CN103393594A - Novel aripiprazole preparation composition - Google Patents
Novel aripiprazole preparation composition Download PDFInfo
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- CN103393594A CN103393594A CN2013103674711A CN201310367471A CN103393594A CN 103393594 A CN103393594 A CN 103393594A CN 2013103674711 A CN2013103674711 A CN 2013103674711A CN 201310367471 A CN201310367471 A CN 201310367471A CN 103393594 A CN103393594 A CN 103393594A
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Abstract
The invention provides a novel aripiprazole preparation composition, and particularly relates to an oral administration drug solution composition which comprises 1.6-2.5mg/ml aripiprazole, an appropriate solvent system (water, a surfactant and a water-soluble thickening agent) and a pH stabilizing agent, wherein pH of a solution is 3.4 to 4.5. The drug solution composition is stable, and higher in drug loading capacity, and facilitates administration.
Description
Technical field
The present invention relates to a kind of compositions of Aripiprazole liquid solution preparation of oral administration.
Technical background
Schizophrenia is a kind of common mental disease, according to World Health Organization (WHO), estimates, the schizoid lifelong prevalence in the whole world is probably 3.8 ‰-8.4 ‰, schizophrenia cause of disease complexity, and still illustrate fully at end.A lot of diseases, in person between twenty and fifty, show as many-sided obstacles such as perception, thinking, emotion, volitional behavior, and ergasia and surrounding and inner experience are inharmonious, are divorced from reality.Take early to find, the principle of early treatment, antipsychotic medications should, as the treatment measure of first-selection, be also the important component part for the treatment of.
Aripiprazole, chemical name: 7-[4-[4-(2,3-Dichlorobenzene base)-1-piperazinyl]-butoxy]-3, the 4-dihydro-quinolinone.U.S. food and FAD FDA are in approval listing on November 15th, 2002 aripiprazole drug substance commodity Abilify by name.Aripiprazole is a kind of atypical antischizophrenic medicine, and the antagonism that reaches the 5-HT2A receptor by the part agonism to D2 and 5-HTlA receptor produces schizophrenia effect (US4734146 and US5005628).Abilify has oral solid formulation and oral administration solution preparation at present.Its oral administration solution drug loading is low, and pH value is little, and zest is large, and adopts complicated solvent system.Pharmaceutical composition drug loading of the present invention and pH value are all large and solvent system is simple, when improving patient's compliance, have also reduced the production cost of medicine.
Summary of the invention
The present invention relates to the pharmaceutical solution formulations compositions for oral administration, said composition comprises Aripiprazole, suitable dicyandiamide solution and pH stabilizing agent.The concentration that exists of Aripiprazole is 1.6mg/ml to 2.5mg/ml, and preferred concentration is 2mg/ml to 2.5mg/ml, and convenient for drug administration, the concentration of Aripiprazole is 2mg/ml more preferably.
Aripiprazole be a kind of be insoluble drug, the saturated concentration in water, ethanol is less than 10
-4G/ml, and the dissolubility of Aripiprazole can be improved significantly in acid water, for example Aripiprazole can be dissolved in acetic acid, and concentration can reach 0.1g/ml.The invention provides a kind of pH and be 3.4 to 4.5 compositions, can effectively improve the dissolubility of Aripiprazole at water, the preferred 3.4-4.0 of pH, maximize in order to make drug solubility, and pH is 3.4-3.6 more preferably.
In the said compositions of the present invention, add the pH stabilizing agent, be used to the pH that remains compositions, be stabilized in acidity.This stabilizing agent is selected from pH buffer salt commonly used, for example citric acid-sodium citrate, acetic acid-sodium acetate and tartaric acid-sodium tartrate, and the pH buffer salt is preferably citric acid-sodium citrate or acetic acid-sodium acetate.Wherein the mol ratio of said citric acid-sodium citrate is 16: 4 to 11: 9, and acetic acid-sodium acetate preferred molar ratio is 16: 4 to 13: 7, and in order to obtain acid larger liquid environment, more preferably mol ratio is 16: 4 to 15: 5.
According to the compositions of above-mentioned pH value, the present invention finds that a kind of mixing water dicyandiamide solution can further make drug solubility get a promotion, and reaches 1.6mg/ml to 2.5mg/ml.Said dicyandiamide solution comprises water, surfactant and thickening agent, the ratio that they exist is 100: 0.01-5: 1-10w/w, preferred proportion is 100: 0.1-5: 1-6w/w, the fill of drug solution when good viscosity is conducive to produce, dicyandiamide solution more preferably ratio is 100: 0.5-5: 1-5w/w, surfactant can effectively improve the dissolving of Aripiprazole, and the further preferred proportion of dicyandiamide solution is 100: 5-10: 1-5w/w.
Compositions of the present invention relates to be used to promoting the surfactant of drug solubility, wherein surfactant is a kind of pharmaceutically useful surfactant, preferably poloxamer cohort or polysorbate cohort is a kind of as surfactant, in order to reach good solubilizing effect, surfactant is a kind of as surfactant in PLURONICS F87, poloxamer188, polysorbate60 and polysorbate80 more preferably, further preferred PLURONICS F87 or the polysorbate80 of using.
compositions of the present invention relates to the thickening agent that increases liquid viscosity and density, this thickening agent is selected from the water soluble polymer polymerization, said high molecular weight water soluble polymer is selected from hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, polyvidone, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, gelatin and agar, preferred hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, polyvidone, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, some thickening agent can promote the solubility property of liquid, more preferably propyl methocel, sodium carboxymethyl cellulose, polyvidone.
The viscosity that the said compositions of the present invention is suitable, be beneficial to the canned of liquid.5 centipoise to 150 centipoises when said liquid viscosity is selected in 20 ℃, viscosity are 5 centipoise to 100 centipoises in the time of 20 ℃ more preferably, and in order to keep the mobility that liquid is good, viscosity is preferred 5 centipoise to 50 centipoises in the time of 20 ℃ further.
In order better to illustrate, technical scheme of the present invention below provide some embodiment, but the present invention is not limited in following examples.
Embodiment 1
The amount of annotating 1,2 citric acid and sodium citrate can be omited the pH value of solution that inching will criticize and transfer to 3.4-3.6;
The sweeting agent of notes 3 also can be selected other medicinal sweeting agents;
The essence of notes 4 also can be selected other common medicine essence.
1. in proportion container, add a part of water (approximately 90%), temperature rises to approximately 50 ℃, adds PLURONICS F87, and appropriateness stirs continuously, is adding wherein benzoic acid, until all dissolve.
2. keep temperature and the mixing speed of previous step, add sodium carboxymethyl cellulose, until all dissolve, solution is even.
3. keep suitable continuous stirring, temperature is down to room temperature, adds Aripiprazole and mixes, and the range estimation medicine dissolves fully.
4. keep suitable continuous stirring, citric acid and sodium citrate, regulate between pH to 3.4-3.6 wherein
5. keep suitable continuous stirring, in the solution of step 4, add sucralose, after range estimation is all dissolved, add Fructus Citri tangerinae essence to mix.
6. keep suitable continuous stirring, to remaining water in adding in the solution of step 5 in batches and mix.
7. the solution of step 6, filter by a kind of defecator.
Embodiment 2
| Composition | mg/ml |
| Aripiprazole | 2.0 |
| Citric acid 1 | 15.4 |
| Sodium citrate 2 | 5.2 |
| Polysorbate80 | 50 |
| HPMC E5 | 20 |
| Ethyl hydroxybenzoate | 1.5 |
| Sodium benzoate | 0.5 |
| Aspartane 3 | 1 |
| Fructus Citri tangerinae essence 4 | 0.5 |
| Water | In right amount |
The amount of annotating 1,2 citric acid and sodium citrate can be omited the pH value of solution that inching will criticize and transfer to 3.4-3.6;
The sweeting agent of notes 3 also can be selected other medicinal sweeting agents;
The essence of notes 4 also can be selected other common medicine essence.
1. in proportion container, add a part of water (approximately 90%), temperature rises to approximately 50 ℃, adds polysorbate80, and appropriateness stirs continuously, is adding wherein ethyl hydroxybenzoate and sodium benzoate, until all dissolve.
2. keep temperature and the mixing speed of previous step, add HPMC E5, until all dissolve, solution is even.
3. keep suitable continuous stirring, temperature is down to room temperature, adds Aripiprazole and mixes, and the range estimation medicine dissolves fully.
4. keep suitable continuous stirring, citric acid and sodium citrate, regulate between pH to 3.4-3.6 wherein
5. keep suitable continuous stirring, in the solution of step 4, add Aspartane, after range estimation is all dissolved, add Fructus Citri tangerinae essence to mix.
6. keep suitable continuous stirring, to remaining water in adding in the solution of step 5 in batches and mix.
7. the solution of step 6, filter by a kind of defecator.
Embodiment 3
| Composition | mg/ml |
| Aripiprazole | 2.0 |
| Citric acid 1 | 15.4 |
| Sodium citrate 2 | 5.2 |
| PLURONICS F87 | 30 |
| Polyvinylpyrrolidone K-15 | 10 |
| Benzoic acid | 1.5 |
| Sucralose 3 | 1 |
| Orange flavor 4 | 0.5 |
| Water | In right amount |
The amount of annotating 1,2 citric acid and sodium citrate can be omited the pH value of solution that inching will criticize and transfer to 3.4-3.6;
The sweeting agent of notes 3 also can be selected other medicinal sweeting agents;
The essence of notes 4 also can be selected other common medicine essence.
1. in proportion container, add a part of water (approximately 90%), temperature rises to approximately 50 ℃, adds PLURONICS F87, and appropriateness stirs continuously, is adding wherein benzoic acid, until all dissolve.
2. keep temperature and the mixing speed of previous step, add polyvinylpyrrolidone K-15, until all dissolve, solution is even.
3. keep suitable continuous stirring, temperature is down to room temperature, adds Aripiprazole and mixes, and the range estimation medicine dissolves fully.
4. keep suitable continuous stirring, citric acid and sodium citrate, regulate between pH to 3.4-3.6 wherein
5. keep suitable continuous stirring, in the solution of step 4, add sucralose, after range estimation is all dissolved, add orange flavor to mix.
6. keep suitable continuous stirring, to remaining water in adding in the solution of step 5 in batches and mix.
7. the solution of step 6, filter by a kind of defecator.
Claims (8)
1. the drug solution compositions of an oral administration, comprising Aripiprazole, pH stabilizing agent and dicyandiamide solution, is characterized in that described Aripiprazole exists with 1.6mg/ml to 2.5mg/ml; Described pH value of solution is 3.4 to 4.0; Described pH stabilizing agent is selected from the buffer salt combination, comprises citric acid-sodium citrate, acetic acid-sodium acetate, tartaric acid-sodium tartrate; Described dicyandiamide solution is comprised of water, surfactant, thickening agent, and wherein said surfactant is pharmaceutically useful surfactant, and described thickening agent is pharmaceutically useful high molecular weight water soluble polymer.
2. drug solution compositions according to claim 1, its pH value of solution is 3.4-3.6.
3. drug solution compositions according to claim 1, wherein the pH stabilizing agent is the combination of citric acid-sodium citrate buffer salt, mol ratio is 16: 4 to 13: 7.
4. drug solution compositions according to claim 1, the ratio that wherein in dicyandiamide solution, water, surfactant and thickening agent form is 100: 0.01-5: 1-10 (w/w).
5. according to claim 1, wherein surfactant is poloxamer and/or polysorbate group.
6. according to claim 1, wherein the thickening agent high molecular weight water soluble polymer is one or more in hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, polyvidone, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, gelatin, agar.
7. according to claim 6, its thickening agent high molecular weight water soluble polymer is hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone.
8. drug solution compositions according to claim 1,5 centipoise to 150 centipoises when its solution viscosity is 20 ℃.
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| CN2013103674711A CN103393594A (en) | 2013-08-22 | 2013-08-22 | Novel aripiprazole preparation composition |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103720654A (en) * | 2014-01-10 | 2014-04-16 | 无锡万全医药技术有限公司 | Aripiprazole micro-emulsion preparation and preparation method thereof |
| CN104906038A (en) * | 2015-06-24 | 2015-09-16 | 万特制药(海南)有限公司 | Aripiprazole nanocrystal and preparation method thereof |
| CN106539752A (en) * | 2015-09-18 | 2017-03-29 | 成都康弘药业集团股份有限公司 | A kind of oral administration solution containing Aripiprazole and preparation method thereof |
| CN109498556A (en) * | 2017-09-15 | 2019-03-22 | 万特制药(海南)有限公司 | Aripiprazole oral solution and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1512884A (en) * | 2001-04-25 | 2004-07-14 | ����˹�ж�-����˹˹������˾ | Aripiprazole oral solution |
| WO2008038003A2 (en) * | 2006-09-26 | 2008-04-03 | Zysis Limited | Pharmaceutical compositions of aripiprazole |
| CN102846543A (en) * | 2011-06-27 | 2013-01-02 | 上海中西制药有限公司 | Aripiprazole pharmaceutic preparation and preparation method thereof |
-
2013
- 2013-08-22 CN CN2013103674711A patent/CN103393594A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1512884A (en) * | 2001-04-25 | 2004-07-14 | ����˹�ж�-����˹˹������˾ | Aripiprazole oral solution |
| WO2008038003A2 (en) * | 2006-09-26 | 2008-04-03 | Zysis Limited | Pharmaceutical compositions of aripiprazole |
| CN102846543A (en) * | 2011-06-27 | 2013-01-02 | 上海中西制药有限公司 | Aripiprazole pharmaceutic preparation and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 黄琳: "阿立哌唑口服液获美国FDA批准上市", 《上海医药》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103720654A (en) * | 2014-01-10 | 2014-04-16 | 无锡万全医药技术有限公司 | Aripiprazole micro-emulsion preparation and preparation method thereof |
| CN104906038A (en) * | 2015-06-24 | 2015-09-16 | 万特制药(海南)有限公司 | Aripiprazole nanocrystal and preparation method thereof |
| CN106539752A (en) * | 2015-09-18 | 2017-03-29 | 成都康弘药业集团股份有限公司 | A kind of oral administration solution containing Aripiprazole and preparation method thereof |
| CN106539752B (en) * | 2015-09-18 | 2019-10-29 | 成都康弘药业集团股份有限公司 | A kind of oral administration solution and preparation method thereof containing Aripiprazole |
| CN109498556A (en) * | 2017-09-15 | 2019-03-22 | 万特制药(海南)有限公司 | Aripiprazole oral solution and preparation method thereof |
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