CN104906038A - Aripiprazole nanocrystal and preparation method thereof - Google Patents
Aripiprazole nanocrystal and preparation method thereof Download PDFInfo
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- CN104906038A CN104906038A CN201510350199.5A CN201510350199A CN104906038A CN 104906038 A CN104906038 A CN 104906038A CN 201510350199 A CN201510350199 A CN 201510350199A CN 104906038 A CN104906038 A CN 104906038A
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- aripiprazole
- nanocrystal suspension
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Abstract
The invention belongs to the field of medicines and in particular relates to aripiprazole nanocrystal suspension and a preparation method thereof. Concretely, the nanocrystal suspension is composed of active ingredients such as aripiprazole, a stabilizing agent and an antiseptic substance; and the preparation method of the nanocrystal suspension adopts one or a combination of more than one of a precipitation method, an emulsification method, a high pressure homogenization method, a medium milling method and a high pressure microjet method. The nanocrystal suspension provided by the invention can be used for effectively solving the problem that solubility of aripiprazole is low, can mask bitter, astringent and pungent tastes of aripirazole and has a good market prospect.
Description
Technical field
The invention belongs to medical art, relate to a kind of pharmaceutical composition for the treatment of psychosis class medicine Aripiprazole.Particularly, a kind of Aripiprazole nanocrystal suspension and preparation method thereof is related to.
Background technology
Schizophrenia is the not bright major psychosis of one group of cause of disease, clinical signs is the inharmonious of many-sided obstacles such as sensory perception, thinking, emotion and behavior and ergasia, be mainly in the person between twenty and fifty between 16 to 25 years old, patient often produces the symptoms such as auditory hallucination, hallucination, vain hope and emotion cognition obstacle.
Aripiprazole chemistry 7-[4-[4-(2 by name, 3-Dichlorobenzene base)-1-piperazinyl]-butoxy]-3,4-dihydro-2(1 hydrogen)-quinolinone, belong 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, obtain U.S. FDA approval listing in November, 2002, being that one is atypical is used for the treatment of schizoid antipsychotic drug.The existing preparation of Aripiprazole mainly contains conventional tablet, oral cavity disintegration tablet, injection, oral solution etc., and listing dosage form is wherein based on oral solid formulation.Due to the particularity of PATIENT POPULATION, patient has any problem when swallowing solid oral dosage form, and oral liquid can not only increase patient's compliance, is also convenient to doctor and designs therapeutic scheme more neatly.
Aripiprazole is poorly water soluble drugs, is prepared into oral liquid and need adds the acceptable adjunct ingredient of other pharmacy to increase its dissolubility or to make it be in stable system.Existing oral liquid generally makes solution by adding polyhydric alcohol, cyclodextrin, surfactant etc., or adds all kinds of suspending agent and suspensoid made by stabilizing agent, or makes the dosage forms such as microsphere microemulsion.Make solution or common suspension generally need add correctives and improve mouthfeel, easily drug safety is caused a hidden trouble; Its complicated process of preparation of microsphere microemulsion, complex operation, cost is higher, is unfavorable for that industrialization is produced, and by preparation characteristics influence, drug dose is wayward.
For above problem, the present invention develops a kind of Aripiprazole nanocrystal suspension.Nanocrystalline drug tool has the following advantages: (1) drug dose is controlled flexibly: directly by medicament nano, and without the need to by carrier material, therefore preparation is by the restriction of envelop rate and medicine carrying; (2) diameter of aspirin particle controllable precise: due to medicine self nanorize, particle size results truly can reflect the size of medicament nano crystal; (3) to the taste masking effect of medicine: medicine is carried out nanorize, make medicine crystal have the effect of taste masking, be specially adapted to the oral compliance improving liquid preparation; (4) preparation method is simple to operate, is applicable to industrialized great production, commonly uses nanocrystal preparation method as media mill method, high pressure homogenization method, the sedimentation method, or multiple technology couplings etc.Aripiprazole is prepared into nanocrystal suspension, not only can improves the dissolubility of medicine in water, and have certain taste masking effect to medicine, patient's compliance can be improved.
Summary of the invention
In view of the foregoing, the invention provides a kind of Aripiprazole nanocrystal suspension and preparation method thereof.
The component that Aripiprazole nanocrystal suspension comprises has: (1) effective ingredient Aripiprazole; (2) the acceptable stabilizing agent of pharmacy; (3) antiseptic; (4) appropriate water.
Aripiprazole nanocrystal suspension according to any one of the present invention, the mean diameter of Aripiprazole is 10-1000nm; Be preferably 100-300nm.
Above-mentioned Aripiprazole nanocrystal suspension, its PDI(polydispersity index, polydispersity index) be less than 0.5.
Above-mentioned Aripiprazole content is 0.01mg/ml to 10mg/ml, is preferably 0.1mg/ml to 3mg/ml.
Above-mentioned stabilizing agent comprise in hypromellose, pluronic, polyvidone, polysorbate, poloxamer, tween, hyprolose, polyvinyl alcohol, arabic gum, tragakanta, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, glucosan, mannitol, saccharide (such as glucose, fructose or sucrose), sodium lauryl sulphate, docusate sodium, arginine salt and sodium chloride any one or multiple; Be preferably hypromellose and poloxamer.Its consumption is 0.01-50%(w/v), be preferably 0.01-20%(w/v).
Above-mentioned antiseptic be selected from benzoic acid, sorbic acid, sodium benzoate, potassium sorbate, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben one or more.Its consumption is 0.01-2%(w/v), be preferably 0.2-0.5%(w/v).
Another aspect of the present invention relates to the preparation method of the Aripiprazole nanocrystal suspension according to any one of the present invention, and it comprises step Aripiprazole, stabilizing agent, antiseptic and water being made suspension;
Particularly, the mixture of Aripiprazole, stabilizing agent and water is adopted one or more method couplings in the sedimentation method, emulsion process, high pressure homogenization method, media mill method or high pressure microjet method, makes Aripiprazole nanosuspension; Preferably, media mill method and high pressure homogenization method coupling is adopted.
More specifically, the mixture of Aripiprazole, stabilizing agent, antiseptic and water is added in ball mill, and the rotating speed of ball mill is risen to 500-4000r/min gradually, be preferably 2000-3000r/min, and keep this rotating speed to mill 0.5-20h, be preferably 1-5h; Subsequently mixture is transferred in high pressure homogenizer, under 10-100MPa pressure, is preferably 20-80MPa, and keep this pressure to carry out 3-10 circulation, be preferably 5-6 time.
Preparation method according to any one of the present invention, also comprises pre-treatment step: Aripiprazole is crossed 40-300 mesh sieve, preferably 100 mesh sieves.
Preparation method according to any one of the present invention, wherein, the mixture of described Aripiprazole, stabilizing agent, antiseptic and water obtains as follows: be dispersed in by Aripiprazole in suitable quantity of water, is separately dissolved in suitable quantity of water by stabilizing agent and antiseptic, both mixing, obtained mixture.
Particle diameter in the present invention or mean diameter can the method known of those skilled in the art measure, such as, recorded by Malvern nano particle size instrument, Malvern laser particle analyzer, Beckman Coulter nano particle size instrument and ZETA potentiometric analyzer etc.
Specific embodiments
Below in conjunction with detailed description of the invention, the present invention is described in further detail, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturer suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
embodiment 1:the preparation of Aripiprazole nanocrystal suspension (1)
Prescription forms:
Preparation method:
By said ratio, principal agent Aripiprazole crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, and particle diameter is about 10-150 μm.Medicine is dispersed in suitable quantity of water, separately PLURONICS F87, sodium benzoate are dissolved in suitable quantity of water, both mixing, obtained mixture, then pass through media mill legal system for thick suspension, rotating speed is 2000rpm, grinding time 1h, again mixture is passed through high pressure homogenizer legal system for nanocrystal suspension, pressure is 100MPa, circulates 5 times.
embodiment 2:the preparation of Aripiprazole nanocrystal suspension (2)
Prescription forms:
Preparation method:
By said ratio, principal agent Aripiprazole crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, and particle diameter is then 10-150 μm.Be dispersed in by medicine in suitable quantity of water, be separately dissolved in suitable quantity of water by polyvidone, docusate sodium, sorbic acid, both mixing, obtained mixture, then pass through high pressure microjet legal system for nanocrystal suspension, cycle-index is 10 times.
embodiment 3:the preparation of Aripiprazole nanocrystal suspension (3)
Prescription forms:
Preparation method:
By said ratio, principal agent Aripiprazole crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, and particle diameter is then 10-150 μm.Be dispersed in by medicine in suitable quantity of water, be separately dissolved in suitable quantity of water by methylcellulose, arginine salt, benzoic acid, both mixing, obtained mixture, then pass through media mill legal system for nanocrystal suspension, rotating speed is 4000rpm, grinding time 2h.
grain diameter measurement is tested
1, experiment material
Aripiprazole nanocrystal suspension, pure water prepared by sample: embodiment 1-3.
Instrument: Malvern nano particle size instrument and ZETA potentiometer.
2, experimental technique
Get Aripiprazole nanocrystal suspension prepared by 0.5ml in cillin bottle, add 4.5ml pure water and dilute 10 times, measure particle diameter (mean diameter) and PDI with Malvern nano particle size instrument and ZETA potentiometer.
3, experimental result
| Project | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Mean diameter/nm | 180.5 | 271. | 230.1 |
| PDI | 0.156 | 0.237 | 0.387 |
Result shows, Aripiprazole nanocrystal suspension particle diameter of the present invention is between 100-500nm, and PDI is below 0.5, and particle size distribution is narrower.
stability experiment
1, experiment material
Aripiprazole nanocrystal suspension, pure water prepared by test sample: embodiment 1-3.
Instrument: Malvern nano particle size instrument and ZETA potentiometer.
2, experimental technique
Aripiprazole nanocrystal suspension prepared by embodiment 1-3, places 1 day, 3 days, 5 days, 10 days respectively under room temperature condition, measure particle diameter and PDI, and compare with 0 day particle size results with Malvern nano particle size instrument and ZETA potentiometer.
Before measurement, get Aripiprazole nanocrystal suspension prepared by 0.5ml embodiment 1-3 respectively in cillin bottle, add 4.5ml pure water and dilute 10 times, measure particle diameter and PDI with Malvern nano particle size and ZETA potentiometer.
3, experimental result
Result shows, Aripiprazole nanocrystal suspension room temperature prepared by embodiment 1-3 is placed all more stable.
preparation mouthfeel is investigated
1, experiment material
Test sample: Aripiprazole nanocrystal suspension prepared by embodiment 1 and 3mg/ml Aripiprazole suspension.
Personnel: volunteer 6.
2, experimental technique
The Aripiprazole suspension 20ml of Aripiprazole nanocrystal suspension 20ml and 3mg/ml prepared by the oral embodiment 1 of every 3 volunteers difference, evaluates the mouthfeel of Aripiprazole nanocrystal suspension.
3, experimental result
Result shows, Aripiprazole is prepared into nanocrystal suspension, effectively can cover the bitterness fiber crops mouthfeel that Aripiprazole sodium has.
Claims (10)
1. an Aripiprazole nanocrystal suspension, is characterized in that: containing as the Aripiprazole of active component, stabilizing agent, antiseptic and appropriate water.
2. nanocrystal suspension according to claim 1, is characterized in that the mean diameter of described Aripiprazole is 10-1000nm, is preferably 100-300nm.
3. nanocrystal suspension according to claim 1, is characterized in that its PDI(polydispersity index, polydispersity index) be less than 0.5.
4. nanocrystal suspension according to claim 1, is characterized in that described Aripiprazole content is 0.01mg/ml to 10mg/ml, is preferably 0.1mg/ml to 3mg/ml.
5. nanocrystal suspension according to claim 1, it is characterized in that in described stabilizer package hypromellose, pluronic, polyvidone, polysorbate, poloxamer, tween, hyprolose, polyvinyl alcohol, arabic gum, tragakanta, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, glucosan, mannitol, saccharide, sodium lauryl sulphate, docusate sodium, arginine salt and sodium chloride any one or multiple; Be preferably hypromellose and poloxamer.
6. stabilizing agent according to claim 4, is characterized in that its consumption is 0.01-50%(w/v), be preferably 0.01-20%(w/v).
7. nanocrystal suspension according to claim 1, it is characterized in that described antiseptic is selected from benzoic acid, sorbic acid, sodium benzoate, potassium sorbate, methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben one or more.
8. antiseptic according to claim 6, is characterized in that its consumption is 0.01-2%(w/v), be preferably 0.2-0.5%.
9. nanocrystal suspension according to claim 1, is characterized in that its preparation method is adopt one or more method couplings in the sedimentation method, emulsion process, high pressure homogenization method, media mill method or high pressure microjet method; Preferable medium grinding method and high pressure homogenization method coupling; Particularly, the mixture of Aripiprazole, stabilizing agent, antiseptic and water is added in ball mill, and the rotating speed of ball mill is risen to 500-4000r/min gradually, and keep this rotating speed to mill 0.5-20h; Subsequently mixture is transferred in high pressure homogenizer, under 10-100MPa pressure, and keeps this pressure to carry out 3-10 circulation.
10. preparation method according to claim 8, is characterized in that comprising pre-treatment step: Aripiprazole is crossed 40-300 mesh sieve, preferably 100 mesh sieves; Preparation method according to claim 8, it is characterized in that the mixture of described Aripiprazole, stabilizing agent, antiseptic and water, obtain as follows: Aripiprazole is dispersed in suitable quantity of water, separately stabilizing agent and antiseptic are dissolved in suitable quantity of water, both mixing, obtained mixture.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105663057A (en) * | 2015-12-30 | 2016-06-15 | 中国药科大学 | Aripiprazole long-acting suspension and preparation method thereof |
| CN106389343A (en) * | 2016-09-24 | 2017-02-15 | 万全万特制药江苏有限公司 | Oral aripiprazole liquid dry suspension agent and preparation method thereof |
| CN108815129A (en) * | 2018-07-12 | 2018-11-16 | 天津双硕医药科技有限公司 | A kind of miscellaneous Shandong amine nanocrystal oral solid drug composition of grace |
| CN110025572A (en) * | 2018-01-11 | 2019-07-19 | 四川科伦药物研究院有限公司 | Lauroyl Aripiprazole suspension and preparation method thereof |
| CN110327296A (en) * | 2019-08-06 | 2019-10-15 | 深圳市泛谷药业股份有限公司 | A kind of Aripiprazole long acting injection and preparation method thereof |
| WO2021104460A1 (en) * | 2019-11-29 | 2021-06-03 | 江苏恩华药业股份有限公司 | Preparation method for paliperidone palmitate suspension |
| WO2023036003A1 (en) * | 2021-09-07 | 2023-03-16 | 四川科伦药物研究院有限公司 | Long-acting brexpiprazole preparation for injection and preparation method therefor |
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| 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 |
| CN103211759A (en) * | 2013-03-28 | 2013-07-24 | 中国人民解放军军事医学科学院毒物药物研究所 | Puerarin nanocrystalline medical composition and preparation method thereof |
| CN103393594A (en) * | 2013-08-22 | 2013-11-20 | 万特制药(海南)有限公司 | Novel aripiprazole preparation composition |
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Patent Citations (3)
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| 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 |
| CN103211759A (en) * | 2013-03-28 | 2013-07-24 | 中国人民解放军军事医学科学院毒物药物研究所 | Puerarin nanocrystalline medical composition and preparation method thereof |
| CN103393594A (en) * | 2013-08-22 | 2013-11-20 | 万特制药(海南)有限公司 | Novel aripiprazole preparation composition |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105663057A (en) * | 2015-12-30 | 2016-06-15 | 中国药科大学 | Aripiprazole long-acting suspension and preparation method thereof |
| CN106389343A (en) * | 2016-09-24 | 2017-02-15 | 万全万特制药江苏有限公司 | Oral aripiprazole liquid dry suspension agent and preparation method thereof |
| CN110025572A (en) * | 2018-01-11 | 2019-07-19 | 四川科伦药物研究院有限公司 | Lauroyl Aripiprazole suspension and preparation method thereof |
| CN108815129A (en) * | 2018-07-12 | 2018-11-16 | 天津双硕医药科技有限公司 | A kind of miscellaneous Shandong amine nanocrystal oral solid drug composition of grace |
| CN110327296A (en) * | 2019-08-06 | 2019-10-15 | 深圳市泛谷药业股份有限公司 | A kind of Aripiprazole long acting injection and preparation method thereof |
| CN110327296B (en) * | 2019-08-06 | 2021-10-22 | 深圳市泛谷药业股份有限公司 | Aripiprazole long-acting injection preparation and preparation method thereof |
| WO2021104460A1 (en) * | 2019-11-29 | 2021-06-03 | 江苏恩华药业股份有限公司 | Preparation method for paliperidone palmitate suspension |
| CN114980865A (en) * | 2019-11-29 | 2022-08-30 | 江苏恩华药业股份有限公司 | Preparation method of paliperidone palmitate suspension |
| CN114980865B (en) * | 2019-11-29 | 2023-07-21 | 苏州恩华生物医药科技有限公司 | Preparation method of paliperidone palmitate suspension |
| WO2023036003A1 (en) * | 2021-09-07 | 2023-03-16 | 四川科伦药物研究院有限公司 | Long-acting brexpiprazole preparation for injection and preparation method therefor |
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Application publication date: 20150916 |