WO2011079767A1 - Formulation solide de zopiclone et son procédé de préparation - Google Patents

Formulation solide de zopiclone et son procédé de préparation Download PDF

Info

Publication number
WO2011079767A1
WO2011079767A1 PCT/CN2010/080345 CN2010080345W WO2011079767A1 WO 2011079767 A1 WO2011079767 A1 WO 2011079767A1 CN 2010080345 W CN2010080345 W CN 2010080345W WO 2011079767 A1 WO2011079767 A1 WO 2011079767A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
agent
zopiclone
alkalizing agent
water
Prior art date
Application number
PCT/CN2010/080345
Other languages
English (en)
Chinese (zh)
Inventor
郑斯骥
张琦
任亚洲
Original Assignee
上海中西制药有限公司
上海中西三维药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海中西制药有限公司, 上海中西三维药业有限公司 filed Critical 上海中西制药有限公司
Publication of WO2011079767A1 publication Critical patent/WO2011079767A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention relates to the field of pharmaceutical preparations, and in particular to a zopiclone solid preparation and a preparation method thereof.
  • 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.
  • the pulverization of zopiclone is generally carried out by mechanical pulverization.
  • 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.
  • the pulverization treatment generally has a particle size of about 100 ⁇ m.
  • the dissolution characteristics of the solid preparation obtained by the pulverization treatment by this method are not yet satisfactory.
  • 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.
  • a method of gradually diluting the pharmaceutically active ingredient with an excipient is gradually expanded to uniformly disperse the zopiclone in the solid preparation.
  • 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?
  • 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.
  • 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 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.
  • 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.
  • 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.
  • the active ingredient was prepared as a zopiclone compound solid preparation.
  • the acidifying agent means an acidic reagent which can completely dissolve zopiclone in an acidic solution containing an acidifying agent.
  • the acidulant should be a pharmaceutically acceptable agent compatible with zopiclone.
  • 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.
  • 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
  • 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.
  • the basic center refers to a group or a moiety in the zopiclone which can bind to hydrogen ions in the acidifier molecule.
  • 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.
  • 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.
  • 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.
  • the amount of the organic solvent can be arbitrarily selected.
  • the concentration of ethanol is preferably a mass percentage
  • 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%.
  • some excipients such as a binder, a surfactant, a solubilizing agent, and a water-soluble carrier of the solid dispersion may be added.
  • a binder a surfactant, a solubilizing agent, and a water-soluble carrier of the solid dispersion
  • 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.
  • 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
  • polyoxyl 40 ester hydroxypropyl- ⁇ -cyclodextrin, ⁇ -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.
  • 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.
  • 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.
  • 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.
  • a racemic body such as DL-sodium tartrate or DL-malate
  • a D-type acid should be selected.
  • a mixture of a conjugate base such as D-sodium tartrate or sodium D-malate
  • 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.
  • the alkalizing agent should be pharmaceutically Acceptable, and compatible with zopiclone.
  • the present invention preferably comprises a combination of an acidifying agent and an alkalizing agent of the following type:
  • the acidifying agent is an inorganic strong acid
  • the alkalizing agent is an inorganic strong base such as hydrochloric acid and sodium hydroxide.
  • the acidifying agent is an inorganic strong acid
  • 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.
  • the acidifying agent is an inorganic strong acid
  • 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.
  • the acidifying agent is an organic weak acid
  • the alkalizing agent is a conjugate base of the organic weak acid
  • 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.
  • the acidifying agent is an organic weak acid
  • the alkalizing agent is an inorganic strong base or an inorganic weak acid strong base salt
  • 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.
  • the acidifying agent is a strong inorganic acid
  • the alkalizing agent is a weak acid
  • 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.
  • 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.
  • A is the total number of molecular anions of the alkalizing agent; the number of hydrogen ions in the alkalizing agent molecule;
  • B is the number of hydrogen ions in the acidifying agent molecule
  • A/B is 1;
  • B is 1;
  • A is 1.
  • 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
  • a hydrochloric acid and sodium hydroxide having a value of 0.1 to 1.
  • 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.
  • 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.
  • 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.
  • extrusion granulation e.g., rocker extrusion, screw extrusion and rotation
  • Extrusion, etc. agitation granulation, fluidized spray granulation, and centrifugal spray granulation.
  • 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.
  • 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.
  • 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.
  • the reagents and starting materials used are commercially available, and some of the starting materials can be prepared according to the prior art methods.
  • 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.
  • 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.
  • the solvent includes water in an aqueous solution of an acidifying agent and an alkalizing agent.
  • 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 ⁇ 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.
  • 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.
  • Example 2 Formulation and preparation method of zopiclone tablets (2.5 mg/tablet)
  • 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)
  • 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.
  • 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.
  • Example 4 Formulation and preparation method of zopiclone tablets (2.5m g / tablet)
  • Lactose 30 sodium carboxymethyl starch 3, microcrystalline cellulose 20, polyethylene glycol 6000 1, excipients
  • Acidifier 5% aqueous hydrochloric acid 4.5 (molar ratio to zopiclone: 0.96)
  • 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
  • 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.
  • Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition.
  • 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.
  • Preparation Opadry powder is added while stirring in water, and stirring is continued for 45 minutes after the addition.
  • 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.
  • 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
  • Povidone K30 polyethylene glycol 6000 1, magnesium stearate 0.3
  • 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 ⁇ 30, 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.
  • 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.
  • 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.
  • Acidifier citric acid monohydrate 1.7 (molar ratio to zopiclone: 1.05)
  • Alkalizing agent sodium citrate dihydrate 0.8 (formula 1 value: 0.34)
  • the cellulose is mixed evenly, and the sodium citrate solution (sodium citrate dissolved in a small amount of water) is added to stir.
  • 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.
  • 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.
  • Acidifier D-malic acid 0.88 (molar ratio to zopiclone: 1.02)
  • Magnesium stearate and colloidal silica were added and mixed uniformly, followed by tableting.
  • 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.
  • Acidifier citrate monohydrate 4 (molar ratio to zopiclone: 0.99)
  • Alkalizing agent sodium citrate dihydrate 4.5 (formula 1 value: 0.8)
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • Example 12 Zopiclone Tablets (2.5 mg / tablet) Formulation and preparation method
  • Lactose 20 microcrystalline cellulose 20, maltitol 20, polyethylene glycol 6000 1, excipients
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 14 Zopicone Tablets (2 mg / tablet) Formulation and Preparation Method
  • Acidifier 5% aqueous hydrochloric acid 4 (molar ratio to zopiclone: 1.06)
  • 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.
  • 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.
  • 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.
  • Acidifier 5% aqueous hydrochloric acid 4.7 (molar ratio to zopiclone: 1)
  • 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
  • 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.
  • Example 16 Zopiclone tablets (2.5 g / tablet) formulation and preparation method
  • Lactose 40 microcrystalline cellulose 25, sodium lauryl sulfate 0.15,
  • 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.
  • 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.
  • Example 17 Zopiclone tablets (2.5 mg / tablet) Formulation and preparation method
  • 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
  • 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.
  • 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.
  • Example 18 Formulation of zopiclone tablets (2.5 m g / tablet) and preparation method thereof
  • Acidifier citrate monohydrate 2 (molar ratio to zopiclone: 1.48)
  • Heart alkalizing agent sodium citrate dihydrate 2.2 (formula 1 value: 0.79)
  • the coating solution is subjected to film coating on the core.
  • 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)
  • 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.
  • 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.
  • Example 20 Zopiclone capsule (2.5 mg / tablet) formula and preparation method
  • Example 15 The pellets before the tableting of Example 15 were passed through a 30 mesh sieve and placed in a hard capsule.
  • Example 22 Left clone piece (3.75m g / piece) formula and preparation method
  • Lactose 70 microcrystalline cellulose 25, polyethylene glycol (6000) 2, hydroxypropyl ⁇ -cyclodextrin 5, carboxy auxiliary
  • Acidifier phthalic acid monohydrate 2.03 (molar ratio to zopiclone: 1.0)
  • 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.
  • 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.
  • 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.
  • 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 ⁇ ⁇ 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Anesthesiology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention a pour objet un procédé de préparation d'une formulation solide de zopiclone et la formulation solide préparée par ledit procédé. Ledit procédé comprend la dissolution de zopiclone dans une solution acide contenant un acidifiant pour obtenir un liquide acide du médicament ; ensuite, le mélange homogène d'un alcalinisant, des excipients et dudit liquide acide du médicament et la réalisation d'une granulation humide ; l'alcalinisant étant un réactif qui rend l'acidité dudit liquide du mélange de l'alcalinisant et du liquide acide inférieure à l'acidité du liquide acide du médicament.
PCT/CN2010/080345 2009-12-29 2010-12-28 Formulation solide de zopiclone et son procédé de préparation WO2011079767A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200910247348.X 2009-12-29
CN200910247348XA CN102106825B (zh) 2009-12-29 2009-12-29 一种佐匹克隆固体制剂及其制备方法

Publications (1)

Publication Number Publication Date
WO2011079767A1 true WO2011079767A1 (fr) 2011-07-07

Family

ID=44171180

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2010/080345 WO2011079767A1 (fr) 2009-12-29 2010-12-28 Formulation solide de zopiclone et son procédé de préparation

Country Status (2)

Country Link
CN (1) CN102106825B (fr)
WO (1) WO2011079767A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1418631A (zh) * 2002-12-19 2003-05-21 王登之 治疗失眠的佐匹克隆口腔崩解片及其制备方法
US20050053653A1 (en) * 2003-09-05 2005-03-10 Argaw Kidane Osmotic delivery of therapeutic compounds by solubility enhancement

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1418631A (zh) * 2002-12-19 2003-05-21 王登之 治疗失眠的佐匹克隆口腔崩解片及其制备方法
US20050053653A1 (en) * 2003-09-05 2005-03-10 Argaw Kidane Osmotic delivery of therapeutic compounds by solubility enhancement

Also Published As

Publication number Publication date
CN102106825A (zh) 2011-06-29
CN102106825B (zh) 2013-04-17

Similar Documents

Publication Publication Date Title
US8906867B2 (en) Production method of solid preparation and the solid preparations produced by the method
TWI673051B (zh) 恩雜魯它脈（ｅｎｚａｌｕｔａｍｉｄｅ）之調和物
JP2001511156A (ja) 高いバイオアベイラビリティーを有するフェノフィブレート医薬組成物及びそれを調製するための方法
BR112015015758B1 (pt) Dispersão sólida, formulação sólida de dose unitária, preparação farmacêutica e uso de uma dispersão sólida
CA3019508A1 (fr) Preparation orale presentant une exceptionnelle aptitude a l'elution
WO2011079609A1 (fr) Procédé de préparation de formulations solides et formulations solides ainsi préparées
JP5103173B2 (ja) ジヒドロピリジン系化合物の分解を防止する方法
TW202137985A (zh) 含有愛萊諾迪肯(irinotecan)之口服固體調配物及其製備方法
CN101454003B (zh) 包含3-[5-[4-(环戊氧基)-2-羟基苯甲酰基]-2-[(3-羟基-1,2-苯并异噁唑-6-基)甲氧基]苯基]丙酸或其盐的口服组合物
US20090088424A1 (en) Methods and compositions for controlling the bioavailability of poorly soluble drugs
WO2011079766A1 (fr) Préparation solide d'aripiprazole et son procédé de production
CN106943367B (zh) 一种马来酸阿法替尼片及其制备方法
EP4079295A1 (fr) Composition présentant une solubilité et une biodisponibilité améliorées de l'olaparib
JP2001261553A (ja) 経口投与製剤
US20110060008A1 (en) Pharmaceutical composition containing acetylcholine esterase inhibitor and method for the preparation thereof
WO2012088992A1 (fr) Procédé de préparation d'une préparation médicale solide et préparation de médicament solide obtenue à partir dudit procédé
JP7046978B2 (ja) 水溶解度及びバイオアベイラビリティが改善された組成物
WO2011079764A1 (fr) Formulation solide d'eszopiclone et son procédé de préparation
JP2022113667A (ja) エドキサバン含有医薬組成物
JP2023551917A (ja) 安定性及び生体利用効率が改善されたオラパリブ固体分散体組成物
WO2020111089A1 (fr) Composition pharmaceutique
CN108096251B (zh) 一种吉非替尼药物组合物及其制备方法
WO2011079767A1 (fr) Formulation solide de zopiclone et son procédé de préparation
US20130035344A1 (en) Pharmaceutical composition for oral administration
JPWO2019230937A1 (ja) 溶出性に優れた経口固形製剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10840556

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10840556

Country of ref document: EP

Kind code of ref document: A1