Pharmaceutical composition of eszopiclone and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly discloses a pharmaceutical composition of eszopiclone and a preparation method of the pharmaceutical composition, and the pharmaceutical composition comprises the following components by weight: 3-5% of eszopiclone; 65-85% of lactose; 5-25% of corn starch; 5-25% of pregelatinized starch; 0.5 to 5% of povidone K30; 0.5-5% of carboxymethyl starch sodium; 0.1-1% of silicon dioxide; and 0.25-5% of magnesium stearate. According to the preparation method provided by the invention, the main drug eszopiclone and lactose are mixed through an equivalent progressive increase method, and then the mixture is mixed with other diluents, disintegrants and adhesives to prepare wet granules, so that non-uniform dispersion of the main drug with a small proportion in the auxiliary materials can be avoided, the content uniformity of the product is ensured, and the problems in the background technology can be effectively solved.

Description

Technical Field

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

[0002] Insomnia is a common health problem with a high incidence rate worldwide. According to the World Health Organization and a number of epidemiological studies, about one-third of adults have experienced insomnia symptoms to varying degrees, and the prevalence of chronic insomnia is between 5% and 10%. With the accelerated pace of life, increased work pressure and the popularity of electronic products, the incidence of insomnia has shown an upward trend year by year.

[0003] Eszopiclone, chemical name: 6-(5-chloro-2-pyridinyl)-7-[(4-methylpiperazin-1-yl)carboxyloxy]-5,6-dihydropyrrolo[3,4-b]pyrazin-5-one, is a non-benzodiazepine sedative hypnotic originally developed by Sunovion Pharmaceuticals and approved for marketing by the U.S. FDA on December 15, 2004. The trade name is LUNESTA ® Eszopiclone is the dextrorotatory single isomer of zopiclone, which has sedative, antianxiety, anticonvulsant and muscle relaxant effects and is clinically used to treat insomnia. Studies have shown that eszopiclone has the following advantages over traditional barbiturate and benzodiazepine sedative hypnotics: (1) It is more effective in improving sleep quality and shortening the time it takes to fall asleep; (2) There are fewer adverse reactions such as residual effects and hangover after taking the medicine; (3) No obvious drug resistance after long-term use; (4) There is no obvious rebound phenomenon when the drug is stopped after long-term use.

[0004] At present, the marketed dosage form of dexzopiclone is tablets, with a total of 3 specifications (1mg, 2mg, and 3mg), of which the 3mg specification is listed as a reference preparation. Neither the original preparation nor the reference preparation has been imported and marketed in my country. Since dexzopiclone is poorly soluble in water, the proportion of the main drug in the existing 1mg, 2mg, and 3mg tablets is relatively low. If the excipients are unevenly dispersed in the preparation, it is very easy to affect the uniformity of the product content; after the preparation is stored for a long time, the excipients may clump, further affecting the quality of the product. Summary of the invention

[0005] In view of the deficiencies in the prior art, the object of the present invention is to provide a pharmaceutical composition of dexzopiclone and a preparation method thereof. The main drug dexzopiclone is mixed with lactose by an equal amount incremental method, and then mixed with the remaining diluents, disintegrants and binders to prepare wet granules, which can avoid uneven dispersion of the main drug, which accounts for a small proportion, in the auxiliary materials, thereby ensuring the uniformity of the content of the product. It has been verified by experiments that the tablets prepared by the present invention have good stability, and the long-term impurity level for 36 months is far lower than the impurity limit of the USP pharmacopoeia standard. It can meet the clinical treatment needs through the generic drug quality and efficacy consistency evaluation, and can effectively solve the problems in the background technology.

[0006] The present invention is achieved through the following technical solutions: A pharmaceutical composition of dexamethasone, comprising the following components by weight percentage: R-zopiclone 3-5%; Lactose 65-85%; Corn starch 5-25%; Pregelatinized starch 5-25%; Povidone K30 0.5-5%; Sodium starch glycolate 0.5-5%; Silicon dioxide 0.1-1%; Magnesium stearate 0.25-5%.

[0007] A further improvement of the present invention is: The pharmaceutical composition comprises the following components by weight percentage: R-zopiclone 3.9%; Lactose 65.7%; Corn starch 13.1%; Pregelatinized starch 6.6%; Povidone K30 3.2%; Sodium starch glycolate 3.9%; Silicon dioxide 0.4%; Magnesium stearate 0.5%.

[0008] Furthermore, the pharmaceutical composition also includes 2-4% of a film coating premix.

[0009] Furthermore, the pharmaceutical composition also includes 2.6% of a film coating premix.

[0010] A further embodiment of the present invention is: A method for preparing a pharmaceutical composition of dexamethasone comprises the following steps: Sieving: pass dexzopiclone, corn starch, pregelatinized starch and sodium starch glycolate through a 100-mesh sieve respectively; Granulation: prepare povidone K30 solution as a binder; weigh equal amounts of s-zopiclone and lactose and add them three times, then add the remaining lactose, corn starch, pregelatinized starch, povidone K30 and sodium carboxymethyl starch into a wet mixing granulator for premixing; add the binder and perform wet granulation; use a sieve to perform wet granulation; Drying and dry granulation: Use a boiling dryer to boil the granules and control the moisture limit to 2.0-3.5%; use a screen to dry granulate; Total mixing: add silicon dioxide and magnesium stearate and mix; Tableting: The mixed granules are tableted to obtain dexzopiclone tablets.

[0011] Furthermore, in the granulation process, the mass concentration of the adhesive povidone K30 solution is 8%, the premixing time is 3 minutes, and the wet granulation uses a 3.0 mm sieve; in the drying and dry granulation processes, the dry granulation uses a 2.0 mm sieve.

[0012] Furthermore, the tableting process is followed by a coating process, and the steps are as follows: weigh a film coating premix, slowly add purified water, and stir evenly to prepare a coating solution, and film-coat the dexzopiclone tablets.

[0013] Furthermore, the mass concentration of the coating solution is 18%.

[0014] Furthermore, there is a packaging step after the coating step. Beneficial Effects

[0015] Compared with the prior art, the present invention has the following obvious advantages: 1. The present invention utilizes the characteristics of dexzopiclone being non-hygroscopic and relatively stable under high temperature and high humidity conditions, and adopts a wet granulation production process to prepare dexzopiclone tablets, which is suitable for industrialized batch production, and the process has low requirements on equipment and is easy to promote.

[0016] 2. The preparation method provided by the present invention first mixes the main drug dexzopiclone with lactose by an equal amount addition method, and then mixes with the remaining diluents, disintegrants and binders to prepare wet granules, which can avoid uneven dispersion of the main drug with a small proportion in the auxiliary materials and ensure the uniformity of the product content; using silicon dioxide as a glidant and magnesium stearate as a lubricant can improve the fluidity of the granules, increase the bulk density, and meet the needs of the subsequent tableting process.

[0017] 3. The excipients used in the present invention are all commonly used excipients for oral solid preparations, the amount of each excipient is lower than the amount of inactive ingredients in the corresponding oral solid dosage form approved by the FDA, and the compatibility of the raw excipients is good.

[0018] 4. Long-term test verification shows that the tablets prepared by the present invention have good stability, and the long-term impurity level for 36 months is far lower than the impurity limit of the USP pharmacopoeia standard; bioequivalence test verification shows that the tablets prepared by the present invention are equivalent to the reference preparation in fasting and postprandial tests, and pass the generic drug quality and efficacy consistency evaluation, which can meet the needs of clinical treatment. DETAILED DESCRIPTION

[0019] The present invention is described in detail below in conjunction with embodiments.

[0020] The formula is as follows: (by weight percentage) Main drug: R-zopiclone 3.9%; Excipients: lactose 65.7%; corn starch 13.1%; pregelatinized starch 6.6%; povidone K30 3.2%; sodium carboxymethyl starch 3.9%; silicon dioxide 0.4%; magnesium stearate 0.5%; film coating premix 2.6%.

[0021] The main drug and excipient information are as follows:

[0022] Example 1: Preparation of a pharmaceutical composition of eszopiclone The main drug accounts for a low proportion in dextropiclone tablets, and the particle size of the raw material dextropiclone may affect the dissolution rate. Considering that the raw material may agglomerate during long-term storage, the raw material dextropiclone is sieved through a 100-mesh sieve in the production process. Among the excipients, lactose is the main diluent. Insufficient dilution can easily affect the uniformity of the content. In the production process, the method of mixing with dextropiclone three times in equal amounts is adopted. For the processing methods of other excipients, please refer to the specific steps of the preparation method.

[0023] The specific steps are as follows: (1) Screening After passing dexzopiclone, corn starch, pregelatinized starch and sodium carboxymethyl starch through a 100-mesh sieve, weigh the prescribed amount for later use; (2) Granulation Prepare 8% mass concentration of povidone K30 solution in advance as a binder for later use; According to the production capacity of the equipment, the granulation is divided into two parts; Weigh the prescribed amount of eszopiclone and lactose in equal amounts and add them three times, then add the remaining lactose, corn starch, pregelatinized starch, povidone K30, and sodium carboxymethyl starch into a wet mixing granulator and premix for 3 minutes; adding the binder and performing wet granulation; Wet granulation was performed using a 3.0 mm sieve; Prepare the second wet granules according to the above steps; (3) Drying and dry granulation The pellets are dried using a fluidizing dryer, with the moisture content controlled at 2.0%-3.5%; Use 2.0 mm sieve to dry granulate; (4) Total mixing Add the s-zopiclone tablet granules into the HLT-1500 lifting hopper mixer, add the prescribed amount of silicon dioxide and magnesium stearate and mix for 20 minutes; (5) Tableting Use φ6.0mm shallow round punch to press the particles into tablets; (6) Coating Weigh 2.60 kg of film coating premix, slowly add purified water, and stir evenly to prepare a coating solution with a mass concentration of 18%, and perform film coating; (7) Packaging Aluminum-plastic filling line is used for aluminum-plastic blister packaging, plus polyester / aluminum / polyethylene pharmaceutical composite bags.

[0024] Example 2: Stability test In accordance with the "Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations)" (2015) and the "9001 Guidelines for Stability Testing of APIs and Preparations" of the 2020 edition of the "Chinese Pharmacopoeia", two batches of products (202003051 and 202003052) prepared according to the above formula and process were subjected to stability tests.

[0025] The stability experiments include: accelerated stability (40℃±2℃, relative humidity 75%±5%) and long-term stability (25℃±2℃, relative humidity 60%±5%) tests. The results are shown in Tables 1 and 2 below.

[0026] Table 1, accelerated test data of 3mg eszopiclone tablets (test conditions: temperature 40℃±2℃, relative humidity 75%±5%)

[0027] Table 2, Long-term test data of 3mg eszopiclone tablets (investigation conditions: temperature 25℃±2℃, relative humidity 60%±5%)

[0028] Conclusion: The 3 mg eszopiclone tablets prepared by the method provided by the present invention have stable quality under long-term conditions (25℃±2℃, relative humidity 60%±5%), and the impurity level for 36 months is much lower than the impurity limit of the USP Pharmacopoeia standard (each known impurity limit: 1.0%, unknown single impurity limit: 0.50%, total impurity limit: 2.0%); under accelerated conditions (40℃±2℃, relative humidity 75%±5%), the related substances increased, which were all lower than 30% of the impurity limit of the USP Pharmacopoeia standard.

[0029] Example 3: Bioequivalence test The bioequivalence test of 3 mg eszopiclone tablets prepared by the method provided by the present invention was carried out by using HPLC-MS / MS detection method. The test design was as follows: a single-center, randomized, open, single-dose, two-cycle, two-sequence, two-crossover fasting and postprandial test. The results are shown in Table 3 below.

[0030] Table 3. Statistical results of the average bioequivalence of eszopiclone in vivo for oral eszopiclone tablets (3 mg)

[0031] Conclusion: The eszopiclone tablets prepared by the method provided by the present invention are equivalent to the reference preparation in fasting and postprandial tests.

[0032] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition of dexamethasone, characterized in that: The pharmaceutical composition comprises the following components by weight percentage: R-zopiclone 3-5%; Lactose 65-85%; Corn starch 5-25%; Pregelatinized starch 5-25%; Povidone K30 0.5-5%; Sodium starch glycolate 0.5-5%; Silicon dioxide 0.1-1%; Magnesium stearate 0.25-5%.

2. A pharmaceutical composition of dexazopiclone according to claim 1, characterized in that: The pharmaceutical composition comprises the following components by weight percentage: R-zopiclone 3.9%; Lactose 65.7%; Corn starch 13.1%; Pregelatinized starch 6.6%; Povidone K30 3.2%; Sodium starch glycolate 3.9%; Silicon dioxide 0.4%; Magnesium stearate 0.5%.

3. A pharmaceutical composition of dexazopiclone according to claim 1, characterized in that: The pharmaceutical composition also includes 2-4% of a film coating premix.

4. A pharmaceutical composition of dexazopiclone according to claim 3, characterized in that: The pharmaceutical composition also includes 2.6% of a film coating premix.

5. A method for preparing a pharmaceutical composition of dexazopiclone according to any one of claims 1 to 4, characterized in that: The following steps are involved: Sieving: pass dexzopiclone, corn starch, pregelatinized starch and sodium starch glycolate through a 100-mesh sieve respectively; Granulation: prepare povidone K30 solution as a binder; weigh equal amounts of s-zopiclone and lactose and add them three times, then add the remaining lactose, corn starch, pregelatinized starch, povidone K30 and sodium carboxymethyl starch into a wet mixing granulator for premixing; add the binder and perform wet granulation; use a sieve to perform wet granulation; Drying and dry granulation: Use a boiling dryer to boil the granules and control the moisture limit to 2.0-3.5%; use a screen to dry granulate; Total mixing: add silicon dioxide and magnesium stearate and mix; Tableting: The mixed granules are tableted to obtain dexzopiclone tablets.

6. The method for preparing a pharmaceutical composition of dexazopiclone according to claim 5, characterized in that: In the granulation process, the mass concentration of the adhesive povidone K30 solution is 8%, the premixing time is 3 minutes, and a 3.0 mm screen is used for wet granulation; in the drying and dry granulation processes, a 2.0 mm screen is used for dry granulation.

7. The method for preparing a pharmaceutical composition of dexazopiclone according to claim 5, characterized in that: The tableting process is followed by a coating process, and the steps are as follows: weighing a film coating premix, slowly adding purified water, and stirring evenly to prepare a coating solution, and film coating the dexzopiclone tablets.

8. The method for preparing a pharmaceutical composition of dexazopiclone according to claim 7, characterized in that: The mass concentration of the coating solution is 18%.

9. The method for preparing a pharmaceutical composition of dexazopiclone according to claim 7, characterized in that: The coating step is followed by a packaging step.

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