CN102106826B - Aripiprazole solid preparation and preparation method thereof - Google Patents
Aripiprazole solid preparation and preparation method thereof Download PDFInfo
- Publication number
- CN102106826B CN102106826B CN2009102473507A CN200910247350A CN102106826B CN 102106826 B CN102106826 B CN 102106826B CN 2009102473507 A CN2009102473507 A CN 2009102473507A CN 200910247350 A CN200910247350 A CN 200910247350A CN 102106826 B CN102106826 B CN 102106826B
- Authority
- CN
- China
- Prior art keywords
- aripiprazole
- acidulant
- basifier
- acid
- sodium
- Prior art date
- Legal status (The legal status 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 status listed.)
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- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims abstract description 199
- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 199
- 238000002360 preparation method Methods 0.000 title claims abstract description 109
- 239000007787 solid Substances 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 62
- 239000008187 granular material Substances 0.000 claims abstract description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 104
- 239000007788 liquid Substances 0.000 claims description 77
- 230000002378 acidificating effect Effects 0.000 claims description 72
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 72
- 235000010603 pastilles Nutrition 0.000 claims description 72
- 239000002904 solvent Substances 0.000 claims description 55
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 53
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 52
- 239000002671 adjuvant Substances 0.000 claims description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 38
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 32
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 20
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- 229930195725 Mannitol Natural products 0.000 claims description 18
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 18
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- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 claims description 6
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- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
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- 230000003518 presynaptic effect Effects 0.000 description 1
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- 229940097325 prolactin Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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Abstract
The invention discloses the preparation method of aripiprazole solid preparation. The method comprises the following steps of dissolving aripiprazole into acidic solution containing an acidifying agent to obtain medicine-containing acidic solution; and then uniformly mixing accessory with the medicine-containing acidic solution to granulate by a wet method. The invention also discloses aripiprazole solid preparation prepared by the method. According to the method disclosed by the invention, the defects of the serious pollution, high loss and serous potential safety hazards brought by mechanical crushing treatment are avoided; and the method is simple, convenient and feasible for operation and easy for industrial production and has high safety coefficient. The aripiprazole solid preparation prepared by the method has the advantages of excellent dissolution property, stability, and content uniformity.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly a kind of Aripiprazole solid preparation and preparation method thereof.
Background technology
Aripiprazole, chemical name 7-[4-[4-(2,3-Dichlorobenzene base)-1-piperazinyl] butoxy]-3,4-dihydro-2 (1 hydrogen)-quinolinone, molecular weight 448.39 belongs to (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide.It is by the exploitation of Japan large tomb company, and head obtains the drugs approved by FDA listing in November, 2002.Aripiprazole is atypical antipsychotic agents, and it has presynaptic dopamine excitement and postsynaptic dopamine D
2The effect of antagonist is with 5-HT
1aAcceptor portion agonism and 5-HT
2Receptor antagonism.Clinical experimental study shows, Aripiprazole all is significantly improved effect to the schizoid positive and negative symptoms, and schizoid relapse rate is reduced, and extrapyramidal system side reaction and the effect of putting on weight are very little, do not cause the rising of Serum Prolactin Level yet, its better tolerance importantly, only find in research small number of patients due to side reaction stopped treatment.
The water solublity of Aripiprazole is relatively poor, therefore at the preparation solid preparation, during as tablet or capsule, need it is crushed to certain fineness, with guarantee this solid preparation oral after stripping rapidly, guarantee absorbance and bioavailability.At present, mechanical crushing method is substantially all adopted in the pulverizing of Aripiprazole.But the processing method of mechanical activation comminution exists that dust is many, contaminated environment and the defective such as loss is large.More serious problem is, because the pharmaceutically active of Aripiprazole is higher, carrying out mechanical activation comminution when processing, and operator very easily occurs suck the Aripiprazole powder and cause headache, the untoward reaction such as drowsiness, and suction for a long time will produce more serious consequence.
In addition, the method that is widely used mechanical activation comminution is at present pulverized active constituents of medicine, and the Universalpulverizer of employing as usual, the particle diameter after pulverization process generally reach 100 microns left and right.Dissolution characteristic by the solid preparation that makes after the method pulverization process is still not ideal enough.
Because the Aripiprazole activity is high, content is lower (general≤as 10wt%), therefore in the technique that mechanical activation comminution is processed, also to relate to the dispersing uniformity problem of itself and mixed with excipients in solid preparation.Usually, adopt active constituents of medicine and excipient equivalent are diluted the method that progressively enlarges, so that Aripiprazole 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.
At present, bibliographical information is arranged on-mechanical process the method reduce the Aripiprazole particle diameter.Chinese patent application CN1871007A discloses a kind of the utilization and has clashed into the standby particle mean size of jet crystallization legal system less than the method for the aseptic shot Aripiprazole of 100 microns, the aseptic shot Aripiprazole that the method makes also can be used for preparing injection Aripiprazole aqueous suspension preparation for the preparation of aseptic cryodesiccated aripiprazole formulations.Chinese patent application CN101066267A discloses and has utilized recrystallization acquisition mean diameter to be no more than the Aripiprazole of 50 microns, and filtration drying, mix the method that makes solid preparation with adjuvant afterwards.But still there is contaminated environment in said method complex operation, and contain the solid preparation of adjuvant for preparation, loss is large, dust is many and to problems such as labor protection requirement height.
Therefore, for Aripiprazole, 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 Aripiprazole 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 Aripiprazole by the mode of mechanical activation comminution in order to overcome existing Aripiprazole solid preparation preparation method, can cause environmental pollution, loss is large, there is serious potential safety hazard, and the dissolution characteristic of Aripiprazole solid pharmaceutical preparation is dissatisfactory defective still, and provide a kind of operation easier, pollute less, there is no 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 Aripiprazole solid preparation obtained by this method.
For solving the problems of the technologies described above, the inventor looks for another way, and unique employing acid leach solution Aripiprazole in pelletization, makes medicine reply solid state afterwards, thus many defectives of having avoided mechanical activation comminution to process.And the inventor is unexpected the discovery also, and the prepared Aripiprazole solid preparation of the method has excellent dissolution characteristic, stability and uniformity of dosage units.
Preparation method of the present invention comprises the steps: Aripiprazole is dissolved in the acid solution that contains acidulant, makes the pastille Acidic Liquid; Afterwards, adjuvant and described pastille Acidic Liquid are evenly mixed, carry out wet granulation.
In the present invention, described Aripiprazole is slightly water-soluble alkalescence active medicine, and its consumption is the selection of the customary amount in solid preparation according to Aripiprazole, is generally the mass percent 1%～20% of wet granulation dry material, better is 2%～15%, and best is 2.5～9%.As required, except Aripiprazole, also can add the other drug active component, be prepared as the Aripiprazole compound solid preparation.
In the present invention, described acidulant refers to make Aripiprazole 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 Aripiprazole.In 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, as one or more in inorganic acid, inorganic middle strong acid and organic monoacid, better be selected from one or more in hydrochloric acid, citric acid, malic acid, lactic acid, hydrobromic acid, nitric acid, sulphuric acid, fumaric acid, succinic acid, maleic acid, acetic acid and phosphoric acid, better is hydrochloric acid, citric acid, malic acid, lactic acid or phosphoric acid, and best is hydrochloric acid, citric acid, malic acid or lactic acid.
The consumption of described acidulant is at least and can makes the consoluet minimum of Aripiprazole, 1～1.2 times of better minimum for this reason, and better is 1～1.05 times.The amount of the acidulant of solubilized Aripiprazole is relevant with factors, and is as relevant in factors such as the hydrion number that can combine with the basic center of Aripiprazole in acidulant kind, solvent species (as the concentration of organic solvent aqueous solution), acidulant and pastille Acidic Liquid preparation conditions (as temperature).Wherein, described basic center refer in Aripiprazole 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 Aripiprazole.Can determine this minimum by simple conventional method: under same solvent and pastille Acidic Liquid preparation condition, adopt the consumption dissolving Aripiprazole 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 Aripiprazole is generally 0.7～2.0, and better is 0.9～1.3.
The present invention is particularly preferably: the hydrochloric acid that the Aripiprazole mole is 0.9～1.2 times, or the citric acid of 0.8～1.3 times of Aripiprazole mole, or the malic acid of 0.8～1.1 times of Aripiprazole mole.
In the present invention, the solvent in the described acid solution that contains acidulant can be the mixed liquor of organic solvent or water and organic solvent, the mixed liquor of preferred water and organic solvent.Described organic solvent is better than the principle of water and selects in the acceptable solvent in medicament field according to its dissolubility to Aripiprazole, better 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., one or more in preferred alcohol, acetone, propylene glycol and glycerol, particularly preferably ethanol.In the mixed liquor of water and organic solvent, the consumption of organic solvent can be selected arbitrarily.When using ethanol water, what the concentration of ethanol was better is mass percent 30%～95%, and better is 50%～75%.In described acid solution, the consumption of solvent is as the criterion to be at least the required granulation liquid minimum of wet granulation, is generally the mass percent 5～100% of wet granulation dry material, and better is 10～75%.
In the present invention's one preferred embodiments, in the described acid solution that contains acidulant, solvent is the ethanol water of mass percent 50%～75%, the amount of solvent be the wet granulation dry material mass percent 8%～60%, acidulant is the hydrochloric acid of 0.9～1.2 times of Aripiprazole mole.
When preparation pastille Acidic Liquid, can add some adjuvants, as the water-solubility carrier of binding agent, surfactant, solubilizing agent and solid dispersion etc.Better, in in Aripiprazole is dissolved in the acid solution that contains acidulant and/or afterwards, also add one or more in the water-solubility carrier of surfactant, solubilizing agent and solid dispersion, then gained pastille Acidic Liquid is carried out subsequent step, namely evenly mix with adjuvant, carry out wet granulation.Wherein, when adding simultaneously the water-solubility carrier of solid dispersion and Aripiprazole 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 Aripiprazole is dissolved in below 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, polyoxyethylene castor oil, Tween 80, s6, lactose, mannitol, sucrose, beta-schardinger dextrin-and maltose alcohol.The addition of described surfactant and/or solubilizing agent is better is 0.05～2 times of Aripiprazole quality.The addition of the water-solubility carrier of described solid dispersion is better is 1～10 times of Aripiprazole quality.Add surfactant and/or solubilizing agent by aforesaid operations, can increase the dissolubility of Aripiprazole in acid solution, reduce solvent load, be beneficial to the operation of follow-up granulation step.It will be further appreciated that, add one or more in the water-solubility carrier of surfactant, solubilizing agent and solid dispersion by aforesaid operations, it is better that especially the water-solubility carrier of solid dispersion can make the dissolution characteristic of gained Aripiprazole solid preparation.
Better, when preparation pastille Acidic Liquid, can also be by heater meanses such as hot baths, the temperature that suitably raises is beneficial to the dissolving of Aripiprazole.When using ethanol water, better is warming up to 40 ℃～70 ℃, and better is 50～65 ℃.
In 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 etc.The content of described adjuvant can be selected according to the conventional knowledge in this area.Wherein, described filler is better is one or more in lactose, microcrystalline Cellulose, pregelatinized Starch, starch, mannitol, sucrose and maltose alcohol.Described binding agent is better is one or more in hypromellose, polyvidone and methylcellulose.Said disintegrating agent is better is one or more in carboxymethyl starch sodium, hyprolose, crospolyvinylpyrrolidone and cross-linking sodium carboxymethyl cellulose.What described lubricant was better is colloidal silica, sodium stearyl fumarate, Pulvis Talci or magnesium stearate.The content of described adjuvant can be selected according to the conventional knowledge in this area.
Adjuvant and described pastille Acidic Liquid are evenly mixed, when carrying out the step of wet granulation, also can add basifier, to reduce acidity, relax the acid-base value of solid preparation.
In 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.Inorganic strong alkali (as sodium hydroxide) for example, weak acid strong alkali salt is (as sodium carbonate, sodium hydrogen phosphate, and the conjugate base of organic monoacid (as sodium citrate, sodium tartrate, natrium malicum and sodium acetate)), or acid lower than the highly acid acidulant, and acid that can be right with its formation buffering.According to this area general knowledge, it is pharmaceutically acceptable that described basifier all should be, and with the compatible reagent of Aripiprazole.
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 sodium tartrate, hydrochloric acid and natrium malicum, or hydrochloric acid and sodium acetate.
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, fumaric acid, succinic acid, maleic acid, acetic acid or malic acid is right, preferably citric acid and sodium citrate.
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, as citric acid and sodium carbonate, malic acid and sodium carbonate, 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, or 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 0.01～1.5, better is 0.1～1.2.
(basifier molal quantity * A)/(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 0.01～1.1 hydrochloric acid and sodium hydroxide, or formula 1 value is 0.1～1.3 citric acid and sodium citrate, or formula 1 value is 0.2～1.0 hydrochloric acid and sodium carbonate.
In 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 rotary squeezing etc.), stirs granulation, fluidized-bed spray granulation and centrifugal spray granulation etc. as extruding.
When using basifier, better any in the following manner carries out concrete operations: mode (1) is evenly mixed basifier or the solution and the adjuvant that contain basifier, more evenly mixes with the pastille Acidic Liquid, pushes and granulates 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 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 stir and granulate.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 completed, can directly obtain the Aripiprazole solid particle preparation, also can be used as the preparation intermediate, through further conventional steps, make the other forms of Aripiprazole solid preparations such as tablet (comprising aripiprazole orally disintegrating tablet) or capsule.
In 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.
In the present invention, agents useful for same and raw material be commercially available getting all.
Further, the invention still further relates to the Aripiprazole 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 Aripiprazole brings is seriously polluted, loss is large and potential safety hazard is serious, it is easy to operation, and safety coefficient is high, easily be applied to suitability for industrialized production.
(2) dissolution characteristic of the Aripiprazole 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 Aripiprazole solid preparation that makes of preparation method of the present invention has better stability and uniformity of dosage units.
Description of drawings
The dissolution curve chart of the aripiprazole orally disintegrating tablet that Fig. 1 makes respectively for comparative example 4 and embodiment 6.
The specific embodiment
The below further illustrates 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.
In following embodiment, the dosage form specification is with the Aripiprazole content meter, as the 5mg/ sheet, contains Aripiprazole 5mg in referring to every.Consumption unit is gram, and percentage ratio is mass percent.The mass percent of Aripiprazole and solvent is the mass percent that accounts for the wet granulation dry material.Wherein, the consumption of solvent comprises the water in the aqueous solution of acidulant and basifier.
Embodiment 5 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (4.4%) (without pretreatment) | |
| | Lactose | 40, |
| Solvent | 75% ethanol water 18 (23.0%) | |
| Acidulant | 10% aqueous hydrochloric acid solution 4.2 (with the Aripiprazole molar ratio: 1.03) | |
| Basifier | 10% sodium hydrate aqueous solution 4.6 (formula 1 value: 1.00) | |
| Preparation technology | Aripiprazole, PVP K30 and 10% aqueous hydrochloric acid solution are put in 75% ethanol water, heating in water bath to 50 ℃ left and right, stirring and dissolving, add 20% lactose to stir, be mixed with the pastille Acidic Liquid, lactose, microcrystalline Cellulose and the 70% carboxymethylstach sodium mix homogeneously of measuring with remainder, add the pastille Acidic Liquid to mix, add while stirring 10% sodium hydrate aqueous solution to make soft material, extruding is granulated, granulate after wet grain drying, tabletting after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Comparative example 4 and 6 aripiprazole orally disintegrating tablets (5mg/ sheet) formula and preparation method
| The comparative example 4 | Embodiment 6 | |
| Medicine | Aripiprazole 5 (2.5%) (crossing 100 orders) | Aripiprazole 5 (2.5%) (without pretreatment) |
| Adjuvant | Mannitol 120, |
Mannitol 120, |
| Solvent | 75% ethanol water 24 (12.1%) | 75% ethanol water 16 (13.9%) |
| Acidulant | \ | 5% aqueous hydrochloric acid solution 8 (with the Aripiprazole molar ratio: 0.98) |
| Basifier | \ | 5% sodium hydrate aqueous solution 3.8 (formula 1 value 0.43) |
| Preparation technology | The Aripiprazole raw material (is crossed 100 mesh sieves, mean diameter is 89.51 microns) put in 75% ethanol water, dispersed with stirring, with mannitol, microcrystalline Cellulose, aspartame mix, and add mentioned solution to stir and make soft material, and extruding is granulated, granulate after wet grain drying adds tabletting after magnesium stearate and crospolyvinylpyrrolidone mix homogeneously. | Aripiprazole and 5% aqueous hydrochloric acid solution are dissolved in 75% ethanol water, heating in water bath to 65 ℃ left and right, stirring and dissolving, be mixed with the pastille Acidic Liquid, with mannitol, microcrystalline Cellulose, aspartame and 5% sodium hydrate aqueous solution mix, add mentioned solution to stir and make soft material, extruding is granulated, and granulate after wet grain drying adds tabletting after magnesium stearate and crospolyvinylpyrrolidone mix homogeneously. |
Embodiment 7 and 8 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Embodiment 7 | Embodiment 8 | ||
| Medicine | Aripiprazole 5 (4.4%) (without pretreatment) | Aripiprazole 5 (4.3%) (without pretreatment) | |
| | Lactose | 60, |
|
| |
50% ethanol water 85 (74.2%) | 50% ethanol water 85 (73.2%) | |
| Acidulant | Citric acid monohydrate 3 (with the Aripiprazole molar ratio: 1.28) | Citric acid monohydrate 3 (with the Aripiprazole molar ratio: 1.28) | |
| Preparation technology | Aripiprazole, citric acid are dissolved in 50% ethanol water; heating in water bath to 40 ℃ left and right; be mixed with the pastille Acidic Liquid; lactose and microcrystalline Cellulose mix homogeneously are placed in multi-functional fluidized-bed spray granulation machine; with peristaltic pump, the pastille Acidic Liquid is sprayed on above-mentioned mixed accessories and granulates; add magnesium stearate and crospolyvinylpyrrolidone in the granule that makes, tabletting after mix homogeneously. | Aripiprazole, citric acid and sodium lauryl sulphate are dissolved in 50% ethanol water; heating in water bath to 40 ℃ left and right; lactose with 1/3rd recipe quantities adds in solution again; be mixed with the pastille Acidic Liquid; lactose and the microcrystalline Cellulose mix homogeneously of surplus are placed in multi-functional fluidized-bed spray granulation machine; with peristaltic pump, mentioned solution is sprayed on mixed accessories and granulates; add magnesium stearate and crospolyvinylpyrrolidone in the granule that makes, tabletting after mix homogeneously. |
Embodiment 9 Aripiprazole sheets (10mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 10 (8.1%) (without pretreatment) | |
| | Lactose | 60, |
| Solvent | 60% ethanol water 30 (24.2%) | |
| Acidulant | Citric acid monohydrate 5 (with the Aripiprazole molar ratio: 1.07) | |
| Preparation technology | Aripiprazole, citric acid and polyethylene glycol 6000 are dissolved in 60% ethanol water, be mixed with the pastille Acidic Liquid, carboxymethylstach sodium mix homogeneously with lactose, microcrystalline Cellulose, 70% amount, add the pastille Acidic Liquid to stir granulation, granulate after wet grain drying adds tabletting after magnesium stearate, colloidal silica and |
| Medicine | Aripiprazole 5 (4.3%) (without pretreatment) | |
| | Lactose | 70, |
| Solvent | Ethanol 20 (17.3%) | |
| Acidulant | Citric acid monohydrate 1.7 (with the Aripiprazole molar ratio: 0.73) | |
| Preparation technology | Aripiprazole, citric acid and PVP K30 are dissolved in ethanol, through 50 ℃ of left and right heating in water bath, be mixed with the pastille Acidic Liquid, carboxymethylstach sodium mix homogeneously with lactose, microcrystalline Cellulose and 70% amount, add the pastille Acidic Liquid to stir and make soft material, extruding is granulated, granulate after wet grain drying, tabletting after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 11 Aripiprazole sheets (10mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 10 (8.3%) (without pretreatment) | |
| | Lactose | 60, |
| Solvent | 50% ethanol water 60 (56.1%) | |
| Acidulant | 10% aqueous hydrochloric acid solution 7.3 (with the Aripiprazole molar ratio: 0.90) | |
| Preparation technology | Aripiprazole, 10% aqueous hydrochloric acid solution and PVP K30 are dissolved in 50% ethanol water, are mixed with the pastille Acidic Liquid; The carboxymethylstach sodium mix homogeneously of lactose, microcrystalline Cellulose and 70% amount is placed in multi-functional fluidized-bed spray granulation machine; with peristaltic pump, the pastille Acidic Liquid is sprayed on above-mentioned mixed accessories and granulates, add tabletting after magnesium stearate, colloidal silica and |
Embodiment 12 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (4.5%) (without pretreatment) | |
| | Lactose | 70, |
| Solvent | 95% ethanol water 15 (22.3%) | |
| Acidulant | 20%DL-lactic acid aqueous solution 10 (with the Aripiprazole molar ratio: 1.99) | |
| Preparation technology | Aripiprazole is placed in 95% ethanol water, add the 20%DL-lactic acid aqueous solution, stirring and dissolving, be mixed with the pastille Acidic Liquid, with lactose and microcrystalline Cellulose mix homogeneously, add the pastille Acidic Liquid to stir granulation, granulate after wet grain drying adds tabletting after magnesium stearate, colloidal silica and crospolyvinylpyrrolidone mixing. |
Embodiment 13 Aripiprazole sheets (10mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 10 (7.2%) (without pretreatment) | |
| | Lactose | 80, |
| Solvent | 50% ethanol water 30 (21.5%) | |
| Acidulant | DL-malic acid 2.4 (with the Aripiprazole molar ratio: 0.80) | |
| Preparation technology | Aripiprazole and DL-malic acid are put in 50% ethanol water, heating in water bath to 50 ℃ left and right, stirring and dissolving, be mixed with the pastille Acidic Liquid, carboxymethylstach sodium mix homogeneously with lactose, microcrystalline Cellulose and 70% amount, and add above-mentioned pastille Acidic Liquid to stir granulation, granulate after wet grain drying, tabletting after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 14 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (4.4%) (without pretreatment) | |
| | Lactose | 60, |
| Solvent | 50% ethanol water 85 (75.1%) | |
| Acidulant | DL-malic acid 1.64 (with the Aripiprazole molar ratio: 1.10) | |
| Preparation technology | Aripiprazole, DL-malic acid are dissolved in 50% ethanol water; heating in water bath to 40 ℃ left and right; be mixed with the pastille Acidic Liquid; mannitol and microcrystalline Cellulose mix homogeneously are placed in multi-functional fluidized-bed spray granulation machine; with peristaltic pump, the pastille Acidic Liquid is sprayed on above-mentioned mixed accessories and granulates; add magnesium stearate and crospolyvinylpyrrolidone in the granule that makes, tabletting after mix homogeneously. |
Embodiment 15 Aripiprazole sheets (5 milli g/piece) formula and preparation method
| Medicine | Aripiprazole 5 (4.5%) (without pretreatment) | |
| | Sucrose | 70, |
| Solvent | 75% ethanol water 18 (21.9%) | |
| Acidulant | 20% phosphate aqueous solution 6.5 (with the Aripiprazole molar ratio: 1.19) | |
| Preparation technology | Aripiprazole and 20% phosphate aqueous solution are dissolved in 75% ethanol water, heating in water bath to 60 ℃ left and right, stirring and dissolving, be mixed with the pastille Acidic Liquid, carboxymethylstach sodium and microcrystalline Cellulose mix homogeneously with sucrose, 70% amount, add mentioned solution to stir granulation, granulate after wet grain drying adds tabletting after the carboxymethylstach sodium mix homogeneously of magnesium stearate, colloidal silica and |
Embodiment 16 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (4.4%) (without pretreatment) | |
| | Lactose | 60, |
| Solvent | Ethanol 24 (20.9%) | |
| Acidulant | Citric acid monohydrate 1.9 (with the Aripiprazole molar ratio: 0.81) | |
| Basifier | Sodium citrate dihydrate 0.27 (formula 1 value 0.10) | |
| Preparation technology | Aripiprazole, citric acid and |
Embodiment 17 Aripiprazole capsules (5mg/ grain) formula and preparation method
| Medicine | Aripiprazole 5 (4.2%) (without pretreatment) |
| Adjuvant | Lactose 76, |
| Solvent | 95% ethanol water 20 (26.1%) |
| Acidulant | 5% aqueous hydrochloric acid solution 11 (with the Aripiprazole molar ratio: 1.35) |
| Basifier | Sodium carbonate 0.8 (formula 1 value: 1.00) |
| Preparation technology | Aripiprazole and 5% aqueous hydrochloric acid solution are added in 95% ethanol water, stirring and dissolving, be mixed with the pastille Acidic Liquid, carboxymethylstach sodium mix homogeneously with sodium carbonate, lactose, microcrystalline Cellulose and 70% amount, add the pastille Acidic Liquid to stir and make soft material, extruding is granulated, and granulate after wet grain drying is encapsulated after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 18 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (4.3%) (without pretreatment) | |
| | Mannitol | 60, |
| Solvent | 50% ethanol water 22 (18.8%) | |
| Acidulant | Citric acid monohydrate 3.0 (with the Aripiprazole molar ratio: 1.28) | |
| Basifier | Sodium citrate dihydrate 1.0 (formula 1 value 0.24) | |
| Preparation technology | Aripiprazole, citric acid acid and sodium lauryl sulphate are placed in 50% ethanol water, heating in water bath to 60 ℃ left and right, stirring and dissolving, be mixed with the pastille Acidic Liquid, with mannitol, microcrystalline Cellulose and sodium citrate mix homogeneously, add the pastille Acidic Liquid to stir granulation, granulate after wet grain drying adds tabletting after magnesium stearate and crospolyvinylpyrrolidone mix homogeneously. |
Embodiment 19 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (4.5%) (without pretreatment) | |
| | Mannitol | 60, |
| Solvent | 60% ethanol water 20 (29.3%) | |
| Acidulant | 5% aqueous hydrochloric acid solution 8.5 (with the Aripiprazole molar ratio: 1.04) | |
| Basifier | 5% sodium hydrate aqueous solution 4.6 (formula 1 value 0.49) | |
| Preparation technology | Aripiprazole and 5% aqueous hydrochloric acid solution are put in 60% ethanol water, heating in water bath to 50 ℃ left and right, stirring and dissolving, be mixed with the pastille Acidic Liquid, 5% sodium hydrate aqueous solution is added in the pastille Acidic Liquid while stirring, then with the carboxymethylstach sodium mix homogeneously of mannitol, microcrystalline Cellulose and 70% amount, add mentioned solution to stir granulation, granulate after wet grain drying, tabletting after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
| Medicine | Aripiprazole 5 (4.5%) (without pretreatment) | |
| | Lactose | 70, |
| Solvent | 75% ethanol water 24 (31.6%) | |
| Acidulant | 5% aqueous hydrochloric acid solution 9 (with the Aripiprazole molar ratio: 1.11) | |
| Basifier | 2% sodium hydrate aqueous solution 2.4 (formula 1 value: 0.11) | |
| Preparation technology | Aripiprazole and 5% aqueous hydrochloric acid solution are dissolved in 75% ethanol water, heating in water bath to 50 ℃ left and right, stirring and dissolving, be mixed with the pastille Acidic Liquid, 2% sodium hydrate aqueous solution is added in the pastille Acidic Liquid while stirring, with carboxymethylstach sodium and the microcrystalline Cellulose mix homogeneously of lactose, 70% amount, add mentioned solution to stir granulation simultaneously, granulate after wet grain drying, tabletting after adding magnesium stearate and remaining the 30% carboxymethylstach sodium mix homogeneously of measuring. |
Embodiment 21 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (4.3%) (without pretreatment) | |
| | Lactose | 60, |
| Solvent | 75% ethanol water 24 (20.5%) | |
| Acidulant | Citric acid one water thing 1.9 (with the Aripiprazole molar ratio: 0.81) | |
| Basifier | Sodium citrate two water things 2.7 (formula 1 value 1.02) | |
| Preparation technology | Aripiprazole, citric acid and |
Embodiment 22 aripiprazole orally disintegrating tablets (5 milli g/piece) formula and preparation method
| Medicine | Aripiprazole 5 (3.1%) (without pretreatment) |
| Adjuvant | Mannitol 120, microcrystalline Cellulose 25, |
| Solvent | 95% ethanol water 18 (15.0%) |
| Acidulant | 10% aqueous hydrochloric acid solution 4.1 (with the Aripiprazole molar ratio: 1.01) |
| Basifier | 0.2% sodium hydrate aqueous solution 2.3 (formula 1 value 0.01) |
| Preparation technology | With Aripiprazole and and sodium lauryl sulphate disperse to add 10% aqueous hydrochloric acid solution in 95% ethanol water, heating in water bath to 65 ℃ left and right, stirring and dissolving adds the mannitol of 40% amount, is mixed with the pastille Acidic Liquid.60% mannitol, aspartame, microcrystalline Cellulose and 0.2% sodium hydrate aqueous solution of measuring stirred make mixed powder.This mixed powder and the stirring of pastille Acidic Liquid are made soft material, and extruding is granulated, and granulate after wet grain drying adds colloidal silica, sodium stearyl fumarate and crospolyvinylpyrrolidone, tabletting after mix homogeneously. |
Embodiment 23 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (4.5%) (without pretreatment) | |
| | Mannitol | 80, |
| Solvent | 75% ethanol water 22 (26.2%) | |
| Acidulant | 10% aqueous hydrochloric acid solution 3.6 (with the Aripiprazole molar ratio: 0.88) | |
| Basifier | 10% sodium hydrate aqueous solution 4.3 (formula 1 value: 1.09) | |
| Preparation technology | Aripiprazole and 10% aqueous hydrochloric acid solution are put in 75% ethanol water, heating in water bath to 50 ℃ left and right, stirring and dissolving, the mannitol of 30% amount is added while stirring, make the pastille Acidic Liquid, then with the mannitol of 10% sodium hydrate aqueous solution, microcrystalline Cellulose, 70% amount and the carboxymethylstach sodium mix homogeneously of 70% amount, add above-mentioned mixed liquor to stir and make soft material, extruding is granulated, granulate after wet grain drying, tabletting after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 24 Aripiprazole sheets (10mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 10 (7.2%) (without pretreatment) | |
| | Lactose | 80, |
| Solvent | 50% ethanol water 30 (21.5%) | |
| Acidulant | DL-malic acid 2.4 (with the Aripiprazole molar ratio: 0.80) | |
| Basifier | Sodium carbonate 0.28 (formula 1 value 0.30) | |
| Preparation technology | Aripiprazole and DL-malic acid are put in 50% ethanol water, heating in water bath to 50 ℃ left and right, stirring and dissolving, be mixed with the pastille Acidic Liquid, then sodium carbonate is put in suitable quantity of water and dissolved, add the carboxymethylstach sodium mix homogeneously of lactose, microcrystalline Cellulose and 70% amount, and add above-mentioned pastille Acidic Liquid to stir granulation, granulate after wet grain drying, tabletting after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 25 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (4.4%) (without pretreatment) | |
| | Sucrose | 70, |
| Solvent | 40% ethanol water 20 (25.7%) | |
| Acidulant | 5% aqueous hydrochloric acid solution 9 (with the Aripiprazole molar ratio: 1.11) | |
| Basifier | Glycine 1.29 (formula 1 value 1.39) | |
| Preparation technology | Aripiprazole, 5% aqueous hydrochloric acid solution are dissolved in 40% ethanol water, heating in water bath to 60 ℃ left and right, stirring and dissolving adds the sucrose of 70% amount to stir, and is mixed with the pastille Acidic Liquid.Glycine is put in suitable quantity of water dissolved, get compound with 30% sucrose and the microcrystalline Cellulose mix homogeneously of measuring.Compound is added in the pastille Acidic Liquid, stir granulation, granulate after wet grain drying adds tabletting after magnesium stearate and crospolyvinylpyrrolidone mix homogeneously. |
Embodiment 26 aripiprazole orally disintegrating tablets (10mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 10 (4.4%) (without pretreatment) |
| Adjuvant | Mannitol 140, |
| Solvent | 30% ethanol water 20 (8.9%) |
| Acidulant | Citric acid monohydrate 4.7 (with the Aripiprazole molar ratio: 1.00) |
| Basifier | Sodium citrate dihydrate 8.6 (formula 1 value 1.31) |
| Preparation technology | Aripiprazole and citric acid monohydrate are dissolved in 30% ethanol water, heating in water bath to 65 ℃ left and right, stirring and dissolving, be mixed with the pastille Acidic Liquid, with mannitol, microcrystalline Cellulose, aspartame and sodium citrate mix, add mentioned solution to stir and make soft material, extruding is granulated, and granulate after wet grain drying adds tabletting after magnesium stearate and crospolyvinylpyrrolidone mix homogeneously. |
Embodiment 27 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (4.5%) (without pretreatment) | |
| | Sucrose | 70, |
| Solvent | 40% ethanol water 20 (25.9%) | |
| Acidulant | 5% aqueous hydrochloric acid solution 9 (with the Aripiprazole molar ratio: 1.) | |
| Basifier | Sodium citrate dihydrate 0.35 (formula 1 value 0.10) | |
| Preparation technology | Aripiprazole, 5% aqueous hydrochloric acid solution are dissolved in 40% ethanol water, heating in water bath to 60 ℃ left and right, stirring and dissolving, be mixed with the pastille Acidic Liquid, then sodium citrate is put in suitable quantity of water and dissolved, add sucrose, microcrystalline Cellulose mix homogeneously, and add above-mentioned pastille Acidic Liquid to stir granulation, granulate after wet grain drying adds tabletting after magnesium stearate and crospolyvinylpyrrolidone mix homogeneously. |
Embodiment 28 Aripiprazole capsules (5mg/ grain) formula and preparation method
| Medicine | Aripiprazole 5 (4.24%) (without pretreatment) |
| Adjuvant | Lactose 76, |
| Solvent | 95% ethanol water 20 (26.3%) |
| Acidulant | 5% aqueous hydrochloric acid solution 11 (with the Aripiprazole molar ratio: 1.35) |
| Basifier | Sodium carbonate 0.16 (formula 1 value: 0.20) |
| Preparation technology | Aripiprazole and 5% aqueous hydrochloric acid solution are added in 95% ethanol water, stirring and dissolving, be mixed with the pastille Acidic Liquid, carboxymethylstach sodium mix homogeneously with lactose, microcrystalline Cellulose and 70% amount, mix with the sodium carbonate that is dissolved in a small amount of water more afterwards, stir and make soft material, extruding is granulated, granulate after wet grain drying, encapsulated after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 29 Aripiprazole sheets (5mg/ sheet) formula and preparation method
| Medicine | Aripiprazole 5 (3.6%) (without pretreatment) | |
| | Lactose | 60, |
| Solvent | Ethanol 15 (10.7%) | |
| Acidulant | Citric acid monohydrate 1.8 (with the molar ratio of Aripiprazole: 0.77) | |
| Basifier | Sodium citrate dihydrate 2.4 (formula 1 value: 0.95) | |
| Preparation technology | Aripiprazole, |
The mensuration of Aripiprazole particle diameter in effect embodiment 1 comparative example 1 and 2, embodiment 1 and 2 Aripiprazole granule
Test instrunment: BT-9300S laser fineness gage; BT-800 Automatic Cycle sampling system.
Test condition: the medium in circulation sample injection system is water, and volume is the 570ml left and right, and the centrifugal pump rotating speed is 1600rpm.
Method of testing: get granule 2g, add circulation sample injection system, the system absorbance of making reaches 15% left and right, opens ultra-sonic dispersion 3 minutes, and continuous 6 sampling tests obtain the particle diameter meansigma methods:
Annotate: D
10, D
50And D
90It is respectively cumulative particle sizes percentile corresponding particle diameter when reaching 10%, 50% and 90%.
Effect embodiment 2 dissolution comparative experimentss
1) mensuration of the Aripiprazole sheet dissolution that makes of comparative example 3 and embodiment 3～5
Dissolution determination method: sample thief, according to dissolution method (two appendix X C the second methods of Chinese Pharmacopoeia version in 2005), take acetate buffer (0.05mol/L acetic acid-0.05mol/L sodium acetate=16.4: the 3.6) 500ml of pH4.0 as solvent, rotating speed is per minute 50 to turn, and operation, got respectively solution 5ml at 5,10,20,30,45 minutes in accordance with the law, fill into the 5ml dissolution medium to stripping rotor, sample is filtered, get subsequent filtrate as sample solution, and the preparation contrast solution.Measuring respectively according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2005), is filler with octadecylsilane chemically bonded silica; Take methanol-0.1% triethylamine solution (90: 10) as mobile phase; The detection wavelength is 255nm, and the stripping quantity that calculates every is recorded in following table.
2) aripiprazole orally disintegrating tablet that makes of comparative example 4 and embodiment 6
Dissolution determination method is the same, result such as following table:
3) mensuration of the Aripiprazole sheet dissolution that makes of embodiment 7 and embodiment 8
Dissolution determination method is the same, result such as following table:
The stable comparative experiments of effect embodiment 3
Laboratory sample: comparative example 3, embodiment 3～5 and 8 Aripiprazole sheet
After sample packaging, in 40 ℃ ± 2 ℃ of temperature, place under the condition of relative humidity 75% ± 5%, sampling checks character, content, dissolution and related substance March.
The assay method of content and related substance: sample thief is appropriate, makes dissolving with the ultrasonic jolting of mobile phase, make approximately to contain the appropriate solution of Aripiprazole in every ml, and as need testing solution, and the preparation contrast solution.Measuring respectively according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2005), is filler with octadecylsilane chemically bonded silica; Take methanol-0.1% triethylamine solution (90: 10) as mobile phase; The detection wavelength is 255nm, and the mensuration of content is according to external standard method, and the mensuration of related substance is calculated according to the main constituent Self-control method, and its result data is recorded in following table.
Effect embodiment 4 uniformity of dosage units comparative experimentss
Laboratory sample: the Aripiprazole sheet of comparative example 3 and embodiment 3 and 4
According to Chinese Pharmacopoeia version appendix XE Content uniformity test in 2005, measure the content (content assaying method is with effect embodiment 3) of every, and calculate uniformity of dosage units (A+1.80S).
Claims (30)
1. the preparation method of an Aripiprazole solid preparation, is characterized in that it comprises the steps: Aripiprazole is dissolved in the acid solution that contains acidulant, makes the pastille Acidic Liquid; Afterwards, adjuvant and described pastille Acidic Liquid are evenly mixed, carry out wet granulation; Described acidulant is one or more in hydrochloric acid, citric acid, lactic acid, malic acid and phosphoric acid; Solvent in the described acid solution that contains acidulant is the mixed liquor of organic solvent or water and organic solvent, and described organic solvent is ethanol.
2. the method for claim 1, it is characterized in that: the consumption of described Aripiprazole is the mass percent 1%～20% of wet granulation dry material.
3. method as claimed in claim 2, it is characterized in that: the consumption of described Aripiprazole is the mass percent 2%～15% of wet granulation dry material.
4. method as claimed in claim 3, it is characterized in that: the consumption of described Aripiprazole is the mass percent 2.5～9% of wet granulation dry material.
5. method as described in claim 1～4 any one, it is characterized in that: the consumption of described acidulant is for making 1～1.2 times of the consoluet minimum of Aripiprazole, described minimum refers to that described acidulant is with the consoluet minimum of Aripiprazole under same solvent and pastille Acidic Liquid preparation condition.
6. method as claimed in claim 5 is characterized in that: the consumption of described acidulant is for making 1～1.05 times of the consoluet minimum of Aripiprazole.
7. method as described in claim 1～4 any one, it is characterized in that: the molar ratio of described acidulant and Aripiprazole is 0.7～2.0.
8. method as claimed in claim 7, it is characterized in that: the molar ratio of described acidulant and Aripiprazole is 0.9～1.3.
9. as the described method of claim 1-4 any one, it is characterized in that: described acidulant is the hydrochloric acid of 0.9～1.2 times of Aripiprazole mole, or the citric acid of 0.8～1.3 times of Aripiprazole mole, or the malic acid of 0.8～1.1 times of Aripiprazole mole.
10. method as described in claim 1～4 any one, it is characterized in that: the mixed liquor of described water and organic solvent is the ethanol water of mass percent 30%～95%.
11. method as claimed in claim 10 is characterized in that: the mixed liquor of described water and organic solvent is the ethanol water of mass percent 50%～75%.
12. method as claimed in claim 10 is characterized in that: in described acid solution, the consumption of solvent is the mass percent 5～100% of wet granulation dry material.
13. method as claimed in claim 12 is characterized in that: in described acid solution, the consumption of solvent is the mass percent 10～75% of wet granulation dry material.
14. as the described method of claim 1-4 any one, it is characterized in that: in the described acid solution that contains acidulant, solvent is the ethanol water of mass percent 50%～75%, the amount of solvent be the wet granulation dry material mass percent 8%～60%, acidulant is the hydrochloric acid of 0.9～1.2 times of Aripiprazole mole.
15. the method for claim 1, it is characterized in that: described Aripiprazole is dissolved in the acid solution that contains acidulant in and/or afterwards, also add one or more in the water-solubility carrier of surfactant, solubilizing agent and solid dispersion, then gained pastille Acidic Liquid is evenly mixed with adjuvant, carry out wet granulation;
Wherein, when adding simultaneously the water-solubility carrier of solid dispersion and Aripiprazole 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 Aripiprazole is dissolved in below amount in the acid solution that contains acidulant fully.
16. method as claimed in claim 15 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, Tween 80, s6, lactose, mannitol, sucrose, beta-schardinger dextrin-and maltose alcohol.
17. method as claimed in claim 15 is characterized in that: the addition of described surfactant and/or solubilizing agent is 0.05～2 times of Aripiprazole quality; The addition of the water-solubility carrier of described solid dispersion is 1～10 times of Aripiprazole quality.
18. the method for claim 1 is characterized in that: when the described pastille Acidic Liquid of preparation, when solvent is ethanol water, be warming up to 40 ℃～70 ℃.
19. method as claimed in claim 18 is characterized in that: when the described pastille Acidic Liquid of preparation, when solvent is ethanol water, be warming up to 50～65 ℃.
20. the method for claim 1, it is characterized in that: described adjuvant and described pastille Acidic Liquid are evenly mixed carrying out, when carrying out the step of wet granulation, also add basifier, the acidity of the mixed liquor of basifier and pastille Acidic Liquid is reduced with respect to the acidity of pastille Acidic Liquid.
21. method as claimed in claim 20 is characterized in that: described basifier is the conjugate base of inorganic strong alkali, weak acid strong alkali salt, organic monoacid, or acid lower than the highly acid acidulant, and acid that can be right with its formation buffering.
22. method as claimed in claim 21 is characterized in that: described basifier is one or more in sodium hydroxide, sodium carbonate, sodium hydrogen phosphate, sodium citrate, sodium tartrate and natrium malicum, sodium acetate, glycine and alanine.
23. method as claimed in claim 20 is characterized in that: described acidulant and basifier are any in following type:
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,
Type 6: described acidulant is inorganic acid, and described basifier is weak acid, and acid that can be right with its formation buffering.
24. method as claimed in claim 23, it is characterized in that: described acidulant and basifier are any in following type: 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, hydrochloric acid and sodium acetate, citric acid and sodium citrate, malic acid and natrium malicum, citric acid and sodium carbonate, malic acid and sodium carbonate, malic acid and sodium hydrogen phosphate, citric acid and sodium hydrogen phosphate, hydrochloric acid and glycine, or hydrochloric acid and alanine.
25. method as claimed in claim 23 is characterized in that: the consumption of described acidulant and basifier satisfies following relation: formula 1 income value is 0.01～1.5;
(basifier molal quantity * A)/(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.
26. method as claimed in claim 25 is characterized in that: described formula 1 income value is 0.1～1.2.
27. method as claimed in claim 25, it is characterized in that: described acidulant and basifier are that formula 1 value is 0.01～1.1 hydrochloric acid and sodium hydroxide, or formula 1 value is 0.1～1.3 citric acid and sodium citrate, or formula 1 value is 0.2～1.0 hydrochloric acid and sodium carbonate.
28. method as described in claim 20～27 any one is characterized in that: any in the following manner carries out concrete operations:
Mode (1) is evenly mixed basifier or the solution and the adjuvant that contain basifier, more evenly mixes with the pastille Acidic Liquid, pushes and granulates 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;
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 stir and granulate.
29. the method for claim 1 is characterized in that: the Aripiprazole solid particle with method as claimed in claim 1 makes through further conventional steps, makes aripirazole tablets or Aripiprazole capsule.
30. the Aripiprazole solid preparation that method as described in claim 1～29 any one makes.
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| PCT/CN2010/080344 WO2011079766A1 (en) | 2009-12-29 | 2010-12-28 | Aripiprazole solid preparation and the production method thereof |
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| US9241876B2 (en) * | 2011-06-27 | 2016-01-26 | Shanghai Zhongxi Pharmaceutical Corporation | Aripiprazole medicament formulation and preparation method therefor |
| US20150174247A1 (en) * | 2012-06-29 | 2015-06-25 | Maruishi Pharmaceutical Co., Ltd. | Oral pharmaceutical preparation of aripiprazole |
| CN106074415B (en) * | 2016-07-22 | 2018-10-30 | 南京正大天晴制药有限公司 | A kind of aripirazole tablets and preparation method thereof |
| CN109419772B (en) * | 2017-08-23 | 2021-03-09 | 北京罗诺强施医药技术研发中心有限公司 | Method and pharmaceutical composition for treating mental disorders by nasal administration |
| CN109589312A (en) * | 2017-10-01 | 2019-04-09 | 万全万特制药（厦门）有限公司 | A kind of Aripiprazole solid dispersions and preparation method thereof |
| CN114668727A (en) * | 2022-03-18 | 2022-06-28 | 浙江圣兆药物科技股份有限公司 | Aripiprazole sustained-release microsphere composition |
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| CN101351192A (en) * | 2006-01-05 | 2009-01-21 | 特瓦制药工业有限公司 | Wet granulation method for preparing pharmaceutical compositions of aripiprazole |
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| CN1709256A (en) * | 2004-06-18 | 2005-12-21 | 成都康弘科技实业（集团）有限公司 | Aripiprazole orally disintegrating tablet formulation and its preparing method |
| CN101107242B (en) * | 2005-01-27 | 2011-08-10 | 桑多斯股份公司 | Salts of aripiprazole |
| CN101351192A (en) * | 2006-01-05 | 2009-01-21 | 特瓦制药工业有限公司 | Wet granulation method for preparing pharmaceutical compositions of aripiprazole |
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