CN102106825A - Solid zopiclone preparation and preparation method thereof - Google Patents
Solid zopiclone preparation and preparation method thereof Download PDFInfo
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- CN102106825A CN102106825A CN200910247348XA CN200910247348A CN102106825A CN 102106825 A CN102106825 A CN 102106825A CN 200910247348X A CN200910247348X A CN 200910247348XA CN 200910247348 A CN200910247348 A CN 200910247348A CN 102106825 A CN102106825 A CN 102106825A
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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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- 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
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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 fugitive non-Benzodiazepines sedative hypnotics fast, can be used for the treatment of short-term or chronic insomnia.Clinical research is verified, takes the 3.75-7.5mg zopiclone at every turn, to starting sleep and keeping sleep quality curative effect is preferably arranged all.
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 defective such as the processing method of mechanical activation comminution exists that dust is many, contaminated environment and loss are big.More serious problem is, because the pharmaceutically active of zopiclone is than 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 quick hypnotic untoward reaction of operator, cause security incident.
In addition, the method that is extensive use of 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 this method pulverization process is still not ideal enough.
Because zopiclone is active high, in solid preparation content lower (≤10wt%), therefore in the technology that mechanical activation comminution is handled, 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 this method technological operation is loaded down with trivial details, can produce equally that dust is many, contaminated environment, loss is big and there are 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 preferable 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,, demand seeking a kind of above-mentioned defective that both can avoid the mechanical activation comminution processing method urgently, can guarantee the preparation method of the zopiclone solid preparation of various function admirables again at zopiclone.
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 big, there is serious potential safety hazard, and the still dissatisfactory defective of the dissolution characteristic of zopiclone solid pharmaceutical preparation, and provide a kind of operation easier, pollute littler, there is not aforementioned potential safety hazard, and can guarantee that the gained 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 afterwards in pelletization, reduction system acidity, and make medicine reply solid state, thus many defectives of having avoided mechanical activation comminution to handle.And the inventor is also unexpected to find that the prepared zopiclone solid preparation of this 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 acid liquid of pastille; Afterwards, with the acid liquid uniform mixing of basifier, adjuvant and described pastille, carry out wet granulation; Wherein, described basifier is to make the acidity of mixed liquor of the acid liquid of basifier and pastille with respect to the reagent of the acidity reduction of the acid liquid of pastille.
Among the present invention, described zopiclone is a 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 preferable is 2～10%.As required, except that zopiclone, also can add the other drug active component, be prepared as the zopiclone compound solid preparation.
Among the present invention, described acidulant is meant and can makes zopiclone 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 is meant and can coexists, 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, for example inorganic acid, inorganic in strong acid and the organic monoacid one or more, preferable 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-zopiclone and S-zopiclone in the zopiclone, select for use acid during as acidulant with optical activity, should select raceme (as DL-tartaric acid, DL-malic acid, DL-fumaric acid or DL-maleic acid), or D type acid (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 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 preferable minimum for this reason, and best is 1～1.05 times.The amount of the acidulant of solubilized zopiclone is with all multifactor relevant, and is relevant as the hydrion number that can combine with the basic center of zopiclone in acidulant kind, solvent species, the acidulant etc. and the acid liquid preparation condition of pastille (as temperature) etc.Wherein, described basic center be meant in the zopiclone can with bonded group of hydrion or position in the acidulant molecule.Therefore, above-mentioned minimum is meant that certain acidulant can be with the consoluet minimum of zopiclone under same solvent and the acid liquid preparation condition of pastille.Can determine this minimum by simple conventional method: under same solvent and the acid liquid preparation condition of pastille, adopt the consumption dissolving zopiclone that increases this acidulant gradually, when just dissolving fully, be minimum.The inventor gropes to draw through a large amount of experiments, and particularly, the molar ratio of acidulant and zopiclone is generally 0.8～1.5, and preferable is 0.9～1.2.
The present invention is preferred especially: 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.When being acidulant with hydrochloric acid, the acid liquid of the pastille 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 of medicament field according to its dissolubility to zopiclone, preferable is can be miscible with water organic solvent, as medicament field water-soluble alcohol kind solvent commonly used, 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 concentration of ethanol was preferable 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 preferable is 15～50%.
When the acid liquid of preparation pastille, can add some adjuvants, as the water-solubility carrier of binding agent, surfactant, solubilizing agent and solid dispersion etc.Preferable, 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 the acid liquid of gained pastille is carried out subsequent step, promptly, carry out wet granulation with basifier and adjuvant uniform mixing.Wherein, when adding the water-solubility carrier of solid dispersion and zopiclone in the acid solution that contains acidulant simultaneously, 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; The water-solubility carrier that can also add solid dispersion afterwards again in this solution, when addition was big, the acid liquid of gained pastille may be suspension or viscous solution form.The present invention especially preferably adds one or more in polyvidone, Polyethylene Glycol (preferred PEG400-8000), sodium lauryl sulphate, poloxamer, tween 80, polyoxyethylene castor oil, polyoxyethylene stearate 40 esters, beta-schardinger dextrin-, lactose, mannitol, sucrose and the maltose alcohol.The addition of described surfactant and/or solubilizing agent is preferable is 0.05～3 times of zopiclone quality.The addition of the water-solubility carrier of described solid dispersion is preferable 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, described basifier is meant the reagent of the acidity of the mixed liquor that can make basifier and the acid liquid of pastille with respect to the acidity reduction of the acid liquid of pastille, for example inorganic strong alkali (as sodium hydroxide), weak acid strong alkali salt are (as sodium carbonate, sodium hydrogen phosphate, and the conjugate base of organic monoacid (as sodium citrate, sodium tartrate, natrium malicum and sodium acetate etc.), or acidity is lower than the highly acid acidulant, and can with the right acid of its formation buffering.When being elected to the active faintly acid conjugate base of apparatus as basifier, should select raceme (as DL-sodium tartrate or DL-natrium malicum), or the conjugate base of D type acid (as D-sodium tartrate or D-natrium malicum), or the conjugate base content of D type acid is at least the mixture (account for 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 the acid of L type.According to this area general knowledge, described basifier should be pharmaceutically acceptable, and with the compatible reagent of zopiclone.
Preferable, the acidulant of the preferred following type of the present invention and the combination of basifier:
Class1: described acidulant is an inorganic acid, and described basifier is inorganic strong alkali, example hydrochloric acid and sodium hydroxide.
Type 2: described acidulant is an inorganic acid, and described basifier is an inorganic weak acid highly basic salt, example hydrochloric acid and sodium carbonate, or hydrochloric acid and sodium hydrogen phosphate.
Type 3: described acidulant is an inorganic acid, and described basifier is an 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 an organic monoacid, described basifier is the conjugate base of this organic monoacid, the buffering that acidulant and basifier are formed 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 an 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, 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 an inorganic acid, and described basifier is a weak acid, and can cushion right acid with its formation, 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 the acid liquid of basifier and the pastille at least amount with respect to the acidity reduction of the acid liquid of pastille.Preferable, the consumption of acidulant and basifier satisfies following relation: formula 1 income value is 0.1～1.5, and 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, as filler, binding agent, disintegrating agent and lubricant or the like.The content of described adjuvant can be selected according to the conventional knowledge in this area.Wherein, described filler is preferable is in lactose, microcrystalline Cellulose, pregelatinized Starch, starch, mannitol, sucrose and the maltose alcohol one or more.Described binding agent is preferable is in hypromellose, polyvidone and the methylcellulose one or more.Said disintegrating agent is preferable is in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone and the cross-linking sodium carboxymethyl cellulose one or more.Described lubricant is preferable 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 (as wobbler extruding, screw extrusion and rotation extruding etc.), stirs granulation, fluidized-bed spray granulation and centrifugal spray granulation etc. as extruding.
Preferable, described with the acid liquid uniform mixing of basifier, adjuvant and described pastille, the concrete operations of carrying out wet granulation are undertaken by in the following mode any: mode (1) is with basifier or contain the solution and the adjuvant uniform mixing of basifier, with the acid liquid uniform mixing of pastille, push and granulate or the stirring granulation again; Mode (2) is mixed the acid liquid of pastille and, basifier or the solution that contains basifier uniformly, granulation liquid, again this granulation liquid and adjuvant are pushed granulation, stirring granulation, fluidized-bed spray granulation or centrifugal spray granulation etc. afterwards; Mode (3) is mixed the acid liquid of pastille 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 is meant, by this area routine operation, with the solution of a small amount of solvent dissolving 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,, make other forms of zopiclone solid preparations such as tablet or capsule through further conventional steps.
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 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 makes 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 handles that zopiclone brought is seriously polluted, loss is big and potential safety hazard is serious, it is easy to operation, and the safety coefficient height 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, the bioavailability height, and individual variation is little.
(3) the zopiclone solid preparation that makes of preparation method of the present invention has preferable stability and uniformity of dosage units.
The specific embodiment
Further specify the present invention with embodiment below, 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 in zopiclone content, as the 2mg/ sheet, contains zopiclone 2mg in being meant 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 milligrams/sheet) prescription and preparation method
Embodiment 4 zopiclone sheets (2.5mg/ sheet) prescription and preparation method
Embodiment 5 zopiclone sheets (2.5 milligrams/sheet) prescription and preparation method
Embodiment 6 zopiclone sheets (2.5 milligrams/sheet) prescription and preparation method
Embodiment 7 zopiclone sheets (2.5 milligrams/sheet) prescription and preparation method
Embodiment 8 zopiclone sheets (3 milligrams/sheet) prescription and preparation method
Embodiment 9 zopiclone sheets (2.5 milligrams/sheet) prescription and preparation method
Embodiment 10 zopiclone sheets (7.5 milligrams/sheet) prescription and preparation method
Embodiment 11 zopiclone sheets (2.5 milligrams/sheet) prescription and preparation method
Embodiment 12 zopiclone sheets (2.5 milligrams/sheet) prescription and preparation method
Embodiment 13 zopiclone sheets (2.5 milligrams/sheet) prescription and preparation method
Embodiment 14 zopiclone sheets (2 milligrams/sheet) prescription and preparation method
Embodiment 15 zopiclone sheets (2.5 milligrams/sheet) prescription and preparation method
Embodiment 16 zopiclone sheets (2.5 milligrams/sheet) prescription and preparation method
Embodiment 17 zopiclone sheets (2.5 milligrams/sheet) prescription and preparation method
Embodiment 18 zopiclone sheets (2.5mg/ sheet) prescription and preparation method
Embodiment 19 zopiclone sheets (2 milligrams/sheet) prescription and preparation method
Embodiment 20 zopiclone capsules (2.5 milligrams/sheet) prescription and preparation method
Get the preceding granule of embodiment 15 tablettings and cross 30 mesh sieves, in the hard capsule of packing into.
Effect embodiment 1 dissolution comparative test
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), is a solvent with water 200ml, and rotating speed is that per minute 50 changes, operation in accordance with the law, and preparation contrast solution.Press ultraviolet visible spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2005), measure absorbance respectively, calculate every stripping quantity at the wavelength place of 304nm.
Effect embodiment 2 stable comparative tests
The zopiclone tablet of comparative example 1, embodiment 1,2 and 4 is put respectively in the high-density polyethylene plastics bottle, and sealing is put into and is quickened 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, solution in contrast with 0.02mol/L hydrochloric acid.According to ultraviolet visible spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2005 A), measure absorbance respectively 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 uniformity of dosage units inspection technique, measure every content (content assaying method is with effect embodiment 2), and calculate uniformity of dosage units (A+1.80S).
Claims (17)
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 acid liquid of pastille; Afterwards, with the acid liquid uniform mixing of basifier, adjuvant and described pastille, carry out wet granulation; Wherein, described basifier is to make the acidity of mixed liquor of the acid liquid of basifier and pastille with respect to the reagent of the acidity reduction of the acid liquid of pastille.
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, and preferable is 2～10%.
3. method as claimed in claim 1 or 2 is characterized in that: described acidulant is one or more in inorganic acid, inorganic middle strong acid and the organic monoacid,
Preferable 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;
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.
4. as each described method of claim 1～3, it is characterized in that: the consumption of described acidulant forms 1～1.2 times of minimum of the acid liquid of described pastille for making zopiclone dissolving, and better is 1～1.05 times.
5. 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, and better is 0.9～1.2.
6. method as claimed in claim 1 or 2 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.
7. as each described method of claim 1～6, it is characterized in that: described basifier is that the conjugate base or the acidity of inorganic strong alkali, weak acid strong alkali salt, organic monoacid is lower than the highly acid acidulant, and can cushion right acid with its formation;
One or more that preferable is in sodium hydroxide, sodium carbonate, sodium hydrogen phosphate, sodium citrate, sodium tartrate and natrium malicum, sodium acetate, glycine and the alanine;
The elected active faintly acid conjugate base 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 the acid of L type.
8. as each described method of claim 1～7, it is characterized in that: described acidulant and basifier are any in the following type:
Class1: described acidulant is an inorganic acid, and described basifier is an inorganic strong alkali;
Type 2: described acidulant is an inorganic acid, and described basifier is an inorganic weak acid highly basic salt;
Type 3: described acidulant is an inorganic acid, and described basifier is an organic monoacid highly basic salt;
Type 4: described acidulant is an organic monoacid, and described basifier is the conjugate base of this organic monoacid;
Type 5: described acidulant is an organic monoacid, and described basifier is inorganic strong alkali or inorganic weak acid highly basic salt; With
Type 6: described acidulant is an inorganic acid, and described basifier is a weak acid, and can cushion right acid with its formation;
Preferable, described acidulant and basifier are: 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.
9. method as claimed in claim 8 is characterized in that: the consumption of described acidulant and basifier satisfies following relation: formula 1 income value is 0.1～1.5, and 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 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.
10. method as claimed in claim 1 or 2 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.
11. as each described method of claim 1～10, it is characterized in that: the solvent in the described acid solution that contains acidulant is the mixed liquor of water or water and organic solvent; Described organic solvent is for being better than the medicament field acceptable solvent of water to the dissolubility of zopiclone;
What the mixed liquor of described water and organic solvent was preferable is the ethanol water of mass percent 10～50%.
12. as each described method of claim 1～11, 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, and better is 15～50%.
13. as each described method of claim 1～12, 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, with the acid liquid of gained pastille and basifier and adjuvant uniform mixing, carry out wet granulation then;
Wherein, when adding the water-solubility carrier of solid dispersion and zopiclone in the acid solution that contains acidulant simultaneously, 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;
In the water-solubility carrier of described surfactant, solubilizing agent and solid dispersion one or more are preferable is in polyvidone, Polyethylene Glycol, sodium lauryl sulphate, poloxamer, polyoxyethylene castor oil, polyoxyethylene stearate 40 esters, tween 80, beta-schardinger dextrin-, lactose, mannitol, sucrose and the maltose alcohol one or more.
14. as each described method of claim 1～13, 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.
15. as each described method of claim 1～14, it is characterized in that: described with basifier, adjuvant and the acid liquid uniform mixing of described pastille, the concrete operations mode of carrying out wet granulation is selected from any in the following manner:
Mode (1) is with basifier or contain the solution and the adjuvant uniform mixing of basifier, again with the acid liquid uniform mixing of pastille, pushes and granulates or stir and granulate;
Mode (2) is mixed the acid liquid of pastille and, basifier or the solution that contains basifier uniformly, granulation liquid, again this granulation liquid and adjuvant are pushed granulations, stirring granulation, fluidized-bed spray granulation or centrifugal spray granulation afterwards; With
Mode (3) is mixed the acid liquid of pastille uniformly with adjuvant, mixes uniformly with the solution that contains basifier more afterwards, pushes and granulates or the stirring granulation.
16. as each described method of claim 1～15, it is characterized in that: the zopiclone solid particle that will make as each described method of claim 1～15 through further conventional steps, makes zopiclone tablet or zopiclone capsule.
17. the zopiclone solid preparation that makes as each described method of claim 1～16.
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 |
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| Publication Number | Publication Date |
|---|---|
| CN102106825A true CN102106825A (en) | 2011-06-29 |
| CN102106825B 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) |
Family Cites Families (2)
| 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 |
| 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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- 2010-12-28 WO PCT/CN2010/080345 patent/WO2011079767A1/en active Application Filing
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| Publication number | Publication date |
|---|---|
| CN102106825B (en) | 2013-04-17 |
| 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. |