CN102106825B - Solid zopiclone preparation and preparation method thereof - Google Patents
Solid zopiclone preparation and preparation method thereof Download PDFInfo
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- CN102106825B CN102106825B CN200910247348XA CN200910247348A CN102106825B CN 102106825 B CN102106825 B CN 102106825B CN 200910247348X A CN200910247348X A CN 200910247348XA CN 200910247348 A CN200910247348 A CN 200910247348A CN 102106825 B CN102106825 B CN 102106825B
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- 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
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- 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
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- 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
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Abstract
The invention discloses a method for preparing a solid zopiclone preparation. The method comprises the following steps of: dissolving zopiclone into acid solution containing an acidulant to obtain medicament-containing acid solution; and uniformly mixing a basifier, excipients and the medicament-containing acid solution, and performing wet granulation, wherein the basifier is a reagent which ensures that the acidity of mixed solution of the basifier and the medicament-containing acid solution is reduced compared with the acidity of the medicament-containing acid solution. The invention also discloses the solid zopiclone preparation prepared by the method. The method overcomes the disadvantages of serious pollution, high loss and serious potential safety hazards caused by mechanical pulverization treatment, is convenient and easy to operate, has high safety factor, and is easily applied to industrialized production. The solid zopiclone preparation prepared by the method has excellent dissolution characteristic, stability and content uniformity.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly a kind of zopiclone solid preparation and preparation method thereof.
Background technology
Zopiclone (zopiclone), molecular weight 388.81 belongs to weak base compound, and slightly soluble in water for a kind of quick fugitive Non-benzodiazepine sedative hypnotics, can be used for the treatment of short-term or chronic insomnia.Clinical research is verified, each serving using the 3.75-7.5mg zopiclone, to starting sleep and keeping sleep quality preferably curative effect is arranged.
Zopiclone is slightly soluble in water, therefore needs when the preparation solid preparation zopiclone to be crushed to certain fineness, can rapid stripping after oral to guarantee this solid preparation.At present, mechanical crushing method is generally all adopted in the pulverizing of zopiclone.But the defective such as the processing method of mechanical activation comminution exists that dust is many, contaminated environment and loss are large.More serious problem is, because the pharmaceutically active of zopiclone is higher, the zopiclone powder that sucks than low dosage can produce hypnotic effect fast, when carrying out the mechanical activation comminution processing, very easily cause the untoward reaction of the quick hypnosis of operator, cause security incident.
In addition, the method that is widely used mechanical activation comminution is at present pulverized active constituents of medicine, the Universalpulverizer of employing as usual, and the particle diameter after the pulverization process generally reaches about 100 microns.Dissolution characteristic by the solid preparation that makes after the method pulverization process is still not ideal enough.
Because zopiclone is active high, in solid preparation content lower (≤10wt%), therefore in the technique that mechanical activation comminution is processed, also relate to the dispersing uniformity problem of itself and mixed with excipients.Usually, adopt active constituents of medicine and excipient equivalent are diluted the method that progressively enlarges, so that zopiclone is uniformly dispersed in solid preparation.But the method technological operation is loaded down with trivial details, can produce equally that dust is many, contaminated environment, loss is large and there are the problems such as potential safety hazard in labor protection.
In addition, the preparation of solid preparation also need consider the various performances of product whether can satisfy the medicament field requirement.For example, whether can guarantee better uniformity of dosage units.Again for example, stability is the investigation emphasis of solid preparation quality, it is included in solid preparation in storage period, and whether content, solid preparation property stability and the stripping stability etc. of the chemical stability of active constituents of medicine, related substance (being impurity) are in the drug standard limit.
Therefore, for zopiclone, demand seeking a kind of defects that both can avoid the mechanical activation comminution processing method urgently, can guarantee again the preparation method of the zopiclone solid preparation of various function admirables.
Summary of the invention
Technical problem to be solved by this invention is to select to control the particle diameter of zopiclone by the mode of mechanical activation comminution in order to overcome existing zopiclone solid preparation preparation method, can cause environmental pollution, loss is large, there is serious potential safety hazard, and the dissolution characteristic of zopiclone solid pharmaceutical preparation is dissatisfactory defective still, and provide a kind of operation easier, pollute less, there is not aforementioned potential safety hazard, and can guarantee that solid preparation has excellent dissolution characteristic, the preparation method of stability and uniformity of dosage units, and zopiclone solid preparation obtained by this method.
For solving the problems of the technologies described above, the inventor looks for another way, unique employing acid leach solution zopiclone, and in pelletization, the reduction system is acid afterwards, and makes medicine reply solid state, thus many defectives of having avoided mechanical activation comminution to process.And the inventor is unexpected the discovery also, and the prepared zopiclone solid preparation of the method has excellent dissolution characteristic, stability and uniformity of dosage units.
Preparation method of the present invention comprises the steps: zopiclone is dissolved in the acid solution that contains acidulant, makes the pastille Acidic Liquid; Afterwards, basifier, adjuvant and described pastille Acidic Liquid are evenly mixed, carry out wet granulation; Wherein, described basifier is the reagent that the acidity of the mixed liquor of basifier and pastille Acidic Liquid is reduced with respect to the acidity of pastille Acidic Liquid.
Among the present invention, described zopiclone is slightly water-soluble alkalescence active medicine, and its consumption is determined according to the customary amount of zopiclone in solid preparation, is generally the mass percent 0.5～15% of wet granulation dry material, and better is 2～10%.As required, except zopiclone, also can add the other drug active component, be prepared as the zopiclone compound solid preparation.
Among the present invention, described acidulant refers to make zopiclone to be dissolved in acid reagent in the acid solution that contains acidulant fully.According to this area general knowledge, described acidulant should be pharmaceutically acceptable, and with the compatible reagent of zopiclone.Among the present invention, described compatibility refers to and can coexist, has no adverse effects.Described acidulant can be single acidulant, also can be the compound acidulant that two or more one-tenth are grouped into, can be selected from various acid, one or more in inorganic acid, inorganic middle strong acid and the organic monoacid for example, better be selected from citric acid, hydrochloric acid, tartaric acid, malic acid, fumaric acid, succinic acid, maleic acid, lactic acid, acetic acid and the phosphoric acid one or more, better is citric acid, hydrochloric acid, malic acid or tartaric acid, and best is citric acid.Because the nature difference of R-ZPC and S-ZPC in the zopiclone, select the acid with optical activity during as acidulant, should select raceme (such as DL-tartaric acid, DL-malic acid, DL-fumaric 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 is at least the D type of mass percent 50% and the mixture of L-type acid (acid accounts for the D type of the following acid more than 50% and the mixture of L-type such as the D type: tartaric acid, malic acid, fumaric acid or maleic acid).
The consumption of described acidulant is at least and can makes the consoluet minimum of zopiclone, 1～1.2 times of better for this reason minimum, and best is 1～1.05 times.The amount of the acidulant of solubilized zopiclone is relevant with factors, and is relevant such as the hydrion number that can combine with the basic center of zopiclone in acidulant kind, solvent species, the acidulant etc. and pastille Acidic Liquid preparation condition (such as temperature) etc.Wherein, described basic center refer in the zopiclone can hydrion be combined in the acidulant molecule group or position.Therefore, above-mentioned minimum refers to that under same solvent and pastille Acidic Liquid preparation condition, certain acidulant can be with the consoluet minimum of zopiclone.Can determine this minimum by simple conventional method: under same solvent and pastille Acidic Liquid preparation condition, adopt the consumption dissolving zopiclone that increases gradually this acidulant, when just dissolving fully, be minimum.The inventor gropes to draw through great many of experiments, and particularly, the molar ratio of acidulant and zopiclone is generally 0.8～1.5, and better is 0.9～1.2.
The present invention is particularly preferably: the citric acid that the zopiclone mole is 0.9～1.1 times, or the hydrochloric acid of 0.95～1.2 times of zopiclone mole.During take hydrochloric acid as acidulant, the pastille Acidic Liquid of preparation can form colloid solution after placing, this colloid solution can be carried out the granulation of subsequent step.
Among the present invention, the solvent in the described acid solution that contains acidulant can be the mixed liquor of water or water and organic solvent, preferred water.Described organic solvent is better than the principle of water and selects in the acceptable solvent in medicament field according to its dissolubility to zopiclone, better is can be miscible with water organic solvent, such as medicament field water-soluble alcohol kind solvent commonly used, such as ethanol, propylene glycol, glycerol, acetone, isopropyl alcohol and the tert-butyl alcohol etc., preferred alcohol.In the mixed liquor of water and organic solvent, the consumption of organic solvent can be selected arbitrarily.When using ethanol water as solvent, what the concentration of ethanol was better is mass percent 10～50%.The consumption of solvent is at least the required granulation liquid minimum of wet granulation and is as the criterion in the described acid solution, is generally the mass percent 5～100% of wet granulation dry material, and better is 15～50%.
When preparation pastille Acidic Liquid, can add some adjuvants, such as the water-solubility carrier of binding agent, surfactant, solubilizing agent and solid dispersion etc.Better, when zopiclone being dissolved in the acid solution that contains acidulant and/or afterwards, also add in the water-solubility carrier of surfactant, solubilizing agent and solid dispersion one or more, then gained pastille Acidic Liquid is carried out subsequent step, namely evenly mix with basifier and adjuvant, carry out wet granulation.Wherein, when adding simultaneously the water-solubility carrier of solid dispersion and zopiclone in the acid solution that contains acidulant, the amount of the water-solubility carrier of the solid dispersion that add this moment need be controlled at and can guarantee that zopiclone is dissolved in below the amount in the acid solution that contains acidulant fully; Afterwards can also be again add the water-solubility carrier of solid dispersion in this solution, when addition was larger, gained pastille Acidic Liquid may be suspension or viscous solution form.The present invention particularly preferably adds one or more in polyvidone, Polyethylene Glycol (preferred PEG400-8000), sodium lauryl sulphate, poloxamer, tween 80, polyoxyethylene castor oil, s6, beta-schardinger dextrin-, lactose, mannitol, sucrose and the maltose alcohol.The addition of described surfactant and/or solubilizing agent is better is 0.05～3 times of zopiclone quality.The addition of the water-solubility carrier of described solid dispersion is better is 1～10 times of zopiclone quality.Press aforesaid operations and add surfactant and/or solubilizing agent, can increase the dissolubility of zopiclone in acid solution, reduce solvent load, be beneficial to the operation of follow-up granulation step.It will be further appreciated that press in the water-solubility carrier that aforesaid operations adds surfactant, solubilizing agent and solid dispersion one or more, it is better that especially the water-solubility carrier of solid dispersion can make the dissolution characteristic of gained zopiclone solid preparation.
Among the present invention, the reagent that described basifier refers to make the acidity of the mixed liquor of basifier and pastille Acidic Liquid to reduce with respect to the acidity of pastille Acidic Liquid, for example inorganic strong alkali (such as sodium hydroxide), weak acid strong alkali salt are (such as sodium carbonate, sodium hydrogen phosphate, and the conjugate base of organic monoacid (such as sodium citrate, sodium tartrate, natrium malicum and sodium acetate etc.), or acidity is lower than the highly acid acidulant, and acid that can be right with its formation buffering.The conjugate base of the elected active weak acid of apparatus is during as basifier, should select raceme (such as DL-sodium tartrate or DL-natrium malicum), or the conjugate base of D type acid (such as D-sodium tartrate or D-malic acid sodium), or the conjugate base content of D type acid is at least the mixture (account for such as the D type mixture of the conjugate base of following D type more than 50% and L-type: sodium tartrate, natrium malicum, fumaric acid sodium or Monosodium maleate) of the conjugate base of the D type of mass percent 50% and L-type acid.According to this area general knowledge, described basifier should be pharmaceutically acceptable, and with the compatible reagent of zopiclone.
Better, the acidulant of the preferred following type of the present invention and the combination of basifier:
Class1: described acidulant is inorganic acid, and described basifier is inorganic strong alkali, example hydrochloric acid and sodium hydroxide.
Type 2: described acidulant is inorganic acid, and described basifier is inorganic weak acid highly basic salt, example hydrochloric acid and sodium carbonate, or hydrochloric acid and sodium hydrogen phosphate.
Type 3: described acidulant is inorganic acid, and described basifier is organic monoacid highly basic salt, example hydrochloric acid and sodium citrate, hydrochloric acid and DL-sodium tartrate, or hydrochloric acid and DL-natrium malicum.
Type 4: described acidulant is organic monoacid, described basifier is the conjugate base of this organic monoacid, the buffering that acidulant and basifier form conjugate acid and base each other is right, for example the buffering of its corresponding conjugate base composition of citric acid, DL-tartaric acid or DL-malic acid is right, and preferably citric acid and sodium citrate buffering are right.
Type 5: described acidulant is organic monoacid, and described basifier is inorganic strong alkali or inorganic weak acid highly basic salt, and it is right that acidulant and basifier form buffering, such as citric acid and sodium carbonate, D-malic acid and sodium carbonate, DL-malic acid and sodium hydrogen phosphate, or citric acid and sodium hydrogen phosphate.
Type 6: described acidulant is inorganic acid, and described basifier is weak acid, and acid that can be right with its formation buffering, for example, and hydrochloric acid and glycine, hydrochloric acid and alanine.
The amount of described basifier is the acidity of the mixed liquor that can make at least basifier and the pastille Acidic Liquid amount with respect to the acidity reduction of pastille Acidic Liquid.Better, the consumption of acidulant and basifier satisfies following relation: formula 1 income value is 0.1～1.5, better is 0.3～1.2.
(basifier molal quantity * A)/(the formula 1 of acidulant molal quantity * B)
Wherein, when acidulant and basifier be Class1,2 or 5 the time, A is the hydrion number in the several basifier molecules of the total valence state of basifier molecular anion;
When acidulant and basifier be Class1,2,3 or 6 the time, B is the hydrion number in the acidulant molecule;
When acidulant and basifier were type 4, A/B was 1;
When acidulant and basifier were type 5, B was 1;
When acidulant and basifier were type 3 or 6, A was 1.
The present invention is most preferably: formula 1 value is 0.6～1.2 citric acid and sodium citrate, and formula 1 value is 0.1～1 hydrochloric acid and sodium carbonate, or formula 1 value is 0.1～1 hydrochloric acid and sodium hydroxide.
Among the present invention, described adjuvant can be selected from any known and widely used adjuvant in this area, such as filler, binding agent, disintegrating agent and lubricant etc.The content of described adjuvant can be selected according to the conventional knowledge in this area.Wherein, described filler is better is in lactose, microcrystalline Cellulose, pregelatinized Starch, starch, mannitol, sucrose and the maltose alcohol one or more.Described binding agent is better is in hypromellose, polyvidone and the methylcellulose one or more.Said disintegrating agent is better is in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone and the cross-linking sodium carboxymethyl cellulose one or more.Described lubricant is better is in colloidal silica, sodium stearyl fumarate, Pulvis Talci and the magnesium stearate one or more.The content of described adjuvant can be selected according to the conventional knowledge in this area.
Among the present invention, described wet granulation can carry out according to conventional steps and condition that this area belongs to the various method of granulating of wet granulation category, granulates (such as wobbler extruding, screw extrusion and rotary squeezing etc.), stirs granulation, fluidized-bed spray granulation and centrifugal spray granulation etc. such as extruding.
Better, described basifier, adjuvant and described pastille Acidic Liquid are evenly mixed, the concrete operations of carrying out wet granulation are undertaken by in the following mode any: mode (1) is evenly mixed basifier or the solution and the adjuvant that contain basifier, evenly mix with the pastille Acidic Liquid again, push and granulate or the stirring granulation; Mode (2) is mixed pastille Acidic Liquid and, basifier or the solution that contains basifier uniformly, gets granulation liquid, this granulation liquid and adjuvant is pushed afterwards granulation, stirring granulation, fluidized-bed spray granulation or centrifugal spray granulation etc. again; Mode (3) is mixed the pastille Acidic Liquid uniformly with adjuvant, mixes uniformly with the solution that contains basifier more afterwards, pushes and granulates or the stirring granulation.The described solution that contains basifier refers to, by this area routine operation, with the solution of a small amount of dissolution with solvents basifier gained, conveniently to carry out the mixing step; Described solvent can be the mixed liquor of water or water and organic solvent.Described organic solvent is with aforementioned.
After wet granulation is finished, can directly obtain the zopiclone solid particle preparation, also can be used as the preparation intermediate, through further conventional steps, make the other forms of zopiclone solid preparations such as tablet or capsule.
Among the present invention, above-mentioned each optimum condition, can be on the basis that meets this area general knowledge combination in any, get final product to get the preferred embodiments of the invention.
Among the present invention, agents useful for same and raw material can get by commercially available, and the part material medicine can be according to existing literature method preparation.
Further, the invention still further relates to the zopiclone solid preparation that is made by said method.
Positive progressive effect of the present invention is:
(1) defective that preparation method of the present invention has avoided that mechanical activation comminution processes that zopiclone brings is seriously polluted, loss is large and potential safety hazard is serious, it is easy to operation, and safety coefficient is high, easily is applied to suitability for industrialized production.
(2) dissolution characteristic of the zopiclone solid preparation that makes of preparation method of the present invention increases significantly than prior art, and bioavailability is high, and individual variation is little.
(3) the zopiclone solid preparation that makes of preparation method of the present invention has better stability and uniformity of dosage units.
The specific embodiment
The below further specifies the present invention with embodiment, but the present invention is not limited.
The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
The dosage form specification is with the zopiclone content meter, such as the 2mg/ sheet, contains zopiclone 2mg in referring to every.
Consumption unit is gram, and percentage ratio is mass percent.
The mass percent of zopiclone and solvent is the mass percent that accounts for the wet granulation dry material.Wherein, solvent comprises the water in the aqueous solution of acidulant and basifier.
Comparative example 1 and embodiment 1 zopiclone sheet (3.75mg/ sheet) prescription and preparation method
Embodiment 2 zopiclone sheets (2.5mg/ sheet) prescription and preparation method
Embodiment 3 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 4 zopiclone sheets (2.5mg/ sheet) prescription and preparation method
Embodiment 5 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 6 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 7 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 8 zopiclone sheets (3 milli g/piece) prescription and preparation method
Embodiment 9 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 10 zopiclone sheets (7.5 milli g/piece) prescription and preparation method
Embodiment 11 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 12 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 13 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 14 zopiclone sheets (2 milli g/piece) prescription and preparation method
Embodiment 15 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 16 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 17 zopiclone sheets (2.5 milli g/piece) prescription and preparation method
Embodiment 18 zopiclone sheets (2.5mg/ sheet) prescription and preparation method
Embodiment 19 zopiclone sheets (2 milli g/piece) prescription and preparation method
Embodiment 20 zopiclone capsules (2.5 milli g/piece) prescription and preparation method
Get the front granule of embodiment 15 tablettings and cross 30 mesh sieves, in the hard capsule of packing into.
Effect embodiment 1 Comparative Study on Dissolution
Sample: comparative example 1, embodiment 1～5 and 18 zopiclone tablet
Dissolution determination method: sample thief, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C three therapeutic methods of traditional Chinese medicine), take water 200ml as solvent, rotating speed is that per minute 50 turns, in accordance with the law operation, and preparation contrast solution.Press ultraviolet visible spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2005), measure respectively absorbance at the wavelength place of 304nm, calculate every stripping quantity.
Effect embodiment 2 stable comparative tests
Comparative example 1, embodiment 1,2 and 4 zopiclone tablet are set high respectively in the density polyethylene plastic bottle, and sealing is put into and is accelerated to investigate case, and in 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% condition is carried out study on the stability.
Content assaying method: get this product an amount of (being equivalent to zopiclone 3mg), put in the 250ml measuring bottle, it is an amount of to add 0.02mol/L hydrochloric acid, shakes up, and filters, and gets subsequent filtrate as need testing solution; It is an amount of that other gets the zopiclone reference substance, makes the solution that contains 12 μ g among every 1ml, in contrast solution with 0.02mol/L hydrochloric acid.According to ultraviolet visible spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2005 A), measure respectively absorbance at the wavelength place of 304nm, calculate content.
Dissolution determination method is with effect embodiment 1.
The determination of related substances method: measuring according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005), is filler with octadecylsilane chemically bonded silica; The detection wavelength is 304nm.The chromatogram of need testing solution and contrast solution chromatogram are relatively.
The experiment of effect embodiment 3 uniformity of dosage units
According to Chinese Pharmacopoeia version appendix in 2005 XE Content uniformity test, measure every content (content assaying method is with effect embodiment 2), and calculate uniformity of dosage units (A+1.80S).
Claims (23)
1. the preparation method of a zopiclone solid preparation is characterized in that it comprises the steps: zopiclone is dissolved in the acid solution that contains acidulant, makes the pastille Acidic Liquid; Afterwards, basifier, adjuvant and described pastille Acidic Liquid are evenly mixed, carry out wet granulation; Wherein, described basifier is the reagent that the acidity of the mixed liquor of basifier and pastille Acidic Liquid is reduced with respect to the acidity of pastille Acidic Liquid, and described basifier is one or more in sodium hydroxide, sodium carbonate, sodium hydrogen phosphate, sodium citrate, sodium tartrate, natrium malicum, sodium acetate, glycine and the alanine; Described acidulant is one or more in citric acid, hydrochloric acid, malic acid or the tartaric acid; Solvent in the described acid solution that contains acidulant is the mixed liquor of water or water and organic solvent, and described organic solvent is ethanol;
The consumption of described acidulant and basifier satisfies following relation: formula 1 income value is 0.1～1.5;
(basifier molal quantity * A)/(the formula 1 of acidulant molal quantity * B)
Wherein, when acidulant and basifier be Class1,2 or 5 the time, A is the hydrion number in the total valence state number of basifier molecular anion-basifier molecule;
When acidulant and basifier be Class1,2,3 or 6 the time, B is the hydrion number in the acidulant molecule;
When acidulant and basifier were type 4, A/B was 1;
When acidulant and basifier were type 5, B was 1;
When acidulant and basifier were type 3 or 6, A was 1;
Wherein, described type is:
Class1: described acidulant is inorganic acid, and described basifier is inorganic strong alkali;
Type 2: described acidulant is inorganic acid, and described basifier is inorganic weak acid highly basic salt;
Type 3: described acidulant is inorganic acid, and described basifier is organic monoacid highly basic salt;
Type 4: described acidulant is organic monoacid, and described basifier is the conjugate base of this organic monoacid;
Type 5: described acidulant is organic monoacid, and described basifier is inorganic strong alkali or inorganic weak acid highly basic salt; With
Type 6: described acidulant is inorganic acid, and described basifier is weak acid, and acid that can be right with its formation buffering.
2. the method for claim 1, it is characterized in that: the consumption of described zopiclone is the mass percent 0.5～15% of wet granulation dry material.
3. method as claimed in claim 2, it is characterized in that: the consumption of described zopiclone is that the mass percent of wet granulation dry material is 2～10%.
4. method as claimed in claim 1 or 2 is characterized in that: when acidulant is when having optical activity sour, should select raceme, or the acid of D type, or D type acid content is at least the D type of mass percent 50% and the mixture of L-type acid.
5. such as each described method of claim 1～3, it is characterized in that: the consumption of described acidulant is for making zopiclone dissolving form 1～1.2 times of minimum of described pastille Acidic Liquid.
6. method as claimed in claim 5 is characterized in that: the consumption of described acidulant is for making the zopiclone dissolving form 1～1.05 times of minimum of described pastille Acidic Liquid.
7. such as each described method of claim 1～3, it is characterized in that: the molar ratio of described acidulant and zopiclone is 0.8～1.5.
8. method as claimed in claim 7, it is characterized in that: the molar ratio of described acidulant and zopiclone is 0.9～1.2.
9. method as claimed in claim 1 or 2, it is characterized in that: described acidulant is the citric acid of 0.9～1.1 times of zopiclone mole, or the hydrochloric acid of 0.95～1.2 times of zopiclone mole.
10. such as each described method of claim 1～3, it is characterized in that: described basifier is that conjugate base or the acidity of inorganic strong alkali, weak acid strong alkali salt, organic monoacid is lower than the highly acid acidulant, and acid that can be right with its formation buffering.
11. the method such as claim 10 is characterized in that:
The conjugate base of the elected active weak acid of apparatus should be selected raceme during as basifier, or the conjugate base of D type acid, or the conjugate base content of D type acid is at least the mixture of the conjugate base of the D type of mass percent 50% and L-type acid.
12. the method for claim 1, it is characterized in that: described acidulant and basifier are any in the following type: hydrochloric acid and sodium hydroxide, hydrochloric acid and sodium carbonate, hydrochloric acid and sodium hydrogen phosphate, hydrochloric acid and sodium citrate, hydrochloric acid and sodium tartrate, hydrochloric acid and natrium malicum, citric acid and sodium citrate, DL-tartaric acid and DL-sodium tartrate, DL-malic acid and DL-natrium malicum, citric acid and sodium carbonate, D-malic acid and sodium carbonate, DL-malic acid and sodium hydrogen phosphate, citric acid and sodium hydrogen phosphate, hydrochloric acid and glycine, or hydrochloric acid and alanine.
13. the method for claim 1 is characterized in that: the consumption of described acidulant and basifier satisfies following relation: formula 1 income value is 0.3～1.2.
14. the method for claim 1 is characterized in that: described acidulant and basifier are that formula 1 value is 0.6～1.2 citric acid and sodium citrate, and formula 1 value is 0.1～1 hydrochloric acid and sodium carbonate, or formula 1 value is 0.1～1 hydrochloric acid and sodium hydroxide.
15. such as each described method of claim 1～3, it is characterized in that:
The mixed liquor of described water and organic solvent is the ethanol water of mass percent 10～50%.
16. such as each described method of claim 1～3, it is characterized in that: the consumption of solvent is the mass percent 5～100% of wet granulation dry material in the described acid solution.
17. method as claimed in claim 16 is characterized in that: the consumption of solvent is the mass percent 15～50% of wet granulation dry material in the described acid solution.
18. such as each described method of claim 1～3, it is characterized in that: described zopiclone is dissolved in the acid solution that contains acidulant in and/or afterwards, also add in the water-solubility carrier of surfactant, solubilizing agent and solid dispersion one or more, then gained pastille Acidic Liquid is evenly mixed with basifier and adjuvant, carry out wet granulation;
Wherein, when adding simultaneously the water-solubility carrier of solid dispersion and zopiclone in the acid solution that contains acidulant, the amount of the water-solubility carrier of the solid dispersion that add this moment need be controlled at and can guarantee that zopiclone is dissolved in below the amount in the acid solution that contains acidulant fully.
19. method as claimed in claim 18 is characterized in that: one or more in the water-solubility carrier of described surfactant, solubilizing agent and solid dispersion are one or more in polyvidone, Polyethylene Glycol, sodium lauryl sulphate, poloxamer, polyoxyethylene castor oil, s6, tween 80, beta-schardinger dextrin-, lactose, mannitol, sucrose and the maltose alcohol.
20. such as each described method of claim 1～3, it is characterized in that: the addition of described surfactant and/or solubilizing agent is 0.05～3 times of zopiclone quality; The addition of the water-solubility carrier of described solid dispersion is 1～10 times of zopiclone quality.
21. such as each described method of claim 1～3, it is characterized in that: described basifier, adjuvant and described pastille Acidic Liquid are evenly mixed, the concrete operations mode of carrying out wet granulation is selected from any in the following manner:
Mode (1) is evenly mixed basifier or the solution and the adjuvant that contain basifier, evenly mixes with the pastille Acidic Liquid again, pushes to granulate or stir and granulate;
Mode (2) is mixed pastille Acidic Liquid and, basifier or the solution that contains basifier uniformly, gets granulation liquid, this granulation liquid and adjuvant is pushed afterwards granulations, stirring granulation, fluidized-bed spray granulation or centrifugal spray granulation again; With
Mode (3) is mixed the pastille Acidic Liquid uniformly with adjuvant, mixes uniformly with the solution that contains basifier more afterwards, pushes and granulates or the stirring granulation.
22. such as each described method of claim 1～3, it is characterized in that: the zopiclone solid particle that will make such as each described method of claim 1～3 through further conventional steps, makes zopiclone tablet or zopiclone capsule.
23. the zopiclone solid preparation that makes such as each described method of claim 1～22.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910247348XA CN102106825B (en) | 2009-12-29 | 2009-12-29 | Solid zopiclone preparation and preparation method thereof |
| PCT/CN2010/080345 WO2011079767A1 (en) | 2009-12-29 | 2010-12-28 | Solid formulation of zopiclone and the preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910247348XA CN102106825B (en) | 2009-12-29 | 2009-12-29 | Solid zopiclone preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102106825A CN102106825A (en) | 2011-06-29 |
| CN102106825B true CN102106825B (en) | 2013-04-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910247348XA Active CN102106825B (en) | 2009-12-29 | 2009-12-29 | Solid zopiclone preparation and preparation method thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102106825B (en) |
| WO (1) | WO2011079767A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1418631A (en) * | 2002-12-19 | 2003-05-21 | 王登之 | Zopiclone oral disintegrant for treating insomnia, and its prepn. method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7611728B2 (en) * | 2003-09-05 | 2009-11-03 | Supernus Pharmaceuticals, Inc. | Osmotic delivery of therapeutic compounds by solubility enhancement |
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2009
- 2009-12-29 CN CN200910247348XA patent/CN102106825B/en active Active
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2010
- 2010-12-28 WO PCT/CN2010/080345 patent/WO2011079767A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1418631A (en) * | 2002-12-19 | 2003-05-21 | 王登之 | Zopiclone oral disintegrant for treating insomnia, and its prepn. method |
Non-Patent Citations (2)
| Title |
|---|
| 张汝华等.制片工艺对药物溶出的影响.《工业药剂学》.中国医药科技出版社,2001,第336-338页. * |
| 陈优生等.提高难溶性药物溶解度的研究.《海峡药学》.2008,第25-27页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102106825A (en) | 2011-06-29 |
| WO2011079767A1 (en) | 2011-07-07 |
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Address after: 201806, Shanghai, Jiading District outer Pine Road No. 446 Patentee after: Shanghai Chinese Medicine Pharmaceutical Co. Ltd. Patentee after: Shanghai Zhongxi Sunve Pharmaceutical Co., Ltd. Address before: 201806, Shanghai, Jiading District outer Pine Road No. 446 Patentee before: Shanghai Zhongxi Pharmaceutical Co., Ltd. Patentee before: Shanghai Zhongxi Sunve Pharmaceutical Co., Ltd. |