CN102106826A - Aripiprazole solid preparation and preparation method thereof - Google Patents
Aripiprazole solid preparation and preparation method thereof Download PDFInfo
- Publication number
- CN102106826A CN102106826A CN2009102473507A CN200910247350A CN102106826A CN 102106826 A CN102106826 A CN 102106826A CN 2009102473507 A CN2009102473507 A CN 2009102473507A CN 200910247350 A CN200910247350 A CN 200910247350A CN 102106826 A CN102106826 A CN 102106826A
- Authority
- CN
- China
- Prior art keywords
- acid
- aripiprazole
- acidulant
- basifier
- 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.)
- Granted
Links
- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 196
- 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 195
- 238000002360 preparation method Methods 0.000 title claims abstract description 106
- 239000007787 solid Substances 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 51
- 239000008187 granular material Substances 0.000 claims abstract description 40
- 239000003814 drug Substances 0.000 claims abstract description 38
- 238000002156 mixing Methods 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 106
- 239000002253 acid Substances 0.000 claims description 104
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 75
- 239000007788 liquid Substances 0.000 claims description 75
- 235000010603 pastilles Nutrition 0.000 claims description 70
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 53
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 53
- 239000002904 solvent Substances 0.000 claims description 53
- 238000003756 stirring Methods 0.000 claims description 53
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
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- 238000005469 granulation Methods 0.000 claims description 34
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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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 19
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 8
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- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000001132 ultrasonic dispersion Methods 0.000 description 1
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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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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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, the 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 big tomb company, and head obtains the drugs approved by FDA listing in November, 2002.Aripiprazole is the atypia psychosis, and it has the exciting and postsynaptic dopamine D of presynaptic dopamine
2The effect of antagonist is with 5-HT
1aAcceptor portion agonism and 5-HT
2Receptor antagonism.Clinical experimental study shows, Aripiprazole all has significant improvement effect to the schizoid positive and negative symptoms, and schizoid relapse rate is reduced, and the effect of extrapyramidal system side reaction and weight increase is very little, do not cause the rising of serum prolactin level yet, its better tolerance is importantly only found small number of patients because side reaction and stopped treatment in the research.
The water solublity of Aripiprazole is relatively poor, therefore, during as tablet or capsule, need it is crushed to certain fineness at the preparation solid preparation, 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 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 Aripiprazole is than higher, carrying out mechanical activation comminution when handling, and operator very easily taken place suck the Aripiprazole powder and cause headache, untoward reaction such as drowsiness, and suction for a long time will produce more serious consequence.
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 Aripiprazole is active high, content is lower (general≤as 10wt%), therefore in the technology that mechanical activation comminution is handled, 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 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.
At present, bibliographical information has been arranged on-mechanical handle the method reduce the Aripiprazole particle diameter.Chinese patent application CN1871007A discloses a kind of bump jet crystallization legal system of utilizing and has been equipped with the method for particle mean size less than 100 microns aseptic shot Aripiprazole, the aseptic shot Aripiprazole that this method makes is used to prepare aseptic cryodesiccated aripiprazole formulations, also can be used for preparing injection Aripiprazole aqueous suspension preparation.Chinese patent application CN101066267A discloses and has utilized recrystallization to obtain mean diameter to be no more than 50 microns Aripiprazole, filtration drying afterwards, with adjuvant mixed the method for solid preparation.But still there is contaminated environment in said method complex operation, and contain the solid preparation of adjuvant for preparation, loss is big, dust is many and to problems such as labor protection requirement height.
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 Aripiprazole solid preparation of various function admirables again at Aripiprazole.
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 big, there is serious potential safety hazard, and the still dissatisfactory defective of the dissolution characteristic of Aripiprazole 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 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 handle.And the inventor is also unexpected to find that the prepared Aripiprazole solid preparation of this 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 acid liquid of pastille; Afterwards, with adjuvant and the acid liquid uniform mixing of described pastille, carry out wet granulation.
Among the present invention, described Aripiprazole is a slightly water-soluble alkalescence active medicine, and its consumption is selected according to the customary amount of Aripiprazole in solid preparation, is generally the mass percent 1%～20% of wet granulation dry material, preferable is 2%～15%, and best is 2.5～9%.As required, except that Aripiprazole, also can add the other drug active component, be prepared as the Aripiprazole compound solid preparation.
Among the present invention, described acidulant is meant and can makes Aripiprazole 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.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, as inorganic acid, inorganic in strong acid and the organic monoacid one or more, preferable be selected from hydrochloric acid, citric acid, malic acid, lactic acid, hydrobromic acid, nitric acid, sulphuric acid, fumaric acid, succinic acid, maleic acid, acetic acid and the phosphoric acid one or more, 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 preferable minimum for this reason, and better is 1～1.05 times.The amount of the acidulant of solubilized Aripiprazole is with all multifactor relevant, as can be relevant with hydrion number and the acid liquid preparation condition of pastille factors such as (as temperature) that the basic center of Aripiprazole combines in acidulant kind, solvent species (as the concentration of organic solvent aqueous solution), the acidulant.Wherein, described basic center be meant in the Aripiprazole 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 Aripiprazole 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 Aripiprazole 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 Aripiprazole is generally 0.7～2.0, and preferable is 0.9～1.3.
The present invention is preferred especially: 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.
Among 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 of medicament field according to its dissolubility to Aripiprazole, 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., in preferred alcohol, acetone, propylene glycol and the glycerol one or more, special preferred alcohol.In the mixed liquor of water and organic solvent, the consumption of organic solvent can be selected arbitrarily.When using ethanol water, what concentration of ethanol was preferable is mass percent 30%～95%, and better is 50%～75%.The consumption of solvent is as the criterion to be at least the required granulation liquid minimum of wet granulation in the described acid solution, is generally the mass percent 5～100% of wet granulation dry material, and preferable 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 0.9～1.2 times a hydrochloric acid of Aripiprazole mole.
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 Aripiprazole 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 the adjuvant uniform mixing.Wherein, when adding the water-solubility carrier of solid dispersion and Aripiprazole 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 Aripiprazole 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, polyoxyethylene castor oil, Tween 80, polyoxyethylene stearate 40 esters, lactose, mannitol, sucrose, beta-schardinger dextrin-and the maltose alcohol.The addition of described surfactant and/or solubilizing agent is preferable is 0.05～2 times of Aripiprazole quality.The addition of the water-solubility carrier of described solid dispersion is preferable is 1～10 times of Aripiprazole quality.Press aforesaid operations and add surfactant and/or solubilizing agent, 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 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 Aripiprazole solid preparation.
Preferable, when preparation pastille acidity liquid, can also be by heater meanses such as hot baths, suitably elevated temperature is beneficial to the dissolving of Aripiprazole.When using ethanol water, preferable is warming up to 40 ℃～70 ℃, and better is 50～65 ℃.
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, hyprolose, crospolyvinylpyrrolidone and the cross-linking sodium carboxymethyl cellulose one or more.What described lubricant was preferable 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.
With adjuvant and the acid liquid uniform mixing of described pastille, when carrying out the step of wet granulation, also can add basifier, to reduce acidity, relax the acid-base value of 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.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 acidity is lower than the highly acid acidulant, and can with the right acid of 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.
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 sodium tartrate, hydrochloric acid and natrium malicum, or hydrochloric acid and sodium acetate.
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, fumaric acid, succinic acid, maleic acid, acetic acid or malic acid is right, preferably citric acid and sodium citrate.
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, malic acid and sodium carbonate, 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, or 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 0.01～1.5, and better is 0.1～1.2.
(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 0.01～1.1 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.
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.
When using basifier, preferable by in the following mode any carries out concrete operations: 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 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 Aripiprazole solid particle preparation, also can be used as the preparation intermediate,, make other forms of Aripiprazole solid preparations such as tablet (comprising aripiprazole orally disintegrating 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 are all commercially available to be got.
Further, the invention still further relates to the Aripiprazole 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 Aripiprazole 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 Aripiprazole 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 Aripiprazole solid preparation that makes of preparation method of the present invention has preferable 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
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.
Among the following embodiment, the dosage form specification is in Aripiprazole content, as the 5mg/ sheet, contains Aripiprazole 5mg in being meant 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) prescription and preparation method
| Medicine | Aripiprazole 5 (4.4%) (no pretreatment) |
| Adjuvant | Lactose 40, microcrystalline Cellulose 60, carboxymethylstach sodium 6,30 POVIDONE K 30 BP/USP 302, magnesium stearate 0.9 |
| 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, 30 POVIDONE K 30 BP/USP 30 and 10% aqueous hydrochloric acid solution are put in 75% ethanol water, about heating in water bath to 50 ℃, stirring and dissolving, the lactose of adding 20% stirs, be mixed with the acid liquid of pastille, lactose, microcrystalline Cellulose and the 70% carboxymethylstach sodium mix homogeneously of measuring with remainder, adding the acid liquid of pastille mixes, add 10% sodium hydrate aqueous solution while stirring and make soft material, extruding is granulated, granulate behind the 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) prescription and preparation method
| The comparative example 4 | Embodiment 6 | |
| Medicine | Aripiprazole 5 (2.5%) (crossing 100 orders) | Aripiprazole 5 (2.5%) (no pretreatment) |
| Adjuvant | Mannitol 120, microcrystalline Cellulose 60, crospolyvinylpyrrolidone 11, aspartame 1, magnesium stearate 1.5 | Mannitol 120, microcrystalline Cellulose 60, crospolyvinylpyrrolidone 11, aspartame 1, magnesium stearate 1.5 |
| 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 above-mentioned solution and stir and make soft material, and extruding is granulated, granulate behind the wet grain drying, tabletting behind adding magnesium stearate and the crospolyvinylpyrrolidone mix homogeneously. | Aripiprazole and 5% aqueous hydrochloric acid solution are dissolved in 75% ethanol water, about heating in water bath to 65 ℃, stirring and dissolving, be mixed with the acid liquid of pastille, with mannitol, microcrystalline Cellulose, aspartame and 5% sodium hydrate aqueous solution mix, adding above-mentioned solution stirs and makes soft material, extruding is granulated, granulate behind the wet grain drying, tabletting behind adding magnesium stearate and the crospolyvinylpyrrolidone mix homogeneously. |
Embodiment 7 and 8 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Embodiment 7 | Embodiment 8 | |
| Medicine | Aripiprazole 5 (4.4%) (no pretreatment) | Aripiprazole 5 (4.3%) (no pretreatment) |
| Adjuvant | Lactose 60, microcrystalline Cellulose 40, crospolyvinylpyrrolidone 6, magnesium stearate 0.6 | Lactose 60, microcrystalline Cellulose 40, crospolyvinylpyrrolidone 6, magnesium stearate 0.6, sodium lauryl sulphate 1.5 |
| Solvent | 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; about heating in water bath to 40 ℃; be mixed with the acid liquid of pastille; lactose and microcrystalline Cellulose mix homogeneously are placed multi-functional fluidized-bed spray granulation machine; with peristaltic pump the acid liquid of pastille is sprayed on the above-mentioned mixed accessories and granulates; in the granule that makes, add magnesium stearate and crospolyvinylpyrrolidone, tabletting behind the mix homogeneously. | Aripiprazole, citric acid and sodium lauryl sulphate are dissolved in 50% ethanol water; about heating in water bath to 40 ℃; lactose with 1/3rd recipe quantities adds in the solution again; be mixed with the acid liquid of pastille; the lactose and the microcrystalline Cellulose mix homogeneously of surplus are placed multi-functional fluidized-bed spray granulation machine; with peristaltic pump above-mentioned solution is sprayed on the mixed accessories and granulates; in the granule that makes, add magnesium stearate and crospolyvinylpyrrolidone, tabletting behind the mix homogeneously. |
Embodiment 9 Aripiprazole sheets (10mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 10 (8.1%) (no pretreatment) |
| Adjuvant | Lactose 60, microcrystalline Cellulose 40, carboxymethylstach sodium 6, polyethylene glycol 6000 2, colloidal silica 0.6, magnesium stearate 0.6 |
| 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 acid liquid of pastille, carboxymethylstach sodium mix homogeneously with lactose, microcrystalline Cellulose, 70% amount, add the acid liquid of pastille and stir granulation, granulate behind the wet grain drying, tabletting behind adding magnesium stearate, colloidal silica and the residue 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 10 Aripiprazole sheets (5 milligrams/sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.3%) (no pretreatment) |
| Adjuvant | Lactose 70, microcrystalline Cellulose 30, carboxymethylstach sodium 6,30 POVIDONE K 30 BP/USP 302, magnesium stearate 0.9 |
| Solvent | Ethanol 20 (17.3%) |
| Acidulant | Citric acid monohydrate 1.7 (with the Aripiprazole molar ratio: 0.73) |
| Preparation technology | Aripiprazole, citric acid and 30 POVIDONE K 30 BP/USP 30 are dissolved in the ethanol, through 50 ℃ of left and right sides heating in water bath, be mixed with the acid liquid of pastille, carboxymethylstach sodium mix homogeneously with lactose, microcrystalline Cellulose and 70% amount, the acid liquid of adding pastille stirs makes soft material, extruding is granulated, granulate behind the wet grain drying, tabletting after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 11 Aripiprazole sheets (10mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 10 (8.3%) (no pretreatment) |
| Adjuvant | Lactose 60, microcrystalline Cellulose 40, carboxymethylstach sodium 6,30 POVIDONE K 30 BP/USP 303, magnesium stearate 0.6, colloidal silica 0.3 |
| 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 30 POVIDONE K 30 BP/USP 30 are dissolved in 50% ethanol water, are mixed with the acid liquid of pastille; The carboxymethylstach sodium mix homogeneously of lactose, microcrystalline Cellulose and 70% amount is placed multi-functional fluidized-bed spray granulation machine; with peristaltic pump the acid liquid of pastille is sprayed on the above-mentioned mixed accessories and granulates, in the granule that makes, add tabletting behind magnesium stearate, colloidal silica and the residue 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 12 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.5%) (no pretreatment) |
| Adjuvant | Lactose 70, microcrystalline Cellulose 30, crospolyvinylpyrrolidone 6, magnesium stearate 0.6, colloidal silica 0.3 |
| 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 95% ethanol water, add the 20%DL-lactic acid aqueous solution, stirring and dissolving, be mixed with the acid liquid of pastille, with lactose and microcrystalline Cellulose mix homogeneously, add the acid liquid of pastille and stir granulation, granulate behind the wet grain drying, tabletting behind adding magnesium stearate, colloidal silica and the crospolyvinylpyrrolidone mixing. |
Embodiment 13 Aripiprazole sheets (10mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 10 (7.2%) (no pretreatment) |
| Adjuvant | Lactose 80, microcrystalline Cellulose 40, carboxymethylstach sodium 6, magnesium stearate 0.6 |
| 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, about heating in water bath to 50 ℃, stirring and dissolving, be mixed with the acid liquid of pastille, carboxymethylstach sodium mix homogeneously with lactose, microcrystalline Cellulose and 70% amount, and add the acid liquid of above-mentioned pastille and stir granulation, granulate behind the wet grain drying adds tabletting behind magnesium stearate and the residue 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 14 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.4%) (no pretreatment) |
| Adjuvant | Lactose 60, microcrystalline Cellulose 40, crospolyvinylpyrrolidone 6, magnesium stearate 0.6 |
| 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; about heating in water bath to 40 ℃; be mixed with the acid liquid of pastille; mannitol and microcrystalline Cellulose mix homogeneously are placed multi-functional fluidized-bed spray granulation machine; with peristaltic pump the acid liquid of pastille is sprayed on the above-mentioned mixed accessories and granulates; in the granule that makes, add magnesium stearate and crospolyvinylpyrrolidone, tabletting behind the mix homogeneously. |
Embodiment 15 Aripiprazole sheets (5 milligrams/sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.5%) (no pretreatment) |
| Adjuvant | Sucrose 70, microcrystalline Cellulose 30, carboxymethylstach sodium 6, magnesium stearate 0.6, colloidal silica 0.3 |
| 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, about heating in water bath to 60 ℃, stirring and dissolving, be mixed with the acid liquid of pastille, carboxymethylstach sodium and microcrystalline Cellulose mix homogeneously with sucrose, 70% amount, add above-mentioned solution and stir granulation, granulate behind the wet grain drying, tabletting behind the carboxymethylstach sodium mix homogeneously of adding magnesium stearate, colloidal silica and residue 30% amount. |
Embodiment 16 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.4%) (no pretreatment) |
| Adjuvant | Lactose 60, microcrystalline Cellulose 40, carboxymethylstach sodium 6, tween 80 0.5, colloidal silica 0.2, sodium stearyl fumarate 0.8 |
| 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 tween 80 are dissolved in the ethanol, about heating in water bath to 55 ℃, stirring and dissolving, be mixed with the acid liquid of pastille, with lactose, the carboxymethylstach sodium and the sodium citrate of microcrystalline Cellulose, 50% amount mix, adding above-mentioned solution stirs and makes soft material, extruding is granulated, granulate behind the wet grain drying, tabletting behind the carboxymethylstach sodium mix homogeneously of adding colloidal silica, sodium stearyl fumarate and 50% amount. |
Embodiment 17 Aripiprazole capsules (5mg/ grain) prescription and preparation method
| Medicine | Aripiprazole 5 (4.2%) (no pretreatment) |
| Adjuvant | Lactose 76, microcrystalline Cellulose 30, carboxymethylstach sodium 6, magnesium stearate 0.9 |
| 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 acid liquid of pastille, carboxymethylstach sodium mix homogeneously with sodium carbonate, lactose, microcrystalline Cellulose and 70% amount, the acid liquid of adding pastille stirs makes soft material, extruding is granulated, and granulate behind the wet grain drying is encapsulated after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 18 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.3%) (no pretreatment) |
| Adjuvant | Mannitol 60, microcrystalline Cellulose 40, crospolyvinylpyrrolidone 6, sodium lauryl sulphate 1, magnesium stearate 0.9 |
| 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 50% ethanol water, about heating in water bath to 60 ℃, stirring and dissolving, be mixed with the acid liquid of pastille, with mannitol, microcrystalline Cellulose and sodium citrate mix homogeneously, add the acid liquid of pastille and stir granulation, granulate behind the wet grain drying, tabletting behind adding magnesium stearate and the crospolyvinylpyrrolidone mix homogeneously. |
Embodiment 19 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.5%) (no pretreatment) |
| Adjuvant | Mannitol 60, microcrystalline Cellulose 40, carboxymethylstach sodium 6, magnesium stearate 0.9 |
| 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, about heating in water bath to 50 ℃, stirring and dissolving, be mixed with the acid liquid of pastille, 5% sodium hydrate aqueous solution is added in the acid liquid of pastille while stirring, with the carboxymethylstach sodium mix homogeneously of mannitol, microcrystalline Cellulose and 70% amount, add above-mentioned solution and stir granulation then, granulate behind the wet grain drying, tabletting after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 20 Aripiprazole sheets (5 milligrams/sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.5%) (no pretreatment) |
| Adjuvant | Lactose 70, microcrystalline Cellulose 30, carboxymethylstach sodium 6, magnesium stearate 0.9 |
| 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, about heating in water bath to 50 ℃, stirring and dissolving, be mixed with the acid liquid of pastille, 2% sodium hydrate aqueous solution is added in the acid liquid of pastille while stirring, with the carboxymethylstach sodium and the microcrystalline Cellulose mix homogeneously of lactose, 70% amount, add above-mentioned solution and stir granulation simultaneously, granulate behind the wet grain drying, tabletting after adding magnesium stearate and remaining the 30% carboxymethylstach sodium mix homogeneously of measuring. |
Embodiment 21 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.3%) (no pretreatment) |
| Adjuvant | Lactose 60, microcrystalline Cellulose 40, carboxymethylstach sodium 6, tween 80 0.25, colloidal silica 0.2, sodium stearyl fumarate 0.8 |
| 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 tween 80 are dissolved in 75% ethanol water, about heating in water bath to 55 ℃, stirring and dissolving, the lactose that adds 20% amount again, be mixed with the acid liquid of pastille, lactose with remainder, the carboxymethylstach sodium and the sodium citrate of microcrystalline Cellulose, 50% amount mix, adding the acid liquid of above-mentioned pastille stirs and makes soft material, extruding is granulated, granulate behind the wet grain drying, tabletting behind the carboxymethylstach sodium mix homogeneously of adding colloidal silica, sodium stearyl fumarate and 50% amount. |
Embodiment 22 aripiprazole orally disintegrating tablets (5 milligrams/sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (3.1%) (no pretreatment) |
| Adjuvant | Mannitol 120, microcrystalline Cellulose 25, crospolyvinylpyrrolidone 10, sodium lauryl sulphate 0.3, aspartame 0.8, sodium stearyl fumarate 1.2, colloidal silica 0.3 |
| 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, about heating in water bath to 65 ℃, stirring and dissolving adds the mannitol of 40% amount, is mixed with the acid liquid of pastille.Mannitol, aspartame, microcrystalline Cellulose and 0.2% sodium hydrate aqueous solution of 60% amount are stirred and make mixed powder.This mixed powder and the acid liquid stirring of pastille are made soft material, and extruding is granulated, and granulate behind the wet grain drying adds colloidal silica, sodium stearyl fumarate and crospolyvinylpyrrolidone, tabletting behind the mix homogeneously. |
Embodiment 23 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.5%) (no pretreatment) |
| Adjuvant | Mannitol 80, microcrystalline Cellulose 20, carboxymethylstach sodium 6, magnesium stearate 0.9 |
| 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, about heating in water bath to 50 ℃, stirring and dissolving, the mannitol of 30% amount is added while stirring, make the acid liquid of pastille, then with the mannitol of 10% sodium hydrate aqueous solution, microcrystalline Cellulose, 70% amount and the carboxymethylstach sodium mix homogeneously of 70% amount, adding above-mentioned mixed liquor stirs and makes soft material, extruding is granulated, granulate behind the wet grain drying, tabletting after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 24 Aripiprazole sheets (10mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 10 (7.2%) (no pretreatment) |
| Adjuvant | Lactose 80, microcrystalline Cellulose 40, carboxymethylstach sodium 6, magnesium stearate 0.6 |
| 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, about heating in water bath to 50 ℃, stirring and dissolving, be mixed with the acid liquid of pastille, then sodium carbonate is put in the suitable quantity of water and dissolved, add the carboxymethylstach sodium mix homogeneously of lactose, microcrystalline Cellulose and 70% amount, and add the acid liquid of above-mentioned pastille and stir granulation, granulate behind the wet grain drying, tabletting after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 25 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.4%) (no pretreatment) |
| Adjuvant | Sucrose 70, microcrystalline Cellulose 30, crospolyvinylpyrrolidone 6, magnesium stearate 0.6 |
| 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, about heating in water bath to 60 ℃, stirring and dissolving, the sucrose that adds 70% amount stirs, and is mixed with the acid liquid of pastille.Glycine put in the suitable quantity of water dissolve, get compound with the sucrose and the microcrystalline Cellulose mix homogeneously of 30% amount.Compound is added in the acid liquid of pastille, stir granulation, granulate behind the wet grain drying, tabletting behind adding magnesium stearate and the crospolyvinylpyrrolidone mix homogeneously. |
Embodiment 26 aripiprazole orally disintegrating tablets (10mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 10 (4.4%) (no pretreatment) |
| Adjuvant | Mannitol 140, microcrystalline Cellulose 50, crospolyvinylpyrrolidone 10, aspartame 1, magnesium stearate 0.9 |
| 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, about heating in water bath to 65 ℃, stirring and dissolving, be mixed with the acid liquid of pastille, with mannitol, microcrystalline Cellulose, aspartame and sodium citrate mix, adding above-mentioned solution stirs and makes soft material, extruding is granulated, granulate behind the wet grain drying, tabletting behind adding magnesium stearate and the crospolyvinylpyrrolidone mix homogeneously. |
Embodiment 27 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (4.5%) (no pretreatment) |
| Adjuvant | Sucrose 70, microcrystalline Cellulose 30, crospolyvinylpyrrolidone 6, magnesium stearate 0.6 |
| 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, about heating in water bath to 60 ℃, stirring and dissolving, be mixed with the acid liquid of pastille, then sodium citrate is put in the suitable quantity of water and dissolved, add sucrose, microcrystalline Cellulose mix homogeneously, and add the acid liquid of above-mentioned pastille and stir granulation, granulate behind the wet grain drying, tabletting behind adding magnesium stearate and the crospolyvinylpyrrolidone mix homogeneously. |
Embodiment 28 Aripiprazole capsules (5mg/ grain) prescription and preparation method
| Medicine | Aripiprazole 5 (4.24%) (no pretreatment) |
| Adjuvant | Lactose 76, microcrystalline Cellulose 30, carboxymethylstach sodium 6, magnesium stearate 0.9 |
| 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 acid liquid of pastille, carboxymethylstach sodium mix homogeneously with lactose, microcrystalline Cellulose and 70% amount, mix with the sodium carbonate that is dissolved in low amounts of water more afterwards, stir and make soft material, extruding is granulated, granulate behind the wet grain drying, encapsulated after adding magnesium stearate and remaining 30% amount carboxymethylstach sodium mix homogeneously. |
Embodiment 29 Aripiprazole sheets (5mg/ sheet) prescription and preparation method
| Medicine | Aripiprazole 5 (3.6%) (no pretreatment) |
| Adjuvant | Lactose 60, sucrose 20, tween 80 0.5, microcrystalline Cellulose 40, crospolyvinylpyrrolidone 10, magnesium stearate 1 |
| 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, tween 80, citric acid and ethanol are mixed, add the sucrose mixing and make the acid liquid of pastille.Crospolyvinylpyrrolidone and sodium citrate mix homogeneously with lactose, microcrystalline Cellulose, 50% amount, add the acid liquid of above-mentioned pastille and stir granulation, granulate behind the wet grain drying, tabletting behind the crospolyvinylpyrrolidone mix homogeneously of adding magnesium stearate and 50% amount. |
The mensuration of Aripiprazole particle diameter in effect embodiment 1 comparative example 1 and 2, embodiment 1 and 2 the Aripiprazole granule
Test instrunment: BT-9300S laser particle size distribution instrument; BT-800 Automatic Cycle sampling system.
Test condition: the medium in the circulation sampling system is a water, and volume is about 570ml, and the centrifugal pump rotating speed is 1600rpm.
Method of testing: get granule 2g, add the circulation sampling system, the system absorbance of making reaches about 15%, opens ultra-sonic dispersion 3 minutes, and continuous 6 sampling tests obtain the particle diameter meansigma methods:
Annotate: D
10, D
50And D
90Be respectively that the cumulative particle sizes percentile reaches 10%, 50% and 90% o'clock pairing particle diameter.
Effect embodiment 2 dissolution comparative experimentss
1) the Aripiprazole sheet determination of dissolution rate that makes of comparative example 3 and embodiment 3～5
Dissolution determination method: sample thief, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C, second method), acetate buffer (0.05mol/L acetic acid-0.05mol/L sodium acetate=16.4: 3.6) 500ml with pH4.0 is a solvent, rotating speed is that per minute 50 changes, and solution 5ml was got in operation respectively at 5,10,20,30,45 minutes in accordance with the law, mend 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 of Chinese Pharmacopoeia version in 2005 D), is filler with octadecylsilane chemically bonded silica; With methanol-0.1% triethylamine solution (90: 10) is 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) the Aripiprazole sheet determination of dissolution rate that makes of embodiment 7 and embodiment 8
Dissolution determination method is the same, result such as following table:
Effect embodiment 3 stable comparative experimentss
Laboratory sample: comparative example 3, embodiment 3～5 and 8 Aripiprazole sheet
Behind sample packaging, in 40 ℃ ± 2 ℃ of temperature, place under the condition of relative humidity 75% ± 5%, character, content, dissolution and related substance are checked in sampling March.
Content and method for determination related substances: sample thief is an amount of, makes dissolving with the ultrasonic jolting of mobile phase, make to contain an amount of solution of Aripiprazole among every ml approximately, and as need testing solution, and the preparation contrast solution.Measuring respectively according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2005 D), is filler with octadecylsilane chemically bonded silica; With methanol-0.1% triethylamine solution (90: 10) is mobile phase; The detection wavelength is 255nm, and Determination on 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 the 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 in 2005 XE uniformity of dosage units inspection technique, measure every content (content assaying method is with effect embodiment 3), and calculate uniformity of dosage units (A+1.80S).
Claims (20)
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 acid liquid of pastille; Afterwards, with adjuvant and the acid liquid uniform mixing of described pastille, carry out wet granulation.
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, and better is 2%～15%, best is 2.5～9%.
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 hydrochloric acid, citric acid, malic acid, lactic acid, hydrobromic acid, nitric acid, sulphuric acid, fumaric acid, succinic acid, maleic acid, acetic acid and the phosphoric acid one or more,
Better is hydrochloric acid, citric acid, malic acid or lactic acid.
4. as each described method of claim 1～3, it is characterized in that: the consumption of described acidulant is for making 1～1.2 times of the consoluet minimum of Aripiprazole, 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 Aripiprazole is 0.7～2.0, and preferable is 0.9～1.3.
6. method as claimed in claim 1 or 2 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.
7. as the described method of claim 1～6, it is characterized in that: the solvent in the described acid solution that contains acidulant is the mixed liquor of organic solvent or water and organic solvent; Described organic solvent is for being better than the medicament field acceptable solvent of water to the dissolubility of Aripiprazole;
What the mixed liquor of described water and organic solvent was preferable is the ethanol water of mass percent 30%～95%, and better is the ethanol water of mass percent 50%～75%.
8. method as claimed in claim 7 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 10～75%.
9. method as claimed in claim 1 or 2, 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 0.9～1.2 times a hydrochloric acid of Aripiprazole mole.
10. as each described method of claim 1～9, it is characterized in that: described Aripiprazole 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 acid liquid of gained pastille and adjuvant uniform mixing, carry out wet granulation then;
Wherein, when adding the water-solubility carrier of solid dispersion and Aripiprazole 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 Aripiprazole 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, Tween 80, polyoxyethylene stearate 40 esters, lactose, mannitol, sucrose, beta-schardinger dextrin-and the maltose alcohol one or more.
11. method as claimed in claim 10 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.
12. as each described method of claim 1～11, it is characterized in that: when the described pastille acidity of preparation liquid, when solvent is ethanol water, be warming up to 40 ℃～70 ℃, better is warming up to 50～65 ℃.
13. as each described method of claim 1～12, it is characterized in that: carry out described with the acid liquid uniform mixing of adjuvant and described pastille, when carrying out the step of wet granulation, also add basifier, the acidity of mixed liquor that makes the acid liquid of basifier and pastille is with respect to the acidity reduction of the acid liquid of pastille.
14. method as claimed in claim 13 is characterized in that: described basifier is the conjugate base of inorganic strong alkali, weak acid strong alkali salt, organic monoacid, or acidity is lower than the highly acid acidulant, and can with the right acid of its formation buffering,
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.
15. method as claimed in claim 13 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,
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, hydrochloric acid and sodium acetate, citric acid and sodium citrate, malic acid and natrium malicum, acetic acid and sodium acetate, 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.
16. method as claimed in claim 15 is characterized in that: the consumption of described acidulant and basifier satisfies following relation: formula 1 income value is 0.01～1.5, and better is 0.1～1.2;
(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.
17. method as claimed in claim 13, 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.
18., it is characterized in that: carry out concrete operations by in the following mode any as each described method of claim 13～17:
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;
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.
19. as each described method of claim 1～18, it is characterized in that: the Aripiprazole solid particle that will make as each described method of claim 1～18 through further conventional steps, makes Aripiprazole tablet or Aripiprazole capsule.
20. the Aripiprazole solid preparation that makes as each described method of claim 1～19.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102473507A CN102106826B (en) | 2009-12-29 | 2009-12-29 | Aripiprazole solid preparation and preparation method thereof |
| PCT/CN2010/080344 WO2011079766A1 (en) | 2009-12-29 | 2010-12-28 | Aripiprazole solid preparation and the production method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009102473507A CN102106826B (en) | 2009-12-29 | 2009-12-29 | Aripiprazole solid preparation and preparation method thereof |
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| CN102106826A true CN102106826A (en) | 2011-06-29 |
| CN102106826B CN102106826B (en) | 2013-06-05 |
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| CN (1) | CN102106826B (en) |
| WO (1) | WO2011079766A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013000391A1 (en) * | 2011-06-27 | 2013-01-03 | 上海中西制药有限公司 | Aripiprazole medicament formulation and preparation method therefor |
| CN106074415A (en) * | 2016-07-22 | 2016-11-09 | 南京正大天晴制药有限公司 | A kind of aripirazole tablets and preparation method thereof |
| CN109419772A (en) * | 2017-08-23 | 2019-03-05 | 北京罗诺强施医药技术研发中心有限公司 | The method and pharmaceutical composition of nose administration treatment mental disease |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150174247A1 (en) * | 2012-06-29 | 2015-06-25 | Maruishi Pharmaceutical Co., Ltd. | Oral pharmaceutical preparation of aripiprazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100336509C (en) * | 2004-06-18 | 2007-09-12 | 成都康弘科技实业（集团）有限公司 | Aripiprazole orally disintegrating tablet formulation and its preparing method |
| CA2594690C (en) * | 2005-01-27 | 2013-08-27 | Sandoz Ag | Salts of aripiprazole |
| EP1879865A1 (en) * | 2005-04-15 | 2008-01-23 | Medichem S.A. | Syntheses and preparations of polymorphs of crystalline aripiprazole |
| PL1808164T3 (en) * | 2006-01-05 | 2009-06-30 | Teva Pharma | Wet granulation method for preparing pharmaceutical compositions of aripiprazole |
| EP1880714A1 (en) * | 2006-07-20 | 2008-01-23 | Helm AG | Amorphous Aripiprazole and Process for the Preparation thereof |
| CN101804038A (en) * | 2010-01-06 | 2010-08-18 | 赵守明 | Huperzine A preparation for treating schizophrenia and nervous function damage and preparation method thereof |
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2009
- 2009-12-29 CN CN2009102473507A patent/CN102106826B/en active Active
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| WO2013000391A1 (en) * | 2011-06-27 | 2013-01-03 | 上海中西制药有限公司 | Aripiprazole medicament formulation and preparation method therefor |
| GB2505860A (en) * | 2011-06-27 | 2014-03-12 | Shanghai Zhongxi Pharmaceutical Corp | Aripiprazole medicament formulation and preparation method therefor |
| US20140135343A1 (en) * | 2011-06-27 | 2014-05-15 | Shanghai Zhongxi Pharmaceutical Corporation | Aripiprazole medicament formulation and preparation method therefor |
| US9241876B2 (en) * | 2011-06-27 | 2016-01-26 | Shanghai Zhongxi Pharmaceutical Corporation | Aripiprazole medicament formulation and preparation method therefor |
| GB2505860B (en) * | 2011-06-27 | 2018-10-31 | Shanghai Zhongxi Pharmaceutical Corp | Aripiprazole medicament formulation and preparation method therefor |
| CN106074415A (en) * | 2016-07-22 | 2016-11-09 | 南京正大天晴制药有限公司 | A kind of aripirazole tablets and preparation method thereof |
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| CN109419772A (en) * | 2017-08-23 | 2019-03-05 | 北京罗诺强施医药技术研发中心有限公司 | The method and pharmaceutical composition of nose administration treatment mental disease |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011079766A1 (en) | 2011-07-07 |
| CN102106826B (en) | 2013-06-05 |
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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. |