present invention also provides a preparation process for the tablet, specifically as follows:

[0023] 1) API processing: Crush the raw materials of trazodone hydrochloride, zolpidem tartrate, sorbitol, microcrystalline cellulose PH101, and low-substituted hydroxypropyl cellulose separately, and pass through an 80-mesh sieve;

[0024] 2) Binder preparation: Dissolve the prescribed amount of polyvinylpyrrolidone K30 in an appropriate amount of water to prepare a 5% - 15% aqueous solution of polyvinylpyrrolidone K30 for standby;

[0025] 3) Weigh the crushed trazodone hydrochloride, zolpidem tartrate, sorbitol, microcrystalline cellulose PH101, and low-substituted hydroxypropyl cellulose and place them in a fluidized bed. Set the air volume to make the materials in a boiling state, and spray the binder solution into the fluidized bed to obtain wet granules. Among them, set the atomization pressure to 1.15 - 1.55 kg / cm2, the liquid inlet speed to 50 - 80 rpm, and spray the binder solution into the fluidized bed by top spraying to obtain wet granules; set the inlet air temperature to 55 - 65 °C, adjust the air volume until the materials boil slightly, dry until the moisture content of the granules ≤ 5%, and discharge the materials;

[0026] 4) Add magnesium stearate to the dried granules and mix for 5 - 10 min, then perform granulation and tabletting with a high-speed granulator; the tablet cores with a hardness in the range of 80 - 160 N;

[0027] 5) Prepare a 15 - 20% solution of the film coating premix, and coat the prepared tablet cores with a high-efficiency coating machine. End the coating when the weight gain reaches 3 - 5% to obtain film-coated tablets.

[0028] For further optimization of the preparation process, the preparation process of the tablets is as follows:

[0029] 1) API processing: Crush the raw materials of trazodone hydrochloride, zolpidem tartrate, sorbitol, microcrystalline cellulose PH101, and low-substituted hydroxypropyl cellulose separately, and pass through an 80-mesh sieve;

[0030] 2) Binder preparation: Dissolve the prescribed amount of polyvinylpyrrolidone K30 in an appropriate amount of water to prepare a 10% aqueous solution of polyvinylpyrrolidone K30 for standby;

[0031] 3) Weigh the crushed trazodone hydrochloride, zolpidem tartrate, sorbitol, microcrystalline cellulose PH101, and low-substituted hydroxypropyl cellulose and place them in a fluidized bed. Set the air volume to make the materials in a boiling state, and spray the binder solution into the fluidized bed to obtain wet granules. Among them, set the atomization pressure to 1.35 kg / cm 2 , the liquid inlet speed to 60 rpm, and spray the binder solution into the fluidized bed by top spraying to obtain wet granules; set the inlet air temperature to 60 °C, adjust the air volume until the materials boil slightly, dry until the moisture content of the granules ≤ 5%, and discharge the materials;

[0032] 4) Add the dried granules and magnesium stearate, mix for 10 min, and perform granulation and tabletting using a high-speed granulator; the tablet cores have a hardness in the range of 80 - 160 N;

[0033] 5) Prepare a 20% solution of the film coating premix, coat the prepared tablet cores using a high-efficiency coating machine, and end the coating when the weight gain reaches 4% to obtain film-coated tablets.

[0034] Compared with the prior art, the technical effects of the present invention are as follows:

[0035] 1) Verified through pharmacological experiments, the sleep latency of the drug composition group of the present invention (taking A2 as an example) is significantly shortened compared with that of the mice in the insomnia model group (P < 0.01), the sleep time is significantly prolonged (P < 0.01), the sleep latency is further shortened compared with diazepam, and the sleep time is significantly prolonged. Compared with the insomnia model group, there are significant differences in 5HT and NE in the serum in the A2 group (P < 0.01). Although the contents of 5HT and NE in the positive drug group are higher than those in the blank group, the contents of 5-hydroxytryptamine (5HT) and norepinephrine (NE) in the A2 group are higher, and there are significant differences compared with the positive drug group (P < 0.05).

[0036] 2) During the optimization process of the tablets, sorbitol and microcrystalline cellulose PH101 have a synergistic effect, and the dissolution rate reaches over 80% in 15 min, with a faster effect. The preparation process is relatively simple and does not require relatively harsh conditions, being suitable for large-scale industrial production. Description of the Drawings

[0037] Figure 1 : Comparison of the pentobarbital sodium-induced sleep latency of mice in different groups.

[0038] Figure 2 : Comparison of the pentobarbital sodium-induced sleep time of mice in different groups.

[0039] Figure 3 : Comparison of 5HT (pg / ml) in the serum of mice in different groups.

[0040] Figure 4 : Comparison of NE (ng / ml) in the serum of mice in different groups. Detailed Embodiments

[0041] In order to make the objectives and technical solutions of the present invention clearer, the following further illustrates the present invention with reference to the embodiments. However, the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. Those skilled in the art should understand that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0042] Example 1: Verification Example of the Core Prescription of the Embodiment of the Present Invention

[0043] This example is a specific example for preparing products A1 - A5 containing trazodone hydrochloride and zolpidem tartrate tablets. The specific prescription compositions of products A1 - A5 are shown in Table 1.

[0044] Table 1: Prescription Compositions of Products A1 - A5 (Dosage for 1000 Tablets)

[0045]

[0046]

[0047] The specific preparation method is as follows:

[0048] 1) API treatment: Crush the raw materials of trazodone hydrochloride, zolpidem tartrate, sorbitol, microcrystalline cellulose PH101, and low-substituted hydroxypropyl cellulose respectively, and pass through an 80-mesh sieve;

[0049] 2) Binder preparation: Dissolve the prescribed amount of povidone K30 in an appropriate amount of water to prepare a 10% povidone K30 aqueous solution for standby;

[0050] 3) Weigh the crushed trazodone hydrochloride, zolpidem tartrate, sorbitol, microcrystalline cellulose PH101, and low-substituted hydroxypropyl cellulose and place them in a fluidized bed. Set the air volume to make the materials in a boiling state, and spray the binder solution into the fluidized bed to obtain wet granules. Among them, set the atomization pressure to 1.35 kg / cm 2 , the liquid inlet speed to 60 rpm, and spray the binder solution into the fluidized bed by top spraying to obtain wet granules; set the inlet air temperature to 60 °C, adjust the air volume until the materials are slightly boiling, dry until the moisture content of the granules ≤ 5%, and discharge;

[0051] 4) Add magnesium stearate to the dried granules and mix for 10 min, then granulate and press tablets with a high-speed granulator; the tablet cores with a hardness in the range of 80 - 160 N;

[0052] 5) Prepare a 20% solution of the film coating premix, and coat the obtained tablet cores with a high-efficiency coating machine. End the coating when the weight gain reaches 4% to obtain film-coated tablets.

[0053] Example 2: Comparative Example of the Prescription of the Present Invention

[0054] This example is a specific example for preparing products A6 - A9 containing trazodone hydrochloride and zolpidem tartrate tablets. The specific prescription compositions of products A6 - A9 are shown in Table 2.

[0055] Table 2: Prescription Compositions of Products A6 - A9 (Dosage for 1000 Tablets)

[0056]

[0057]

[0058] Note: a represents the replaced product, such as mannitol. a : Sorbitol in this example is replaced by mannitol, and the dosage remains unchanged; the content refers to the relevant dosage composition of Group A3.

[0059] The preparation process is the same as that shown in Example 1.

[0060] Example 3: In this example, in order to verify the appearance, hardness and water content of the tablets

[0061] Table 3: Prescription composition of Products A6 - A9 (batch size 1000 tablets)

[0062]

[0063] As can be seen from Table 3, for A1 - A5 (the prescription of the present invention): after 6 months, the hardness remains > 90 N, the water content ≤ 3.1%, and there is no capping; for A6 - A7 (comparison): after 6 months, the hardness decreases by > 10 N (78.8 - 80.4 N), the water content increases to 4.2%, and capping occurs (due to the replacement of sorbitol with mannitol or xylitol); Conclusion: The combination of sorbitol and microcrystalline cellulose PH101 is crucial for long-term stability. Example 4: In this example, in order to verify the in vitro cumulative dissolution of the tablets.

[0064] Detection method for in vitro cumulative dissolution of zolpidem tartrate: According to the second paddle method in General Chapter 0931 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition, take 1 tablet of this product, use 500 ml of 0.1 mol / 1 hydrochloric acid solution as the dissolution medium, rotate at a speed of 50 revolutions per minute, operate according to the law, sample at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes, filter, and take the subsequent filtrate as the test solution. Determine according to the method under content uniformity, and calculate the dissolution amount of each tablet. The limit is 80% of the labeled amount, and the test dissolution data results are all from the average values of 5 tablets.

[0065] Detection method for in vitro cumulative dissolution of trazodone hydrochloride: According to the second paddle method in General Chapter 0931 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition, take 1 tablet of this product, use 500 ml of 0.1 mol / 1 hydrochloric acid solution as the dissolution medium, rotate at a speed of 50 revolutions per minute, operate according to the law, sample at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes, filter, and take the subsequent filtrate as the test solution. Determine according to the method under content uniformity, and calculate the dissolution amount of each tablet. The limit is 80% of the labeled amount, and the test dissolution data results are all from the average values of 5 tablets.

[0066] Table 4. Dissolution of the tablets prepared in the present invention in 0.1 mol / L hydrochloric acid solution

[0067]

[0068] As can be seen from Table 4, in the present invention (A1 - A5): the two drugs are synchronously released to 100% within 60 minutes, and the dissolution degrees at 15 minutes are both > 80%, meeting the requirement of rapid onset; in the control group (A7): after mannitol is replaced, the dissolution of trazodone is only 76% at 45 minutes, and the dissolution of zolpidem is lagged (only 69% at 15 minutes); the inventor believes that the hydrophilicity of sorbitol may promote water penetration and jointly regulate the drug release rate with microcrystalline cellulose. Thus, it can be seen that the prescription and dosage of the present invention have achieved unexpected technical effects.

[0069] Pharmacological experiment: Application of the pharmaceutical composition of the present invention in improving sleep

[0070] SPF - level Kunming mice, half male and half female, with a body weight of 18 - 22 g, were purchased from Lunan Pharmaceutical Group Co., Ltd. Experimental animal license: SYXK(Lu)20230023. After one - week adaptive feeding, with a 12 - h light / dark cycle (9:00 - 21:00), the indoor temperature was maintained at 23℃ ± 5℃, and the humidity was maintained at 35% - 45%. The mice could freely access food and water.

[0071] Grouping

[0072] The mice were randomly divided into a blank group, an insomnia model group, a positive drug group, and an A2 group, with 8 mice in each group.

[0073] Drug - administration plan

[0074] Blank group and insomnia model group: Before intragastric administration, the mice were weighed, and the mice were given an equal volume of normal saline according to their body weight, with a drug - administration volume of 0.1 mL / 10 g. Positive drug group: The mice were given a 1 mg / kg diazepam suspension according to their body weight, with a diazepam dosage of 45.5 mg / Kg and a drug - administration volume of 0.1 mL / 10 g. A2 group: The tablets containing zolpidem tartrate and trazodone hydrochloride were prepared into a suspension. The dosage of trazodone hydrochloride for mice was 22.75 mg / Kg, and that of zolpidem tartrate was 2.275 mg / Kg, with a drug - administration volume of 0.1 mL / 10 g. Each group was administered once a day for 7 consecutive days.

[0075] Index detection

[0076] 1) Pentobarbital - sodium - induced sleep experiment

[0077] 30 min after the end of drug administration on the 7th day, after each mouse was labeled at the tail, 50 mg / kg sodium pentobarbital was intraperitoneally injected, and the drug administration volume was 0.1 mL / 10 g. The sleep latency and sleep time of each mouse were recorded. The sleep latency was determined as the time from the end of injection to the disappearance of the righting reflex in the mouse, and the sleep time was determined as the time from the mouse falling asleep to the mouse recovering the righting reflex.

[0078] 2) Detection of biochemical indexes

[0079] The drug administration method was the same as described above. After 7 days of drug administration, the mice were sacrificed by decapitation after blood was collected by eye socket puncture. The hippocampus and hypothalamus were separated and the surface blood stains were rinsed with pre-cooled normal saline. The whole blood was centrifuged at 4 °C, 3000 r / s for 15 min, and the supernatant was aspirated for standby. The content of IL-6 in the mouse serum was determined using an ELISA kit; after the hippocampus and hypothalamus were weighed, 9 times the amount of PBS buffer was added, and after adding steel beads, low-temperature homogenization was started. The mixture was centrifuged at 4 °C, 3000 r / s for 15 min, and the supernatant was aspirated and aliquoted. The levels of 5-HT and NE in the two brain regions of the hippocampus and hypothalamus were determined using an ELISA kit respectively.

[0080] Statistical analysis

[0081] In this chapter, the experiments were statistically processed using GraphPad Prism 9.0. The results of one-way ANOVA were used, and P < 0.05 was considered to indicate a statistically significant difference.

[0082] Result analysis

[0083] 1) The results of sleep latency and sleep time showed that the sleep latency of group A2 was extremely significantly lower than that of the insomnia model group, and its sleep time was significantly higher than that of the insomnia model group (see Table 4, Figure 1-2 ).

[0084] Table 4 Sleep latency and sleep time induced by sodium pentobarbital in mice of different groups

[0085] Sleep latency (s) Sleep time (min) Blank group <![CDATA[132.79±18.78 a > 126.36±31.00 Insomnia model group 188.08±18.21 63.16±8.12 Positive drug group <![CDATA[117.39±12.15 a > 134.19±21.16 Group A2 <![CDATA[108.79±10.88 ab > 144.44±23.65

[0086] Note: a indicates a significant difference compared with the insomnia model group (P < 0.05 or P < 0.01); b indicates a significant difference compared with the blank group (P < 0.05)

[0087] As can be seen from Table 4, compared with the blank group, the sleep latency of the mice in the insomnia model group was significantly prolonged (P < 0.01), and the sleep time was significantly shortened (P < 0.01), indicating that the model was successfully established. Group A2 showed a better effect than the positive drug, with a further shortened sleep latency and a further prolonged sleep time.

[0088] Figure 1 : Comparison of pentobarbital sodium-induced sleep latency in mice of different groups. Compared with the blank group, the sleep latency in group A2 was significantly reduced, with a significant difference (P<0.05).

[0089] Figure 2 : Comparison of pentobarbital sodium-induced sleep time in mice of different groups. Compared with the insomnia model group, the sleep time in the blank group was prolonged, with a significant difference (P<0.05); compared with the positive drug group and group A2, there was a significant difference in the blank group (P<0.05).

[0090] 2) Detect the contents of 5-HT and NE in the serum of mice. After administration, the specific data of group A2 are shown in Table 5 and Figures 3-4 as follows.

[0091] Table 5 Detection results of serum 5-HT and NE contents in mice after administration

[0092]

[0093]

[0094] Note: a indicates a significant difference compared with the insomnia model group (P<0.05 or P<0.01); b indicates a significant difference compared with the positive drug group (P<0.05 or P<0.01); c indicates a significant difference compared with the positive drug group (P<0.05 or P<0.01).

[0095] Table 5 shows the contents of 5-HT (pg / ml) in serum and NE (ng / ml) in serum after different administration groups. Compared with the insomnia model group, there were significant differences in the blank group, positive drug group, and group A2 (P<0.05 or P<0.01); at the same time, it can be seen that there were significant differences between group A2 and the positive drug group and the blank group (P<0.05 or P<0.01).

[0096] Figure 3 : Comparison of 5-HT (pg / ml) in the serum of mice in different groups. Compared with the insomnia model group, there were significant differences in the blank group, positive drug group, and group A2 (P<0.05 or P<0.01). Although the content of 5-HT in the positive drug group was higher than that in the blank group, the content of 5-HT in group A2 was higher, with a significant difference compared with the positive drug group (P<0.05).

[0097] Figure 4:Comparison of NE (ng / ml) in the sera of mice in different groups. Compared with the insomnia model group, there were significant differences in the blank group, positive drug group, and A2 group (P < 0.05 or P < 0.01). There was a significant difference between the A2 group and the positive drug group (P < 0.05 or P < 0.01).

Claims

1. Use of trazodone hydrochloride in the preparation of a medicament for treating sleep disorders.

2. A pharmaceutical composition for improving sleep disorders, characterized in that, The said pharmaceutical composition is composed of zolpidem tartrate and trazodone hydrochloride, and the mass ratio is 0.5 - 1:2.5 - 12.

5.

3. The pharmaceutical composition according to claim 1, wherein The said pharmaceutical composition is composed of zolpidem tartrate and trazodone hydrochloride, and the mass ratio is 0.5 - 1:5 - 10, and further preferably 1:

10.

4. The pharmaceutical composition according to claim 1, wherein The said pharmaceutical composition is prepared into a solid oral preparation, and the dose of trazodone hydrochloride in each unit preparation is 50 - 100 mg, and the dose of zolpidem tartrate is 5 - 10 mg.

5. The pharmaceutical composition according to claim 1, wherein The said pharmaceutical composition is prepared into a solid oral preparation, and the dose of trazodone hydrochloride in each unit preparation is 50 mg or 100 mg, and the dose of zolpidem tartrate is 10 mg or 5 mg.

6. The pharmaceutical composition according to claim 1, characterized in that, The said pharmaceutical composition is prepared into a solid oral preparation, and the dose of trazodone hydrochloride in each unit preparation is 75 mg, and the dose of zolpidem tartrate is 7.5 mg.

7. The pharmaceutical composition according to any one of claims 1-6, characterized in that, The said pharmaceutical composition is a solid oral preparation, including tablets, capsules or granules.

8. The pharmaceutical composition according to claim 7, wherein Calculated by weight ratio, the said tablets are prepared from the following raw materials: the dose of trazodone hydrochloride is 25 - 125 parts, the dose of zolpidem tartrate is 5 - 10 parts, microcrystalline cellulose PH101 133 - 220 parts, sorbitol 138 - 238 parts, low-substituted hydroxypropyl cellulose 22 parts, polyvinylpyrrolidone K30 10.5 parts, magnesium stearate 3.5 parts, coating powder 16 parts and an appropriate amount of water; further preferably, the said tablets are prepared from the following raw materials: the dose of trazodone hydrochloride is 50 - 100 parts, the dose of zolpidem tartrate is 5 - 10 parts, microcrystalline cellulose PH101 200 - 220 parts, sorbitol 138 - 168 parts, low-substituted hydroxypropyl cellulose 22 parts, polyvinylpyrrolidone K30 10.5 parts, magnesium stearate 3.5 parts, coating powder 16 parts and an appropriate amount of water.

9. A method for preparing the pharmaceutical composition according to claim 8, characterized in that, The preparation process of the said tablets is as follows: 1) Raw material treatment: Crush the raw materials of trazodone hydrochloride, zolpidem tartrate, sorbitol, microcrystalline cellulose PH101, and low-substituted hydroxypropyl cellulose respectively, and pass through an 80-mesh sieve. 2) Binder preparation: Dissolve the prescribed amount of polyvinylpyrrolidone K30 in an appropriate amount of water to prepare a 5% - 15% polyvinylpyrrolidone K30 aqueous solution for standby. 3) Weigh the crushed trazodone hydrochloride, zolpidem tartrate, sorbitol, microcrystalline cellulose PH101, and low-substituted hydroxypropyl cellulose and place them in a fluidized bed. Set the air volume and make the materials in a boiling state, and spray the binder solution into the fluidized bed to obtain wet granules. Among them, set the atomization pressure to 1.15 - 1.55 kg / cm2, the liquid inlet speed to 50 - 80 rpm, and spray the binder solution into the fluidized bed by the top-spray method to obtain wet granules; set the inlet air temperature to 55 - 65 °C, adjust the air volume to make the materials slightly boiling, dry until the moisture content of the granules ≤ 5%, and discharge the materials. 4) Add magnesium stearate to the dried granules and mix for 5 - 10 min, and use a high-speed granulator to granulate and press tablets; the tablet cores with a hardness in the range of 80 - 160 N. 5) Prepare the film coating premix into a 15 - 20% solution, coat the prepared tablet cores with a high - efficiency coating machine, and end the coating when the weight gain reaches 3 - 5% to obtain film - coated tablets.

10. The method according to claim 9, characterized in that The preparation process of the tablets is as follows: 1) API treatment: Crush the raw materials of trazodone hydrochloride, zolpidem tartrate, sorbitol, microcrystalline cellulose PH101, and low - substituted hydroxypropyl cellulose respectively, and pass through an 80 - mesh sieve. 2) Binder preparation: Dissolve the prescribed amount of povidone K30 in an appropriate amount of water to prepare a 10% aqueous povidone K30 solution for standby. 3) Weigh the crushed trazodone hydrochloride, zolpidem tartrate, sorbitol, microcrystalline cellulose PH101, and low-substituted hydroxypropyl cellulose, place them in a fluidized bed, set the air volume and make the material in a boiling state, and spray the binder solution into the fluidized bed to obtain wet granules. Among them, set the atomization pressure to 1.35 kg / cm 2 , the liquid inlet speed is 60 rpm, and spray the binder solution into the fluidized bed by top spraying to obtain wet granules; set the inlet air temperature to 60 °C, adjust the air volume until the material boils slightly, dry until the moisture content of the granules ≤ 5%, and discharge the material; 4) Add magnesium stearate to the dried granules and mix for 10 min, then granulate and press tablets with a high - speed granulator; the tablet cores with a hardness in the range of 80 - 160 N. 5) Prepare the film coating premix into a 20% solution, coat the prepared tablet cores with a high - efficiency coating machine, and end the coating when the weight gain reaches 4% to obtain film - coated tablets.

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