WO2011079767A1 - Solid formulation of zopiclone and the preparation method thereof - Google Patents

Abstract

A preparation method of a solid formulation of zopiclone and the solid formulation prepared by the method are disclosed. Said method comprises dissolving zopiclone in an acidic solution containing an acidifier to obtain an acidic liquid of the drug; following, homogeneously mixing an alkalizer, excipients and the acidic liquid of the drug and carrying out wet-granulation; wherein the alkalizer is a reagent that makes the acidity of the mixture liquid of the alkalizer and the acidic liquid less than the acidity of the acidic liquid of the drug.

Description

 Zopicone solid preparation and preparation method thereof

TECHNICAL FIELD The present invention relates to the field of pharmaceutical preparations, and in particular to a zopiclone solid preparation and a preparation method thereof.

Background technique

 Zopiclone, molecular weight 388.81, is a weak base compound, slightly soluble in water. It is a fast-acting non-benzodiazepine sedative sleeping pill that can be used for the treatment of short-term or chronic insomnia. Clinical studies have shown that taking 3.75-7.5 mg of zopiclone each time has a good effect on starting sleep and maintaining sleep quality.

 Zopiclone is slightly soluble in water, so it is necessary to pulverize zopiclone to a certain degree of fineness in preparing a solid preparation to ensure rapid dissolution of the solid preparation after oral administration. At present, the pulverization of zopiclone is generally carried out by mechanical pulverization. However, the mechanical pulverization treatment method has many defects such as dust, pollution, and loss. A more serious problem is that due to the high drug activity of zopiclone, inhalation of lower doses of zopiclone powder can quickly produce hypnotic effects, and in the case of mechanical pulverization, it is prone to adverse reactions leading to rapid hypnosis of the operator. , causing a security incident.

 In addition, at present, mechanical pulverization is widely used to pulverize the active ingredient of the drug, and the pulverization treatment generally has a particle size of about 100 μm. The dissolution characteristics of the solid preparation obtained by the pulverization treatment by this method are not yet satisfactory.

Due to the high activity of zopiclone, the content in the solid preparation is low (10% by weight), so in the process of mechanical pulverization treatment, the problem of dispersion uniformity mixed with the excipient is also involved. Usually, a method of gradually diluting the pharmaceutically active ingredient with an excipient is gradually expanded to uniformly disperse the zopiclone in the solid preparation. However, the method is cumbersome in process operation, and also causes many problems such as dust, environmental pollution, large loss, and safety hazards in labor protection. In addition, the preparation of the solid preparation also needs to consider whether the various properties of the product can meet the requirements of the pharmaceutical field. For example, is it possible to ensure a better content uniformity? For another example, stability is the focus of the quality of the solid preparation, including the chemical stability of the active ingredient of the active ingredient, the content of the relevant substance (ie, impurities), the stability of the solid preparation property, and the dissolution stability during the storage period of the solid preparation. Whether it is within the limits of the drug standard.

 Therefore, in view of zopiclone, it is urgent to seek a method for preparing a solid preparation of zopiclone which can avoid the above-mentioned defects of the mechanical pulverization treatment method and which is excellent in various properties.

Summary of the invention

 The technical problem to be solved by the present invention is to overcome the existing method for preparing a solid preparation of zopiclone by mechanically pulverizing and controlling the particle size of zopiclone, which causes environmental pollution, large loss, serious safety hazard, and The dissolution characteristics of the cloning solid pharmaceutical preparations are not ideally deficient, and provide a simpler operation, less pollution, no aforementioned safety hazards, and can ensure that the obtained solid preparation has excellent dissolution characteristics, stability and content uniformity. A preparation method, and a zopiclone solid preparation prepared by the method.

 In order to solve the above technical problems, the inventors have taken a different approach, and uniquely used an acidic solution to dissolve the zopicl clone, and then in the granulation process, the acidity of the system is lowered, and the drug is returned to a solid state, thereby avoiding many defects of the mechanical pulverization treatment. Further, the inventors have unexpectedly found that the zopiclone solid preparation prepared by the method has excellent dissolution characteristics, stability, and content uniformity.

 The preparation method of the present invention comprises the steps of: dissolving zopiclone in an acidic solution containing an acidifying agent to prepare a medicated acidic liquid; and then uniformly mixing the alkalizing agent, the auxiliary material and the medicated acidic liquid; Wet granulation; wherein the alkalizing agent is a reagent which lowers the acidity of the mixed solution of the alkalizing agent and the drug-containing acidic liquid with respect to the acidity of the drug-containing acidic liquid.

 In the present invention, the zopiclone is a poorly water-soluble weakly basic active drug, and the amount thereof is determined according to the conventional content of the zopiclone in the solid preparation, generally the mass percentage of the wet granulated dry material.

0.5 to 15%, preferably 2 to 10%. In addition to zopiclone, other drugs can be added as needed. The active ingredient was prepared as a zopiclone compound solid preparation.

 In the present invention, the acidifying agent means an acidic reagent which can completely dissolve zopiclone in an acidic solution containing an acidifying agent. According to common knowledge in the art, the acidulant should be a pharmaceutically acceptable agent compatible with zopiclone. In the present invention, the compatibility means coexistence without adverse effects. The acidifying agent may be a single acidifying agent, or a composite acidifying agent composed of two or more components, and may be selected from various acids, such as one or more of inorganic strong acid, inorganic medium strong acid and organic weak acid. Preferably, it is one or more selected from the group consisting of citric acid, hydrochloric acid, tartaric acid, malic acid, fumaric acid, succinic acid, maleic acid, lactic acid, acetic acid and phosphoric acid, more preferably citric acid, hydrochloric acid, Malic acid or tartaric acid, the best is tannic acid. Due to the difference in the nature of R-zoicone and S-zopiclone in zopiclone, when an optically active acid is used as the acidifying agent, the racemate should be selected (eg DL-tartaric acid, DL-malic acid, DL-rich). Horse acid or DL-maleic acid), or D-type acid (such as D-tartaric acid, D-malic acid, D-fumaric acid, D-maleic acid), or D-type acid content of at least 50% by mass A mixture of D-type and L-type acids (such as a mixture of D-type and L-forms of D-type acid of more than 50% of the following acids: tartaric acid, malic acid, fumaric acid or maleic acid).

 The acidifying agent is used in an amount at least the minimum amount which enables complete solubilization of zopiclone, preferably from 1 to 1.2 times the minimum amount, and most preferably from 1 to 1.05 times. The amount of acidifying agent that can dissolve zopiclone is related to various factors such as the type of acidifying agent, the type of solvent, the number of hydrogen ions in the acidifying agent that can be combined with the basic center of zopiclone, and the conditions for preparing the acidic solution containing the drug. (such as temperature) and so on. Wherein, the basic center refers to a group or a moiety in the zopiclone which can bind to hydrogen ions in the acidifier molecule. Therefore, the above minimum amount means the minimum amount by which an acidifying agent can completely dissolve zopiclone under the conditions of the same solvent and the pharmaceutically acidic solution. The minimum amount can be determined by a simple conventional method: in the same solvent and drug-containing acidic solution, the amount of the acidifying agent is gradually increased to dissolve the zopiclone, and when it is completely dissolved, it is the minimum amount. The inventors have found through extensive experiments that, in particular, the molar ratio of the acidifying agent to zopiclone is generally from 0.8 to 1.5, preferably from 0.9 to 1.2.

The present invention is particularly preferably: citric acid having a molar amount of zopiclone of 0.9 to 1.1 times, or hydrochloric acid having a molar amount of zopiclone of 0.95 to 1.2 times. When hydrochloric acid is used as an acidifying agent, the prepared acid-containing acidic solution will be placed after being placed. A colloidal solution is formed which can be subjected to granulation in a subsequent step.

 In the present invention, the solvent in the acidic solution containing the acidifying agent may be water or a mixture of water and an organic solvent, preferably water. The organic solvent is selected according to the principle that the solubility of zopiclone is better than water in a solvent acceptable for the pharmaceutical field, preferably a water-miscible organic solvent, such as water solubility commonly used in the pharmaceutical field. An alcohol solvent such as ethanol, propylene glycol, glycerin, acetone, isopropanol or tert-butanol is preferably ethanol. In the mixture of water and an organic solvent, the amount of the organic solvent can be arbitrarily selected. When an aqueous ethanol solution is used as the solvent, the concentration of ethanol is preferably a mass percentage

10 to 50%. The amount of the solvent in the acidic solution is at least the minimum amount of the granulating liquid required for wet granulation, and is generally from 5 to 100% by mass of the wet granulated dry material, preferably from 15 to 50%.

In the preparation of the drug-containing acidic liquid, some excipients such as a binder, a surfactant, a solubilizing agent, and a water-soluble carrier of the solid dispersion may be added. Preferably, one or more of the water-soluble carrier of the surfactant, the solubilizer and the solid dispersion are added simultaneously and/or after the zopiclone is dissolved in the acidic solution containing the acidifying agent, and then The obtained drug-containing acidic liquid is subjected to a subsequent step of uniformly mixing with the alkalizing agent and the auxiliary material to carry out wet granulation. Wherein, when the water-soluble carrier of the solid dispersion and the zopiclone are simultaneously added to the acidic solution containing the acidifying agent, the amount of the water-soluble carrier of the solid dispersion added at this time is controlled to ensure that the zopiclone is completely dissolved in the The amount of the acidifying agent in the acidic solution is below; after that, the water-soluble carrier of the solid dispersion may be further added to the solution, and when the amount added is large, the obtained drug-containing acidic liquid may be in the form of a suspension or a viscous liquid. The present invention particularly preferably incorporates povidone, polyethylene glycol (preferably polyethylene glycol 400-8000), sodium lauryl sulfate, poloxamer, Tween-80, polyoxyethylene castor oil, stearic acid One or more of polyoxyl 40 ester, hydroxypropyl-β-cyclodextrin, β-cyclodextrin, lactose, mannitol, sucrose, and maltitol. The surfactant and/or solubilizer is preferably added in an amount of 0.05 to 3 times the mass of zopiclone. The water-soluble carrier of the solid dispersion is preferably added in an amount of from 1 to 10 times the mass of zopiclone. By adding a surfactant and/or a solubilizing agent as described above, the solubility of zopiclone in an acidic solution can be increased, the amount of the solvent can be reduced, and the subsequent granulation step operation can be facilitated. It is worth mentioning that one or more of the water-soluble carriers of the surfactant, solubilizer and solid dispersion are added as described above, especially solid dispersion. The water-soluble carrier of the body can further improve the dissolution characteristics of the obtained zopiclone solid preparation.

 In the present invention, the alkalizing agent refers to a reagent capable of lowering the acidity of the mixture of the alkalizing agent and the drug-containing acidic liquid with respect to the acidity of the drug-containing acidic liquid, such as an inorganic strong base such as sodium hydroxide. a weak acid strong base salt (such as sodium carbonate, disodium hydrogen phosphate, and a conjugate base of an organic weak acid (such as sodium citrate, sodium tartrate, sodium malate, and sodium acetate), or an acidity lower than a strong acid acidifier, and An acid capable of forming a buffer pair. When a conjugate base having an optically active weak acid is used as the alkalizing agent, a racemic body (such as DL-sodium tartrate or DL-malate) or a D-type acid should be selected. a mixture of a conjugate base (such as D-sodium tartrate or sodium D-malate) or a D-type acid having a conjugate base content of at least 50% by weight of a conjugate base of a D-type and an L-type acid (eg, D-type 50 a mixture of the following D-type and L-type conjugate bases: sodium tartrate, sodium malate, sodium fumarate or sodium maleate). According to common knowledge in the art, the alkalizing agent should be pharmaceutically Acceptable, and compatible with zopiclone.

 Preferably, the present invention preferably comprises a combination of an acidifying agent and an alkalizing agent of the following type:

 Type 1 : The acidifying agent is an inorganic strong acid, and the alkalizing agent is an inorganic strong base such as hydrochloric acid and sodium hydroxide.

 Type 2: The acidifying agent is an inorganic strong acid, and the alkalizing agent is an inorganic weak acid strong base salt such as hydrochloric acid and sodium carbonate, or hydrochloric acid and disodium hydrogen phosphate.

 Type 3: The acidifying agent is an inorganic strong acid, and the alkalizing agent is an organic weak acid strong base salt such as hydrochloric acid and sodium citrate, hydrochloric acid and DL-sodium tartrate, or hydrochloric acid and DL-malate.

 Type 4: the acidifying agent is an organic weak acid, the alkalizing agent is a conjugate base of the organic weak acid, and the acidifying agent and the alkalizing agent are buffer pairs of conjugated acid and base, for example, tannic acid, DL a buffer pair of tartaric acid or DL-malic acid with its corresponding conjugate base, preferably a buffer of tannic acid and sodium citrate.

 Type 5: The acidifying agent is an organic weak acid, the alkalizing agent is an inorganic strong base or an inorganic weak acid strong base salt, and the acidifying agent and the alkalizing agent form a buffer pair, such as capric acid and sodium carbonate, D-Apple Acid and sodium carbonate, DL-malic acid and disodium hydrogen phosphate, or citric acid and disodium hydrogen phosphate.

Type 6: The acidifying agent is a strong inorganic acid, the alkalizing agent is a weak acid, and can be shaped A buffered pair of acids, for example, hydrochloric acid and glycine, hydrochloric acid and alanine.

 The amount of the alkalizing agent is such an amount that at least the acidity of the mixed solution of the alkalizing agent and the drug-containing acidic liquid is lowered relative to the acidity of the drug-containing acidic liquid. Preferably, the amount of the acidifying agent and the alkalizing agent satisfies the following relationship: The value obtained by the formula 1 is 0.1 to 1.5, more preferably 0.3 to 1.2.

 (Molar number of alkalizing agent X A) I (molar number of acidizing agent X B) Formula 1

Wherein, when the acidifying agent and the alkalizing agent are of type 1, 2 or 5, A is the total number of molecular anions of the alkalizing agent; the number of hydrogen ions in the alkalizing agent molecule;

 When the acidifying agent and the alkalizing agent are of type 1, 2, 3 or 6, B is the number of hydrogen ions in the acidifying agent molecule;

 When the acidifying agent and the alkalizing agent are of type 4, A/B is 1;

 When the acidifying agent and the alkalizing agent are of type 5, B is 1;

 When the acidifying agent and the alkalizing agent are of the type 3 or 6, A is 1.

 Most preferred in the present invention: a citric acid and sodium citrate having a value of the formula 1 of 0.6 to 1.2, a hydrochloric acid and sodium carbonate having a value of the formula 1 of 0.1 to 1, or a hydrochloric acid and sodium hydroxide having a value of 0.1 to 1.

 In the present invention, the excipient may be selected from any of the excipients known and widely used in the art, such as fillers, binders, disintegrants, lubricants and the like. The content of the excipients can be selected according to the conventional knowledge in the art. Wherein the filler is preferably one or more of lactose, microcrystalline cellulose, pregelatinized starch, starch, mannitol, sucrose, and maltitol. The binder is preferably one or more of hypromellose, povidone and methylcellulose. The disintegrant is preferably one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and croscarmellose sodium. The lubricant is preferably one or more of colloidal silica, sodium stearyl fumarate, talc and magnesium stearate. The amount of the excipients can be selected according to the conventional knowledge in the art.

In the present invention, the wet granulation can be carried out according to the conventional steps and conditions of various granulation methods in the art which are in the wet granulation category, such as extrusion granulation (e.g., rocker extrusion, screw extrusion and rotation). Extrusion, etc., agitation granulation, fluidized spray granulation, and centrifugal spray granulation.

 Preferably, the specific operation of uniformly mixing the alkalizing agent, the auxiliary material and the drug-containing acidic liquid to perform wet granulation is carried out according to any one of the following modes: mode (1) alkalizing agent Or the alkalizing agent-containing solution and the auxiliary material are uniformly mixed, and then uniformly mixed with the drug-containing acidic liquid, and subjected to extrusion granulation or stirring granulation; and (2) the medicated acidic liquid, the alkalizing agent or the alkalizing agent The solution is uniformly mixed to obtain a granulating liquid, and then the granulating liquid and the auxiliary material are subjected to extrusion granulation, agitation granulation, fluidized spray granulation or centrifugal spray granulation, etc.; mode (3) The liquid and the auxiliary material are uniformly mixed, and then uniformly mixed with the alkalizing agent-containing solution, and subjected to extrusion granulation or stirring granulation. Mode (4) mixing the drug-containing acidic liquid with less than 1/3 of the auxiliary material, and the alkalizing agent or the alkalizing agent-containing solution (the specific operation may be: firstly 1/3 or less of the auxiliary material and alkalization) The agent or the alkalizing agent-containing solution is uniformly mixed, and the obtained mixture is mixed with the drug-containing acidic liquid, or, first, 1/3 or less of the auxiliary material and the drug-containing acidic liquid are mixed, and then with an alkalizing agent or an alkalizing agent-containing agent. The solution is uniformly mixed), and then mixed with the remaining auxiliary materials for extrusion granulation or agitation granulation. The above 1/3 or less may be usually 1/5 to 1/10 or less. The excipients in the above-mentioned 1/3 or less of the excipients are preferably water-soluble excipients. In the above manner, the alkalizing agent-containing solution refers to a solution obtained by dissolving an alkalizing agent in a small amount of solvent according to a routine operation in the art to facilitate mixing; the solvent may be water or water. A mixture with an organic solvent. The organic solvent is the same as described above.

 After the wet granulation is completed, the zopiclone solid granule preparation can be directly obtained, or can be used as a preparation intermediate, and further forms of zopiclone solid preparation such as a tablet or a capsule can be obtained by further conventional pulverization.

 In the present invention, each of the above preferred conditions can be arbitrarily combined on the basis of common knowledge in the art, and preferred embodiments of the present invention can be obtained.

 In the present invention, the reagents and starting materials used are commercially available, and some of the starting materials can be prepared according to the prior art methods.

 Further, the present invention also relates to a zopiclone solid preparation prepared by the above method.

The positive progress of the invention is as follows: (1) The preparation method of the invention avoids the defects of serious pollution, large loss and serious safety hazard caused by mechanical pulverization treatment of zopiclone, and the operation is simple Easy to operate, high safety factor, easy to apply to industrial production. (2) The dissolution characteristics of the zopiclone solid preparation prepared by the preparation method of the present invention are remarkably improved as compared with the prior art, and the bioavailability is high and the individual difference is small. (3) The zopiclone solid preparation prepared by the production method of the present invention has better stability and content uniformity.

detailed description

 The invention will be further illustrated by the following examples, but the invention is not limited thereto. The experimental methods in the following examples that do not specify the specific conditions are usually in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer.

 The dosage form specification is based on the zopiclone content, for example, 2 mg/tablet means 2 mg of zopiclone per tablet. The unit of use is gram and the percentage is the mass percentage.

 The mass percentage of zopiclone and solvent is the mass percentage of the wet granulated dry material. Among them, the solvent includes water in an aqueous solution of an acidifying agent and an alkalizing agent.

Comparative Example 1 and Example 1 Zopicone tablets (3.75 m _g / tablet) formulation and preparation method

量的羧甲淀粉钠混合均匀， 将羟丙 橼酸和水配制成含药酸性液， 乳糖、 甲纤维素用 80 Ό热水分散后加水 淀粉、 2/3量的羧甲淀粉钠和枸橼酸 搅拌溶解， 对上述混合料进行搅拌 钠混合均匀，加入含药酸性液进行搅 制成软材， 挤压制粒， 湿粒经干燥 拌制成软材，挤压制粒，湿颗粒干燥 后整粒， 加入硬脂酸镁和 1/3量的 后整粒， 加入硬脂酸镁和 1/3量羧甲 羧甲淀粉钠混合均匀后压片。 淀粉钠混合均匀后压片。

The amount of sodium carboxymethyl starch is evenly mixed. Hydroxypropionic acid and water are formulated into a drug-containing acidic solution. Lactose and methyl cellulose are dispersed with 80 Ό hot water, then water starch is added, and 2/3 amount of sodium carboxymethyl starch and strontium are added. The acid is stirred and dissolved. The mixture is stirred and mixed with sodium. The acid solution is added to stir the soft material into a soft material. The wet granules are dried and mixed into soft materials, extruded and granulated. After the wet granules are dried, the granules are dried. The whole granules were added with magnesium stearate and a 1/3 amount of the whole granules, and magnesium stearate and 1/3 amount of sodium carboxymethyl starch were uniformly mixed and then compressed. The starch sodium is uniformly mixed and then compressed.

 Raw materials, gastric solution Opadry 4.5, water 19

 Package

 Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition, and it is formulated into a coating.

 Process solution, film coating of the core. Example 2 Formulation and preparation method of zopiclone tablets (2.5 mg/tablet)

心 乳糖 40、 微晶纤维素 25、 羧甲淀粉钠 1、 甘露醇 2、 辅料

Heart lactose 40, microcrystalline cellulose 25, sodium carboxymethyl starch 1, mannitol 2, excipients

 Poloxamer 1, magnesium stearate 0.3, colloidal silica 0.2 solvent water 8, 95% aqueous ethanol solution 4 (16.0%)

 Acidifier citric acid monohydrate 1.6 (molar ratio to zopiclone: 1.19) alkalizing agent sodium citrate dihydrate 1.4 (formula 1 value: 0.63)

 Prepare a drug-containing acidic solution by preparing zopiclone, poloxamer, mannitol, citric acid, 95% aqueous ethanol solution and water, and mix lactose, microcrystalline cellulose, sodium carboxymethyl starch and sodium citrate. The process is added to the acid-containing liquid and stirred to form a soft material, which is extruded and granulated. The wet granules are dried and then granulated, and magnesium stearate and colloidal silica are added, and the mixture is uniformly mixed and then compressed.

 Raw material film coating premix (stomach solution Opadry) 3, water 13

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core.

Example 4 Formulation and preparation method of zopiclone tablets (2.5m _g / tablet)

 Drug Zopiclone 2.5 (4.2%, no pretreatment)

 Lactose 30, sodium carboxymethyl starch 3, microcrystalline cellulose 20, polyethylene glycol 6000 1, excipients

 Cross-linked povidone 2, colloidal silica 0.15, magnesium stearate 0.3 Solvent Water 11 (25.8%)

 Acidifier 5% aqueous hydrochloric acid 4.5 (molar ratio to zopiclone: 0.96)

 Alkalizing agent sodium carbonate 0.07 (formula 1 value: 0.21)

 Heart

 Zopiclone, polyethylene glycol 6000, 5% aqueous hydrochloric acid and 2/3 of water are formulated into a drug-containing acidic solution, lactose, microcrystalline cellulose, 2/3 amount of sodium carboxymethyl starch and cross-linked poly-dimensional Ketone mixed preparation

 Evenly, add sodium carbonate solution (prepared with 1/3 amount of water) to mix, then add acid-containing process

 The solution was stirred and granulated, and the wet granules were dried and then granulated, and magnesium stearate, 1/3 amount of sodium carboxymethyl starch and colloidal silica were added and uniformly mixed, followed by tableting.

 Raw material film coating premix (stomach solution Opadry) 2.1, water 9

 Package

 Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition.

 Process coating solution, film coating of the core.

Example 5 Zopiclone tablets (2.5 mg / tablet) Formulation and preparation method

Tablet drug zopiclone 2.5 (1.9%, no pretreatment) Heart lactose 60, microcrystalline cellulose 60, croscarmellose sodium 5, excipients

 Magnesium stearate 0.8, talcum powder 3

 Solvent water 2, 95% aqueous ethanol solution 12 ( 17.8%)

 Acidifier 5% aqueous hydrochloric acid 5 (molar ratio to zopiclone: 1.06) alkalizing agent 5% aqueous sodium hydroxide solution 5 (formula 1 value: 0.91)

 Zopiclone is mixed with 5% aqueous hydrochloric acid solution, 95% aqueous ethanol solution and water to prepare a drug-containing acidic solution. Lactose, microcrystalline cellulose and 2/3 amount of croscarmellose sodium are uniformly mixed and added.

 The 5% aqueous solution of sodium hydroxide is uniformly mixed, and then the acidic solution containing the drug is added for stirring and granulation.

 The wet granules are dried and then granulated, and magnesium stearate, 1/3 amount of croscarmellose sodium and talc are added and uniformly mixed, followed by tableting.

 Raw material film coating premix (stomach solution Opadry) 5, water 21

 Package

 Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition.

 Process coating liquid, film coating of the core.

Example 6 Zupicone Tablets (2.5 mg / tablet) formulation and preparation method

 Drug zopiclone 2.5 (3.0%, no pretreatment)

 Lactose 37.5, microcrystalline cellulose 37.5, povidone K30 2

 Excipient

 Magnesium stearate 0.5, colloidal silica 0.2

 Solvent water 40 (48.5%)

 Tablet acidifier DL-tartaric acid 1 (molar ratio to zopiclone: 1.04)

 Heart alkalizing agent DL-sodium tartrate dihydrate 1.3 (Formula 1 value: 0.85)

 Zopiclone, povidone K30, DL-tartaric acid and water are formulated into a drug-containing acidic liquid, and a DL-sodium tartrate solution (dissolved in a small amount of water) is added as a granulating liquid while stirring. Lactose, Process Microcrystalline cellulose is placed in a fluidized spray granulator for fluidized spray granulation. After the granules are granulated, magnesium stearate and colloidal silica are added, and the mixture is uniformly mixed and then tableted.

 Raw material hypromellose 2, polyethylene glycol 6000 0.35, titanium dioxide 0.4, water 16 pack

 Preparation Dispersion of hypromellose with hot water at 80 ° C, stirring with water, stirring, adding polyethylene glycol

 Process 6000 and homogenized titanium dioxide are formulated into a coating liquid for film coating of the core.

Example 7 Zopiclone tablets (2.5 mg / tablet) formulation and preparation method

Tablet drug zopiclone 2.5 ( 3.6%, no pretreatment) Heart sucrose 25, microcrystalline cellulose 30, starch 5, sodium carboxymethyl starch 2, excipients

 Povidone K30 1, polyethylene glycol 6000 1, magnesium stearate 0.3

 Solvent water 11 ( 15.9%)

 Acidifier citrate monohydrate 1.2 (molar ratio to zopiclone: 0.89) basifying agent dihydrogen disodium dihydrate dodecahydrate 1.1 (formula 1 value: 1.08)

 The zopiclone, polyethylene glycol 6000, povidone Κ30, citric acid and water are formulated into a medicated acidic solution, sucrose, microcrystalline cellulose, sodium carboxymethyl starch and mixed uniformly, and added to the medicated acidic solution.

 Stirring and granulating, adding disodium hydrogen phosphate solution (disodium hydrogen phosphate dissolved in a small amount of water) while stirring

 In the middle), the agitation granulation is continued, the wet granules are dried and then granulated, and the strontium stearate is added and uniformly mixed, followed by tableting.

 Raw material film coating premix (stomach solution Opadry) 2.4, water 10

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core.

Example 8 Zopicone Tablets (3 mg / tablet) Formulation and Preparation Method

 Drug Zopiclone 3 (2.9%, no pretreatment)

 Mannitol 60, microcrystalline cellulose 30, hydroxypropyl cellulose 5, povidone Κ 30 1, excipients

 Hypromellose 0.33, colloidal silica 0.2, magnesium stearate 0.6 Solvent Water 22 (21.4%)

 Acidifier citric acid monohydrate 1.7 (molar ratio to zopiclone: 1.05)

 Alkalizing agent sodium citrate dihydrate 0.8 (formula 1 value: 0.34)

 Core

 Disperse the hypromellose in 80°C hot water, stir it with water, and mix it with zopiclone, povidone K30, citric acid and water to form a drug-containing acidic solution, mannitol, microcrystalline cellulose, hydroxypropyl Preparation

 The cellulose is mixed evenly, and the sodium citrate solution (sodium citrate dissolved in a small amount of water) is added to stir.

 Further, the acid-containing solution is added for stirring and granulation, and the wet granules are dried and then granulated, and magnesium stearate and colloidal silica are added and uniformly mixed, followed by tableting.

 Raw material film coating premix (stomach solution Opadry) 4, water 18

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core.

Example 9 Zopicone Tablets (2.5 mg / tablet) Formulation and Preparation Method

Tablet drug zopiclone 2.5 (3.7%, no pretreatment) Heart lactose 40, sucrose 2, starch 20, sodium carboxymethyl starch 2

 Excipient

 Magnesium stearate 0.3, colloidal silica 0.1 Solvent Water 12 ( 17.6%)

 Acidifier D-malic acid 0.88 (molar ratio to zopiclone: 1.02)

 Alkalizing agent Sodium carbonate 0.3 (Formula 1 value: 0.86)

 Preparation of zopiclone, sucrose, D-malic acid and water into a drug-containing acidic solution, lactose, starch preparation

 Mix well with sodium carbonate, add medicated acidic solution for agitation granulation, wet granules after drying and granules, process

 Magnesium stearate and colloidal silica were added and mixed uniformly, followed by tableting.

 Raw material film coating premix (stomach solution Opadry) 2.5, water 11

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core.

Example 10 Zopicone Tablets (7.5 mg / tablet) Formulation and Preparation Method

 Drug Zopiclone 7.5 ( 8.9%, no pretreatment)

 Lactose 40, microcrystalline cellulose 25, povidone K30 2

 Excipient

 Hypromellose 0.5, magnesium stearate 0.25, colloidal silica 0.15 solvent water 40 (47.7%)

 Acidifier citrate monohydrate 4 (molar ratio to zopiclone: 0.99)

 Piece

 Alkalizing agent sodium citrate dihydrate 4.5 (formula 1 value: 0.8)

 Core

 Disperse the hypromellose with hot water at 80 ° C, stir with water, stir it, mix it with zopiclone, povidone K30, citric acid and water to make a drug-containing acidic solution, and add sodium citrate (dissolved) while stirring. Preparation

 In a small amount of water), as a granulating liquid. Lactose, microcrystalline cellulose in a fluidized spray granulator, process

 The fluidized spray granulation was carried out, and after the granules were granulated, magnesium stearate and colloidal silica were added, and the mixture was uniformly mixed and then tableted.

 Raw material hypromellose 2, polyethylene glycol 6000 0.4, titanium dioxide 0.5, water 17 pack

 Preparation Dispersion of hypromellose with hot water at 80 ° C, stirring with water, stirring, adding polyethylene glycol

 Process 6000 and homogenized titanium dioxide are formulated into a coating liquid for film coating of the core.

Example 11 Zopicone Tablets (2.5 mg / tablet) Formulation and preparation method

Tablet drug zopiclone 2.5 (0.5%, no pretreatment) Heart lactose 340, microcrystalline cellulose 150, sodium carboxymethyl starch 7.5,

 Excipient

 Povidone K30 5, magnesium stearate 3, colloidal silica 1.5 solvent 95% aqueous ethanol solution 20, water 200 (42.8%)

 Acidifier citric acid monohydrate 1.5 (molar ratio to zopiclone: 1.11) alkalizing agent sodium citrate dihydrate 2.5 (formula 1 value: 1.19)

 The zopiclone, povidone oxime 30, citric acid, 95% aqueous ethanol solution and water are formulated into a drug-containing acidic liquid, and sodium citrate (dissolved in a small amount of water) is added as a granulating liquid while stirring. Milk preparation

 Sugar, microcrystalline cellulose and 2/3 amount of sodium carboxymethyl starch in a fluidized spray granulator for fluidization

 Spray granulation, after granulating the granules, magnesium stearate, 1/3 amount of sodium carboxymethyl starch and colloidal silica were added, and the mixture was uniformly mixed and then compressed.

 Raw material film coating premix (stomach solution Opadry) 20, water 85

 Package

 Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition, and it is formulated into a coating.

 Process coating liquid, film coating of the core.

Example 12 Zopiclone Tablets (2.5 mg / tablet) Formulation and preparation method

 Drug Zopiclone 2.5 (3.9%, no pretreatment)

 Lactose 20, microcrystalline cellulose 20, maltitol 20, polyethylene glycol 6000 1, excipients

 Sodium stearate fumarate 0.5, colloidal silica 0.2

 Solvent water 11 ( 17.0%)

 Tablet Acidifier 5% aqueous hydrochloric acid 5 (molar ratio to zopiclone: 1.06) Heart alkalizing agent Sodium carbonate 0.36 (Formula 1 value: 0.99)

 The zopiclone, polyethylene glycol 6000, 5% aqueous hydrochloric acid solution and water are formulated into a drug-containing acidic preparation liquid, lactose, maltitol, microcrystalline cellulose and sodium carbonate are uniformly mixed, and the medicinal acid-containing acidic liquid is added to carry out stirring granulation. After the wet granules are dried, the whole granules are added, and sodium stearate and colloidal silica are added and uniformly mixed, followed by tableting.

 Raw material film coating premix (stomach solution Opadry) 3, water 13

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core.

Example 13 Zopiclone Tablets (2.5 mg / tablet) Formulation and Preparation Method

Tablet drug zopiclone 2.5 (4.2%, no pretreatment) Heart mannitol 25, microcrystalline cellulose 30, poloxamer 1,

 Excipient

 Magnesium stearate 0.3, colloidal silica 0.2

 Solvent 95% aqueous ethanol solution 3, water 5 (22.4%)

 Acidifier 5% aqueous hydrochloric acid 5.6 (molar ratio to zopiclone: 1.19) alkalizing agent sodium carbonate 0.2 (formula 1 value: 0.49)

 Prepare a drug-containing acidic solution by preparing zopiclone, poloxamer, 5% aqueous hydrochloric acid solution, 95% aqueous ethanol solution and water, and mix mannitol, microcrystalline cellulose and sodium carbonate uniformly, and add the acidic acid solution to stir. Granulation, the wet granules are dried and then granulated, and magnesium stearate and colloidal silica are added and uniformly mixed, followed by tableting.

 Raw material film coating premix (stomach solution Opadry) 2.2, water 10

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core. Example 14 Zopicone Tablets (2 mg / tablet) Formulation and Preparation Method

 Drug Zopiclone 2 (1.6%, no pretreatment)

 Lactose 60, microcrystalline cellulose 60, sodium carboxymethyl starch 5,

 Excipient

 Hypromellose 0.6, magnesium stearate 0.75

 Solvent water 13 ( 16.2%)

 Acidifier 5% aqueous hydrochloric acid 4 (molar ratio to zopiclone: 1.06)

 Piece

 Alkalizing agent 0.5% aqueous sodium hydroxide 4 (Formula 1 value: 0.09)

 Heart

 The hypromellose was dispersed in hot water at 80 ° C, stirred and dissolved with water, and formulated with zopiclone, 5% aqueous hydrochloric acid and water to prepare a drug-containing acidic solution, lactose, microcrystalline cellulose and 2/3 amount of carboxymethyl. Preparation

 The sodium starch is evenly mixed, and mixed with 0.5% aqueous sodium hydroxide solution, and then added to the process.

 The acidic solution of the drug is stirred and granulated, and the wet granules are dried and then granulated, and magnesium stearate and 1/3 amount of sodium carboxymethyl starch are added and uniformly mixed, followed by tableting.

 Raw material film coating premix (stomach solution Opadry) 5, water 21

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core.

Example 15 Zopiclone Tablets (2.5 mg / tablet) Formulation and Preparation Method

Tablet drug zopiclone 2.5 (1.8%, no pretreatment) Heart lactose 60, sucrose 5, microcrystalline cellulose 60, starch 5,

 Excipient

 Cross-linked povidone 2, magnesium stearate 0.8, talc 2

 Solvent water 18 ( 16.2%)

 Acidifier 5% aqueous hydrochloric acid 4.7 (molar ratio to zopiclone: 1)

 Alkalizing agent Glycine 0.75 (Formula 1 value: 1.55)

 Zopiclone, sucrose, 5% aqueous hydrochloric acid and 3/4 of water were formulated into a drug-containing acidic solution, and a granulated solution was prepared by adding a glycine solution (prepared with 1/4 amount of water) while stirring. Lactose, microcrystalline technology Cellulose, starch and crospovidone are uniformly mixed. The granulating liquid is added for stirring and granulation. The wet granules are dried and then granulated. After adding magnesium stearate and talc, the mixture is uniformly mixed and then compressed. Raw material film coating premix (stomach solution Opadry) 5, water 21

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core. Example 16 Zopiclone tablets (2.5 g / tablet) formulation and preparation method

 Drug zopiclone 2.5 ( 3.5%, no pretreatment)

 Lactose 40, microcrystalline cellulose 25, sodium lauryl sulfate 0.15,

 Excipient

 Magnesium stearate 0.25, colloidal silica 0.15

 Solvent water 12 ( 16.9%)

 Tablet acidifier D-tartaric acid 0.5, citric acid monohydrate 0.68 (molar ratio to zopiclone: 1.02) Cardiotheter D-sodium tartrate dihydrate 0.77, sodium citrate dihydrate 1 (formula 1 value) : 1.03 ) Preparation of an acidic solution by preparing zopiclone, D-tartaric acid, citric acid, sodium decyl sulfate and water. Lactose, microcrystalline cellulose, sodium D-tartrate and sodium citrate are mixed evenly. Adding acid solution containing process chemicals for agitation granulation, wet granules are dried and granulated, and magnesium stearate and colloidal silica are added to mix evenly. After pressing.

 Raw material film coating premix (stomach solution Opadry) 2.8, water 12

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core.

 Example 17 Zopiclone tablets (2.5 mg / tablet) Formulation and preparation method

Tablet drug zopiclone 2.5 (1.9%, no pretreatment) Heart lactose 60, microcrystalline cellulose 60, sodium carboxymethyl starch 5,

 Excipient

 Tween -80 0.13, sodium stearate, 0.8, talc 2 solvent water 12, 95% aqueous ethanol solution 6 ( 17.3%)

 Acidifier 5% aqueous hydrochloric acid 4.9 (molar ratio to zopiclone: 1.04) alkalizing agent sodium citrate dihydrate 0.6 (formula 1 value: 0.31)

 Zopiclone, 5% aqueous hydrochloric acid, and 2/3 of water, 95% aqueous ethanol, and Tween-80 were formulated into a drug-containing acidic solution. Lactose, microcrystalline cellulose, 50% amount of sodium carboxymethyl starch and strontium

 Sodium citrate solution (dissolved in 1/3 of water) is evenly mixed, added with acid-containing solution, stirred and granulated, wet process

 After the granules are dried, the granules are added, sodium stearate sodium stearate, 50% sodium carboxymethyl starch and talc powder are added and uniformly mixed, followed by tableting.

 Raw material film coating premix (stomach solution Opadry) 5, water 21

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core.

Example 18 Formulation of zopiclone tablets (2.5 m _g / tablet) and preparation method thereof

 Drug zopiclone 2.5 (2.8%, no pretreatment)

 Lactose 37.5, microcrystalline cellulose 37.5, sodium carboxymethyl starch 4.2, polyethylene glycol 6000 1, excipients

 Hypromellose 0.5, Magnesium stearate 0.5, Colloidal silica 0.15 Solvent Water 17 ( 19.3%)

 Acidifier citrate monohydrate 2 (molar ratio to zopiclone: 1.48)

 Heart alkalizing agent sodium citrate dihydrate 2.2 (formula 1 value: 0.79)

 Disperse the hypromellose with hot water at 80 ° C, stir and dissolve with water, mix with zopiclone, polyethylene glycol 6000, citric acid and water, add 65% lactose to prepare the drug-containing preparation process acidity Liquid, the remaining lactose, microcrystalline cellulose, 2/3 amount of sodium carboxymethyl starch and sodium citrate are mixed evenly, added to the acidic solution containing the drug for stirring and granulation, the wet granules are dried and then granulated, and stearic acid is added. Magnesium, colloidal silica and 1/3 amount of sodium carboxymethyl starch were uniformly mixed and then compressed. Raw material film coating premix (stomach solution Opadry) 3.5, water 15

 Package

 Add Opadry powder in water while stirring, continue stirring for 45 minutes after adding, and prepare the garment.

 The coating solution is subjected to film coating on the core.

Example 19 Zopicone Tablets (2 mg / tablet) Formulation and Preparation Method

Tablet drug zopiclone 2 (1.5%, no pretreatment) Heart lactose 60, microcrystalline cellulose 60, sodium carboxymethyl starch 5,

 Excipient

 Hypromellose 0.6, magnesium stearate 0.75

 Solvent water 8, 95% aqueous ethanol solution 11 ( 17.1%)

 Acidifier citric acid monohydrate 0.86 (molar ratio to zopiclone: 0.80) alkalizing agent 5% aqueous sodium hydroxide solution 3.3 (formula 1 value: 1.01)

 Disperse the hypromellose in 95% aqueous solution of ethanol, add water and citric acid to stir and dissolve, and prepare the drug-containing acidic solution, lactose, microcrystalline cellulose and 2/3 amount of carboxymethyl starch with zopiclone.

 The sodium is evenly mixed, and the aqueous solution of sodium hydroxide is added to be evenly mixed, and then the chemical solution containing the drug is added.

 The mixture was stirred and granulated, and the wet granules were dried and then granulated, and magnesium stearate and 1/3 amount of sodium carboxymethyl starch were added and uniformly mixed, followed by tableting.

 Raw material film coating premix (stomach solution Opadry) 5, water 21

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core.

Example 20 Zopiclone capsule (2.5 mg / tablet) formula and preparation method

 The pellets before the tableting of Example 15 were passed through a 30 mesh sieve and placed in a hard capsule.

工艺 衣溶液， 对片芯进行薄膜包衣。 实施例 22 \左匹克隆片 (3.75m_g/片）配方及制备方法

The coating solution is applied to the core of the film. Example 22 \Left clone piece (3.75m _g / piece) formula and preparation method

 Drug Zopiclone 3.75 (3.4%, no pretreatment)

 Lactose 70, microcrystalline cellulose 25, polyethylene glycol (6000) 2, hydroxypropyl β-cyclodextrin 5, carboxy auxiliary

 Sodium starch sodium 4, colloidal silica 0.1, magnesium stearate 0.8

 Solvent water 21 ( 19.0%)

 Acidifier phthalic acid monohydrate 2.03 (molar ratio to zopiclone: 1.0)

 Piece

 Alkalizing agent sodium citrate dihydrate 2.84 (formula 1 value: 1.0)

 Heart

 Zopiclone, 2/3 water and citric acid were stirred and dissolved. Polyethylene glycol and hydroxypropyl β-cyclodextrin were added to prepare a drug-containing acidic solution. Add 1/5 of lactose and add 枸橼 while stirring. Sodium liquid preparation

 (Sodium citrate is dissolved in 1/3 of water), then added to microcrystalline cellulose, 2/3 amount of sodium carboxymethyl starch and process

 The remaining lactose is stirred and granulated, and the wet granules are dried and granulated, and mixed with magnesium stearate, colloidal silica and 1/3 amount of sodium carboxymethyl starch to form a tablet.

 Raw material film coating premix (stomach solution Opadry) 3.5, water 15

 Package

 Preparation Opadry powder was added while stirring in water, and stirring was continued for 45 minutes after the addition, and it was formulated into a coating.

 Process coating liquid, film coating of the core.

Effect Example 1 Dissolution comparison test

 Samples: Comparative Example 1. Zopiclone tablets of Examples 1 to 5, 18 and 22

 Dissolution method: Take the sample, according to the dissolution method (Chinese Pharmacopoeia 2005 edition two appendix X C third method), with water 200ml as solvent, the rotation speed is 50 rpm, operate according to law, and prepare a control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2005 edition two appendix IV A), the absorbance was measured at a wavelength of 304 nm, and the amount of dissolution per tablet was calculated.

对比 1 40.1 64.6 89.3 94.9

Comparison 1 40.1 64.6 89.3 94.9

1 60.6 91.4 98.5 99.7

2 64.0 90.2 100.2 100.6

3 71.3 93.1 100.6 100.5

4 70.9 93.6 99.8 99.6

5 64.7 90.2 100.3 100.1

18 73.6 94.1 99.8 99.7

22 75.2 95.4 99.7 99.8 Effect example 2 Stability comparison test

 The zopiclone tablets of Comparative Example 1, Examples 1, 2 and 4 were placed in high-density polyethylene plastic bottles, sealed, and placed in an accelerated test chamber at a temperature of 40 ° C ± 2 ° C, relative humidity. Stability was investigated at 75% ± 5%.

 Determination method: Take the appropriate amount of this product (equivalent to 3mg of zopiclone), place it in a 250ml volumetric flask, add 0.02mol/L hydrochloric acid, shake well, filter, and take the filtrate as the test solution; An appropriate amount of the reference substance was cloned, and a solution containing 12 g per 1 ml was prepared using 0.02 mol/L hydrochloric acid as a control solution. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2005 edition two appendix IV A), the absorbance was measured at a wavelength of 304 nm, and the content was calculated.

 The dissolution measurement method was the same as in the effect of Example 1.

 Determination of related substances: According to high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix V D) determination, using 18 垸 垸 silicon germanium bonded silica as a filler; detection wavelength is 304nm. The chromatogram of the test solution is compared to the chromatogram of the control solution.

加速前 加速后 加速前 加速后 加速前 加速后 加速前 加速后 对比 1 白色片 白色片 99.1 98.8 89.3 87.1 0.09 0.60

Acceleration before acceleration, acceleration before acceleration, acceleration before acceleration, acceleration after acceleration, comparison after 1 white piece of white film 99.1 98.8 89.3 87.1 0.09 0.60

1 white piece white piece 99.7 99.3 98.5 99.1 0.11 0.51

2 white film white film 101.4 100.7 100.2 99.8 0.10 0.48

4 White film White film 99.1 99.5 99.8 99.1 0.09 0.50 Effect example 3 Content uniformity experiment

 According to the Chinese Pharmacopoeia 2005 edition appendix XE content uniformity test method, the content of each tablet was determined (the content determination method was the same as the effect example 2), and the content uniformity (A+1.80S:) was calculated.

Claims

Rights request A method for preparing a solid preparation of zopiclone, which comprises the steps of: dissolving zopiclone in an acidic solution containing an acidifying agent to prepare a medicated acidic liquid; and thereafter, basifying agent and auxiliary agent And the above-mentioned drug-containing acidic liquid is uniformly mixed and subjected to wet granulation; wherein the alkalizing agent is a reagent for lowering the acidity of the mixed solution of the alkalizing agent and the drug-containing acidic liquid with respect to the acidity of the drug-containing acidic liquid. .  The method according to claim 1, wherein the zopiclone is used in an amount of 0.5 to 15% by mass, preferably 2 to 10% by mass based on the dry granulated dry material.  3. The method according to claim 1 or 2, wherein: the acidifying agent is one or more of an inorganic strong acid, an inorganic medium strong acid, and an organic weak acid.  Preferably selected from one or more of the group consisting of citric acid, hydrochloric acid, tartaric acid, malic acid, fumaric acid, succinic acid, maleic acid, lactic acid, acetic acid and phosphoric acid,  More preferably tannic acid, hydrochloric acid, malic acid or tartaric acid;  When the acidifying agent is an optically active acid, a racemic body, or a D-type acid, or a mixture of D-type and L-type acids having a D-type acid content of at least 50% by mass may be selected.  The method according to any one of claims 1 to 3, wherein the acidulant is used in an amount of from 1 to 1.2 times the minimum amount of the pharmaceutically acceptable acidic solution to dissolve the zopiclone. More preferably, it is 1 to 1.05 times.  The method according to any one of claims 1 to 3, wherein the molar ratio of the acidifying agent to zopiclone is from 0.8 to 1.5, more preferably from 0.9 to 1.2.  The method according to claim 1 or 2, wherein the acidifying agent is citric acid having a molar amount of 0.9 to 1.1 times of zopiclone, or hydrochloric acid having a molar amount of zopiclone of 0.95 to 1.2 times. The method according to any one of claims 1 to 6, wherein the alkalizing agent is an inorganic strong base, a weak acid strong base salt, a conjugate base of an organic weak acid, or an acidity lower than a strong acid acidification. Agent, and An acid capable of forming a buffer pair with it;  Preferred are sodium hydroxide, sodium carbonate, disodium hydrogen phosphate, sodium citrate, sodium tartrate and sodium malate, sodium acetate, glycine and alanine;  When a conjugate base having an optically active weak acid is selected as the alkalizing agent, the racemate or the conjugate base of the D-type acid or the D-type of the D-type acid having a conjugate base content of at least 50% by mass should be selected. And a mixture of conjugate bases of L-type acid.  The method according to any one of claims 1 to 7, wherein the acidifying agent and the alkalizing agent are any one of the following types:  Type 1: The acidifying agent is an inorganic strong acid, the alkalizing agent is an inorganic strong base; Type 2: the acidifying agent is an inorganic strong acid, and the alkalizing agent is an inorganic weak acid strong base salt; The acidifying agent is an inorganic strong acid, the alkalizing agent is an organic weak acid strong base salt; the type 4: the acidifying agent is an organic weak acid, and the alkalizing agent is a conjugate base of the organic weak acid;  Type 5: the acidifying agent is an organic weak acid, and the alkalizing agent is an inorganic strong base or an inorganic weak acid strong base salt;  Type 6: the acidifying agent is a strong inorganic acid, the alkalizing agent is a weak acid, and an acid capable of forming a buffer pair;  Preferably, the acidifying agent and alkalizing agent are: hydrochloric acid and sodium hydroxide, hydrochloric acid and sodium carbonate, hydrochloric acid and disodium hydrogen phosphate, hydrochloric acid and sodium citrate, hydrochloric acid and sodium tartrate, hydrochloric acid and sodium malate , citric acid and sodium citrate, DL-tartaric acid and DL-sodium tartrate, DL-malic acid and DL-malate, tannic acid and sodium carbonate, D-malic acid and sodium carbonate, DL-malic acid and Disodium hydrogen phosphate, citric acid and disodium hydrogen phosphate, hydrochloric acid and glycine, or hydrochloric acid and alanine. 9. The method according to claim 8, wherein: the amount of the acidifying agent and the alkalizing agent is as follows: The value obtained by the formula 1 is 0.1 to 1.5, more preferably 0.3 to 1.2 _; (Number of moles of alkalizing agent XA) I (molar number of acidizing agent XB) Formula 1 Wherein, when the acidifying agent and the alkalizing agent are of type 1, 2 or 5, A is the total valence number of the alkalinizing agent molecule anion and the number of hydrogen ions in the alkalizing agent molecule;  When the acidifying agent and the alkalizing agent are of type 1, 2, 3 or 6, B is the number of hydrogen ions in the acidifying agent molecule;  When the acidifying agent and the alkalizing agent are of type 4, A/B is 1;  When the acidifying agent and the alkalizing agent are of type 5, B is 1;  When the acidifying agent and the alkalizing agent are of the type 3 or 6, A is 1.  The method according to claim 1 or 2, wherein: the acidifying agent and the alkalizing agent are sodium citrate and sodium citrate having a formula 1 value of 0.6 to 1.2, and the formula 1 value is 0.1 〜 1 hydrochloric acid and sodium carbonate, or the formula 1 value of 0.1 to 1 hydrochloric acid and sodium hydroxide.  The method according to any one of claims 1 to 10, wherein the solvent in the acid solution containing the acidifier is water or a mixture of water and an organic solvent; the organic solvent is a pair The solubility of zopiclone is superior to that of water in the field of pharmaceuticals;  The mixture of water and organic solvent is preferably a 10% to 50% by mass aqueous solution of ethanol.  The method according to any one of claims 1 to 11, wherein the amount of the solvent in the acidic solution is 5 to 100% by mass of the wet granulated dry material, more preferably 15 to 50. %.  The method according to any one of claims 1 to 12, wherein: at the same time as and/or after the zopiclone is dissolved in the acidic solution containing the acidifying agent, a surfactant is further added, a solubilizing agent and one or more of the water-soluble carriers of the solid dispersion, and then uniformly mixing the obtained drug-containing acidic liquid with the alkalizing agent and the auxiliary material, and performing wet granulation;  Wherein, when the water-soluble carrier of the solid dispersion and the zopiclone are simultaneously added to the acidic solution containing the acidifying agent, the amount of the water-soluble carrier of the solid dispersion added at this time is controlled to ensure that the zopiclone is completely dissolved in the The amount of the acidifying agent in the acidic solution is below; One or more of the water-soluble carriers of the surfactant, solubilizer and solid dispersion Preferred are povidone, polyethylene glycol, sodium lauryl sulfate, poloxamer, polyoxyethylene castor oil, polyoxyl 40 stearate, Tween-80, hydroxypropyl-β. One or more of cyclodextrin, β-cyclodextrin, lactose, mannitol, sucrose, and maltitol.  The method according to any one of claims 1 to 13, wherein: the surfactant and/or the solubilizing agent are added in an amount of 0.05 to 3 times the mass of zopiclone; The water-soluble carrier of the body is added in an amount of 1 to 10 times the mass of zopiclone.  The method according to any one of claims 1 to 14, wherein the specific operation mode of performing wet granulation by uniformly mixing the alkalizing agent, the auxiliary material and the drug-containing acidic liquid is selected from the group consisting of Any of the following ways:  Mode (1) uniformly mixing the alkalizing agent or the alkalizing agent-containing solution and the auxiliary material, and uniformly mixing with the drug-containing acidic liquid, and performing extrusion granulation or stirring granulation;  Mode (2) uniformly mixing the drug-containing acidic liquid with the alkalizing agent or the alkalizing agent-containing solution to obtain a granulating liquid, and then subjecting the granulating liquid and the auxiliary material to extrusion granulation, stirring granulation, and flow Spray granulation or centrifugal spray granulation;  Mode (3) uniformly mixing the drug-containing acidic liquid with the auxiliary material, and then uniformly mixing with the alkalizing agent-containing solution, and performing extrusion granulation or stirring granulation;  Mode (4) uniformly mixing the drug-containing acidic liquid with 1/3 or less of the auxiliary material, and the alkalizing agent or the alkalizing agent-containing solution, and then mixing with the remaining auxiliary materials for extrusion granulation or stirring granulation; The excipients in the excipients of 1/3 or less are preferably water-soluble excipients.  The method according to any one of claims 1 to 15, wherein the zopiclone solid particles obtained by the method according to any one of claims 1 to 15 are subjected to further conventional steps. A zopiclone tablet or a zopiclone capsule is prepared.  17. A zopiclone solid preparation obtained by the method according to any one of claims 1 to 16.