A kind of zolpidem tartrate tablets and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and in particular to a zolpidem tartrate tablet and a preparation method thereof. The tablet preparation method is as follows: polyethylene glycol 4000 is heated and melted, stearic acid macrogol glyceride is added, stirred to dissolve, zolpidem tartrate raw material is added, pH value is adjusted, stirred to dissolve, the molten liquid is added to a mixed powder of a filler and a disintegrant, stirred evenly, a lubricant is added, mixed evenly, and tabletted. The zolpidem tartrate tablet of the present invention shows excellent stability, the content of its effective ingredient is substantially unchanged, the content of related substances is low, the dissolution effect meets the requirements of the Chinese Pharmacopoeia, the drug safety is improved, the shelf life is extended, and the large-scale production of the chemical industry can be further expanded.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a zolpidem tartrate tablet and a preparation method thereof. Background Art

[0002] Zolpidem tartrate is a non-benzodiazepine, γ-aminobutyric acid A-benzodiazepine receptor agonist that can selectively antagonize γ-aminobutyric acid A complex receptors and promote the action of GABA. It has a strong sedative and hypnotic effect and is mainly used for hypnosis in clinical practice. It takes effect 30 minutes after taking the medicine and has a half-life in the blood of about 2.5 hours. Compared with benzodiazepines, zolpidem has fewer sequelae, and long-term use is less likely to produce tolerance and dependence. It almost does not cause rebound insomnia and is the first choice for non-benzodiazepines to treat insomnia.

[0003] At present, the common preparations of zolpidem tartrate that have been marketed include: common tablets, capsules, sublingual tablets, oral sprays and solutions. Common tablets and capsules are usually taken before going to bed and can take effect quickly, but the effect is short-lived, generally 2 to 6 hours. Patients with early awakening symptoms often need to get up in the middle of the night to take the medicine again, which seriously interferes with sleep quality. Zolpidem oral spray is used for short-term treatment of patients with difficulty falling asleep and insomnia; sublingual tablets are quickly absorbed through the oral mucosa and are used for short-term treatment of patients with difficulty falling asleep and insomnia, but patients also need to get up in the middle of the night to take the medicine again, which interferes with sleep quality and reduces compliance. The zolpidem sustained-release preparation developed by Sanofi-Aventis abroad can take effect quickly, but the drug release time is slow, and the blood drug concentration is maintained at a high level for a long time. Due to the large total amount of drug released, long-term use of the drug often causes drowsiness and dizziness the next day, and the incidence of anxiety reaches 6.3%, accompanied by headaches, gastrointestinal reactions and other serious adverse reactions.

[0004] Chinese patent CN117357493A discloses a zolpidem tartrate orally disintegrating sustained-release tablet and a preparation method thereof. The invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a zolpidem tartrate orally disintegrating sustained-release tablet and a preparation method thereof. The sustained-release tablet comprises zolpidem tartrate, a sustained-release material, benzyl benzoate or / and methyl cyclodextrin, a filler, a disintegrant, a colorant and a lubricant. The tablet has a certain sustained-release effect on the basis of maintaining the rapid disintegration characteristics, but sometimes the dosage cannot reach the threshold and cannot play a role.

[0005] Chinese patent CN1334729A discloses a controlled-release dosage form containing zolpidem or its salt, which can release zolpidem in a predetermined time according to a biphasic dissolution distribution; CN103230381B discloses a zolpidem tartrate timed pulse controlled-release micropellet, which can be delayed for a certain period of time and then released rapidly. There are many other prior arts of controlled-release drug delivery systems or timed drug delivery systems similar to the above, which generally produce a drug release time lag effect through different material coating layers outside the micropellet or tablet core, or multiple drug-containing layers to adjust the drug release rate. Such preparations often have the disadvantages of incomplete release of active drug ingredients, and also have the defect of strictly limiting the amount of drug in each drug layer, and the process operation is difficult.

[0006] Chinese patent CN115429768A, a zolpidem tartrate timed release tablet, the present invention belongs to the field of pharmaceutical preparations, and specifically relates to zolpidem tartrate timed release tablets and a preparation method thereof. The zolpidem tartrate timed release tablets contain 8-12 mg of zolpidem tartrate, 5.0%-50.0% of sustained-release material, 40%-90% of filler, 0.1%-1% of binder, 2.0%-10.0% of disintegrant, 5%-20% of effervescent disintegrant, 0.1%-3% of glidant, and 0.1%-2% of lubricant. The zolpidem tartrate timed release tablets prepared by the present invention can timely control the release of the drug in the body, ensure that the insomnia patient releases the drug in the body in a timely manner after taking the drug and is within an effective blood drug concentration range to prevent early awakening. Summary of the invention

[0007] The present invention overcomes the deficiencies of the prior art and provides a zolpidem tartrate tablet and a preparation method thereof. The zolpidem tartrate tablet has a substantially unchanged content during an accelerated test, a low content of related substances, and dissolution that meets key requirements, thereby greatly improving medication safety and extending shelf life.

[0008] Specifically, the tablet preparation method of the present invention is: heating and melting polyethylene glycol 4000, adding stearic acid macrogol glyceride, stirring to dissolve, then adding zolpidem tartrate raw material, adjusting the pH value to 4.0-6.0, stirring to dissolve, adding the molten liquid to the mixed powder of filler and disintegrant, stirring evenly, then adding lubricant, mixing evenly, and tableting.

[0009] Furthermore, the weight ratio of tartaric acid pyrazolyl alcohol to stearic acid macrogol glyceride is 1:2-5.

[0010] Furthermore, the weight ratio of alcohol glyceride is 1:3.5.

[0011] Furthermore, the weight ratio of pyrazolyl tartrate to polyethylene glycol 4000 is 1:6-11.

[0012] Furthermore, the weight ratio of pyrazolyl tartrate to polyethylene glycol 4000 is 1:8.5.

[0013] Furthermore, the filler is selected from at least one of sorbitol, mannitol, microcrystalline cellulose, lactose and starch; more preferably, the weight ratio of sorbitol to microcrystalline cellulose is 2:1-3; more preferably, the weight ratio of sorbitol to microcrystalline cellulose is 1:1.

[0014] Furthermore, the disintegrant is selected from at least one of low-substituted hypromellose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked carboxymethyl starch; preferably, the disintegrant is selected from low-substituted hypromellose.

[0015] Furthermore, the lubricant is selected from at least one of magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and talc.

[0016] Furthermore, the pH adjuster is citric acid.

[0017] Furthermore, the tablet preparation method is: heating and melting polyethylene glycol 4000, adding stearic acid macrogol glyceride, stirring to dissolve, then adding zolpidem tartrate raw material, adjusting the pH value to 5.0 with citric acid, stirring to dissolve, adding the molten liquid to the mixed powder of sorbitol, microcrystalline cellulose and low-substituted hydroxypropyl methylcellulose, stirring evenly, then adding magnesium stearate, mixing evenly, and tableting.

[0018] Compared with the prior art, the technical effects of the present invention are:

[0019] The zolpidem tartrate tablets of the present invention overcome the instability defect of the zolpidem tartrate tablets during storage. During the accelerated test, the zolpidem tartrate tablets of the present invention show excellent stability, the content of the effective ingredients is substantially unchanged, the content of related substances is low, the dissolution effect meets the requirements of the Chinese Pharmacopoeia, the drug safety is improved, the shelf life is prolonged, and the large-scale production of the chemical industry can be further expanded. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 : The results of the content of each embodiment at 0, 1, 2, 3, and 6 months.

[0021] Figure 2 : The results of the detection of the contents of the related substances in the related embodiments at 0, 1, 2, 3 and 6 months.

[0022] Figure 3 : The dissolution test results of the related embodiments were tested at 0, 1, 2, 3 and 6 months. Specific embodiments

[0024] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art 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.

[0025] Example 1: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0026] Heat and melt 42.5 g of polyethylene glycol 4000, add 17.5 g of stearic acid macrogol glyceride, stir to dissolve, then add 5 g of zolpidem tartrate raw material, adjust the pH value to 5.0 with citric acid, stir to dissolve, add the molten liquid to a mixed powder of 108.5 g of sorbitol, 108.5 g of microcrystalline cellulose and 15 g of low-substituted hydroxypropyl methylcellulose, stir evenly, then add 3 g of magnesium stearate, mix evenly, and compress into tablets with a tablet weight of 300 mg.

[0027] Example 2: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0028] Heat and melt 30 g of polyethylene glycol 4000, add 10 g of stearic acid macrogol glyceride, stir to dissolve, then add 5 g of zolpidem tartrate raw material, adjust the pH value to 4.0 with citric acid, stir to dissolve, add the molten liquid to a mixed powder of 118.5 g of sorbitol, 118.5 g of microcrystalline cellulose and 15 g of low-substituted hydroxypropyl methylcellulose, stir evenly, then add 3 g of magnesium stearate, mix evenly, and compress into tablets with a tablet weight of 300 mg.

[0029] Example 3: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0030] Heat and melt 55 g of polyethylene glycol 4000, add 25 g of stearic acid macrogol glyceride, stir to dissolve, then add 5 g of zolpidem tartrate raw material, adjust the pH value to 5.0 with citric acid, stir to dissolve, add the molten liquid to a mixed powder of 98.5 g of sorbitol, 98.5 g of microcrystalline cellulose and 15 g of low-substituted hydroxypropyl methylcellulose, stir evenly, then add 3 g of magnesium stearate, mix evenly, and compress into tablets with a tablet weight of 300 mg.

[0031] Example 4: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0032] Heat and melt 42.5 g of polyethylene glycol 4000, add 17.5 g of stearic acid macrogol glyceride, stir to dissolve, then add 5 g of zolpidem tartrate raw material, adjust the pH value to 5.0 with citric acid, stir to dissolve, add the molten liquid to a mixed powder of 144 g of sorbitol, 72 g of microcrystalline cellulose and 16 g of low-substituted hydroxypropyl methylcellulose, stir evenly, then add 3 g of magnesium stearate, mix evenly, and compress into tablets with a tablet weight of 300 mg.

[0033] Example 5: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0034] Heat and melt 42.5 g of polyethylene glycol 4000, add 17.5 g of stearic acid macrogol glyceride, stir to dissolve, then add 5 g of zolpidem tartrate raw material, adjust the pH value to 5.0 with citric acid, stir to dissolve, add the molten liquid to a mixed powder of 86.8 g of sorbitol, 130.2 g of microcrystalline cellulose and 15 g of low-substituted hydroxypropyl methylcellulose, stir evenly, then add 3 g of magnesium stearate, mix evenly, and compress into tablets with a tablet weight of 300 mg.

[0035] Example 6: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0036] Heat and melt 42.5 g of polyethylene glycol 4000, add 17.5 g of stearic acid macrogol glyceride, stir to dissolve, then add 5 g of zolpidem tartrate raw material, adjust the pH value to 5.0 with citric acid, stir to dissolve, add the molten liquid to a mixed powder of 86.8 g of lactose, 130.2 g of microcrystalline cellulose and 15 g of cross-linked sodium carboxymethyl cellulose, stir evenly, then add 3 g of calcium stearate, mix evenly, and compress into tablets with a tablet weight of 300 mg.

[0037] Comparative Example 1: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0038] Heat and melt 42.5 g of polyethylene glycol 4000, add 5 g of zolpidem tartrate raw material, adjust the pH value to 5.0 with citric acid, stir to dissolve, add the molten liquid to a mixed powder of 108.5 g of sorbitol, 108.5 g of microcrystalline cellulose and 15 g of low-substituted hydroxypropyl methylcellulose, stir evenly, add 3 g of magnesium stearate, mix evenly, and press into tablets with a tablet weight of 300 mg.

[0039] Comparative Example 2: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0040] Heat and melt 17.5 g of stearic acid macrogol glyceride and 5 g of zolpidem tartrate raw materials, add the molten liquid to a mixed powder of 108.5 g of sorbitol, 108.5 g of microcrystalline cellulose and 15 g of low-substituted hydroxypropyl methylcellulose, stir evenly, then add 3 g of magnesium stearate, mix evenly, and press into tablets with a tablet weight of 300 mg.

[0041] Comparative Example 3: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0042] 42.5 g of polyethylene glycol 4000, 17.5 g of stearic acid macrogol glyceride and 5 g of zolpidem tartrate raw material are added to 95% ethanol and dissolved, and then the pH value is adjusted to 5.0 with citric acid, and stirred to dissolve. The molten liquid is added to a mixed powder of 108.5 g of sorbitol, 108.5 g of microcrystalline cellulose and 15 g of low-substituted hydroxypropyl methylcellulose, and stirred evenly. Then 3 g of magnesium stearate is added, mixed evenly, and tableted. The tablet weight is 300 mg.

[0043] Comparative Example 4: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0044] Heat and melt 10 g of polyethylene glycol 4000, add 50 g of stearic acid macrogol glyceride, stir to dissolve, then add 5 g of zolpidem tartrate raw material, adjust the pH value to 5.0 with citric acid, stir to dissolve, add the molten liquid to a mixed powder of 108.5 g of sorbitol, 108.5 g of microcrystalline cellulose and 15 g of low-substituted hydroxypropyl methylcellulose, stir evenly, then add 3 g of magnesium stearate, mix evenly, and compress into tablets with a tablet weight of 300 mg.

[0045] Comparative Example 5: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0046] Heat and melt 42.5 g of polyethylene glycol 4000, add 17.5 g of stearic acid macrogol glyceride, stir to dissolve, then add 5 g of zolpidem tartrate raw material, adjust the pH value to 5.0 with hydrochloric acid, stir to dissolve, add the molten liquid to a mixed powder of 108.5 g of sorbitol, 108.5 g of microcrystalline cellulose and 15 g of low-substituted hydroxypropyl methylcellulose, stir evenly, then add 3 g of magnesium stearate, mix evenly, and press into tablets with a tablet weight of 300 mg.

[0047] Comparative Example 6: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0048] Heat and melt 42.5 g of polyethylene glycol 4000, add 17.5 g of stearic acid macrogol glyceride, stir to dissolve, then add 5 g of zolpidem tartrate raw material, stir to dissolve, add the molten liquid to a mixed powder of 108.5 g of sorbitol, 108.5 g of microcrystalline cellulose and 15 g of low-substituted hydroxypropyl methylcellulose, stir evenly, then add 3 g of magnesium stearate, mix evenly, and press into tablets, with a tablet weight of 300 mg.

[0049] Comparative Example 7: A tablet containing zolpidem tartrate, the dosage and preparation process are as follows:

[0050] Heat and melt 42.5 g of polyethylene glycol 4000, add 17.5 g of stearic acid macrogol glyceride, stir to dissolve, then add 5 g of zolpidem tartrate raw material, adjust the pH value to 5.0 with citric acid, stir to dissolve, add the molten liquid to a mixed powder of 108.5 g of monocalcium phosphate, 108.5 g of calcium carbonate and 15 g of low-substituted hydroxypropyl methylcellulose, stir evenly, then add 3 g of magnesium stearate, mix evenly, and compress into tablets with a tablet weight of 300 mg.

[0051] Verification Example

[0052]

Content determination

[0053] Chromatographic conditions and system suitability test: octadecylsilane bonded silica gel is used as filler; acetonitrile-methanol-0.05mol / L phosphoric acid solution (adjusted to pH 5.5 with triethylamine) (18:23:59) is used as mobile phase; detection wavelength is 254nm. The number of theoretical plates calculated based on the zolpidem tartrate peak should be no less than 2000. The separation degree of zolpidem tartrate and adjacent impurity peaks should meet the requirements.

[0054] Determination method: Take 20 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount of fine powder (equivalent to 25 mg of zolpidem tartrate), place in a 50 mL volumetric flask, add mobile phase to dissolve and dilute to scale, shake well, pass, take an appropriate amount of filtrate, add mobile phase to make a test solution containing about 10 μg of zolpidem tartrate per 1 mL. Accurately measure 20 μL and inject into the liquid chromatograph to record the chromatogram; take an appropriate amount of zolpidem tartrate reference substance and determine it in the same way. Calculate by peak area according to the external standard method to obtain.

[0055] [Content Uniformity]: Take 1 tablet of this product, place it in a 100mL volumetric flask, add an appropriate amount of 0.1mol / L hydrochloric acid solution, shake to dissolve zolpidem tartrate, dilute to the scale with 0.1mol / L hydrochloric acid solution, shake well, filter, accurately measure an appropriate amount of the filtrate, add 0.1mol / L hydrochloric acid solution to quantitatively dilute to make a solution containing about 10μg per 1mL. According to the spectrophotometric method, measure the absorbance at a wavelength of 294nm. Take an appropriate amount of zolpidem tartrate reference substance, measure it in the same way, and calculate the content of each tablet.

[0056] [Dissolution]: Take one tablet of this product, use 500ml of 0.1mol / 1 hydrochloric acid solution as the dissolution medium, rotate at 50 revolutions per minute, operate according to the law, take samples after 2 minutes, 4 minutes, 10 minutes, 15 minutes, and 30 minutes, filter, and take the filtrate as the test solution. Determine according to the method under the content uniformity item and calculate the dissolution amount of each tablet. The limit is 80% of the labeled amount, which should meet the regulations.

[0057] [Related substances]: Take the filtrate under the content determination item as the test solution; take an appropriate amount of the test solution and dilute it with the mobile phase to a solution containing about 2.5rg per 1ml as the control solution. Perform the test according to the chromatographic conditions under the content determination item, take 20ml of the control solution and inject it into the liquid chromatograph, adjust the detection sensitivity so that the main component peak height is about 25% of the full scale; then take 20ml of the test solution and inject it into the liquid chromatograph, and record the chromatogram to twice the retention time of the main peak. If impurity peaks are visible in the chromatogram of the test solution, the sum of the areas of the impurity peaks shall not be greater than the main peak area of ​​the control solution (0.5%) (impurity peaks and tartaric acid peaks with peak areas less than 1 / 10 of the main peak area of ​​the control solution are negligible).

[0058] Accelerated test: Store at 40°C±2°C, 75%±5%RH (relative humidity) for 6 months. Test the above test indicators at 1, 2, 3 and 6 months.

[0059] Experimental results analysis

[0060] Figure 1 : Results of the content of each example at 0, 1, 2, 3, and 6 months. It can be seen that during the accelerated test, the content of Examples 1-6 did not change substantially, and the larger changes were in Comparative Example 3 and Comparative Example 7, where the content decreased significantly during storage.

[0061] Figure 2: The results of the detection of the contents of the related substances in the relevant examples at 0, 1, 2, 3, and 6 months. It can be seen that during the accelerated test, the contents of the related substances in Examples 1-3 were controlled at about 0.01% and basically did not change. The larger changes were that the contents of the related substances in Comparative Example 3, Comparative Example 5, and Comparative Example 6 increased significantly during the storage process.

[0062] Figure 3 : The results of the dissolution tests of the relevant examples at 0, 1, 2, 3, and 6 months. It can be seen that in the accelerated test process, the dissolution of Examples 1-6 was completely dissolved at 2 minutes and / or 5 minutes, while the dissolution of Comparative Example 1, Comparative Example 2, Comparative Example 4, and Comparative Example 7 was significantly reduced during storage, and the inventors believe that this may be closely related to the excipients used and the dosage.

Claims

1. A tablet containing zolpidem tartrate, characterized in that: The tablet preparation method comprises the following steps: heating and melting polyethylene glycol 4000, adding stearic acid macrogol glyceride, stirring to dissolve, then adding zolpidem tartrate raw material, adjusting pH value to 4.0-6.0 with citric acid, stirring to dissolve, adding the molten liquid to a mixed powder of a filler and a disintegrant, stirring evenly, then adding a lubricant, mixing evenly, and tableting; the weight ratio of zolpidem tartrate to stearic acid macrogol glyceride is 1:2-5; the weight ratio of zolpidem tartrate to polyethylene glycol 4000 is 1:6-11; the filler is selected from at least one of sorbitol, microcrystalline cellulose, and lactose; the disintegrant is selected from at least one of low-substituted hydroxypropyl methylcellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked carboxymethyl starch; and the lubricant is selected from at least one of magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and talc.

2. The tablet according to claim 1, characterized in that The weight ratio of the tartaric acid pyrazolyl alcohol to the stearic acid macrogol glyceride is 1:3.

5.

3. The tablet according to claim 1, characterized in that The weight ratio of tartaric acid pyrazolpyridamole to polyethylene glycol 4000 is 1:8.

5.

4. The tablet according to claim 1, characterized in that The filler is selected from sorbitol and microcrystalline cellulose in a weight ratio of 2:1-3.

5. The tablet according to claim 1, characterized in that The filler is selected from sorbitol and microcrystalline cellulose in a weight ratio of 1:

1.

6. The tablet according to claim 1, characterized in that The disintegrant is selected from low-substituted hypromellose.

7. The tablet according to claim 1, characterized in that The tablet preparation method comprises the following steps: heating and melting polyethylene glycol 4000, adding stearic acid macrogol glyceride, stirring to dissolve, then adding zolpidem tartrate raw material, adjusting the pH value to 5.0 with citric acid, stirring to dissolve, adding the molten liquid to a mixed powder of sorbitol, microcrystalline cellulose and low-substituted hydroxypropyl methylcellulose, stirring evenly, then adding magnesium stearate, mixing evenly, and tableting.

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