CN101239043B - 5-fluorouracil self-emulsifying nano-scale freeze-dried powder and preparation thereof - Google Patents
5-fluorouracil self-emulsifying nano-scale freeze-dried powder and preparation thereof Download PDFInfo
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- CN101239043B CN101239043B CN2008100640727A CN200810064072A CN101239043B CN 101239043 B CN101239043 B CN 101239043B CN 2008100640727 A CN2008100640727 A CN 2008100640727A CN 200810064072 A CN200810064072 A CN 200810064072A CN 101239043 B CN101239043 B CN 101239043B
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Abstract
The invention discloses a preparation method of a 5-fluorouracil powder with self-emulsifiable nanometer grade. The main raw materials are: active material 5-fluorouracil medical powder, fat phase, emulsifier and natural polyelectrolyte used as carrier. The preparation method is stated as follows: 5-fluorouracil medical powder is prepared to a solution with a certain concentration by distilled water; then added with emulsifier and natural polyanion carrier are added, the mixture is stirred till the reaction is finished; the mixture liquor is poured into fat phase and stirred to emulsion which is placed still for an hour after being added with calcium chloride liquor and richly stirred; the supernatant liquid is taken off and stirred for an hour with natural polycation carrier liquor; then the final liquor after being frozen and dried is the 5-fluorouracil powder with self-emulsifiable nanometer grade. The powder with self-emulsifiable nanometer grade is characterized in that: the dispersion degree is high, the stability is good, the bioavailability of the 5-fluorouracil can be effectively elevated and the healing effect of the medicine is elevated.
Description
(1) technical field
The invention belongs to medicine 5-fluorouracil technology, be specifically related to a kind of 5-fluorouracil self-emulsifying nano-scale freeze-dried powder and preparation method thereof.
(2) background technology
(5-Fluorouacil 5-Fu) is a kind of pyrimidines antimetabolic medicine to 5-fluorouracil, since nineteen fifty-seven, exploitation was come out, has occupied important position in chemotherapy of tumors.It can be singly with or drug combination treat various types of malignant tumor.But its major defect is fat-soluble little, the oral absorption difficulty, and toxic and side effects is bigger, has limited the further application of 5-Fu.In order to prolong drug effect, reduce toxic and side effects, Chinese scholars has been carried out number of research projects.Recently, aspect the 5-Fu administering mode and the relevant basic research in drug distribution aspect very active.The macromolecule medicine carrying microballoons is the novel form that development in recent years is got up, and medicine has excellent biological compatibility and biodegradability behind its enclose, is expected to become the important drugs in the chemotherapy research.
Nanosecond science and technology are meant the characteristic and the interaction of going up research material (comprising the manipulation of atom and molecule) at nanoscale (1 nanometer is between 100 nanometers), and the Science and Technology that utilizes the multidisciplinary intersection of these characteristics.The particle diameter of nanoparticle is generally less than 1 μ m; the main distinction of it and micron particle carrier is the ultra micro small size; can the penetrate tissue gap and absorbed by cell; can be by the blood capillary of human body minimum; thereby be widely studied as new medicine carrier system; having become field very active in the research of medicine novel formulation, is the important research direction of domestic and international medicine and pharmacology.But medicine embedding or be dissolved in the inside of nanoparticle, also adsorbable or coupling is on its surface.
Self-emulsifying drug delivery system (self-emulsifying drug delivery systems, SEDDS) be by oil phase, surfactant (surfactant, SA), cosurfactant (cosurfactant, CoSA) solid of Zu Chenging or liquid preparation, its basic feature be can be in gastrointestinal tract or the situation of ambient temperature suitable (being often referred to 37 ℃) and gentle agitation under, it is Emulsion about 5um that spontaneous emulsification becomes particle diameter.When containing hydrophilic surfactant active (HLB＞12) higher (＞40%) or using cosurfactant simultaneously, under mild agitation, can make meticulous Emulsion (particle diameter＜100nm), then be called as self-micro-emulsification medicine-releasing system (Self-micro-emulsifying drugdelivery systems, SMEDDS).The SEDDS preparation can improve the dissolubility of insoluble drug and fat-soluble medicine, promotes the infiltration rate and the degree of medicine, improves bioavailability of medicament, can avoid the hydrolysis of water unstable medicine and medicine to the gastrointestinal pessimal stimulation simultaneously.SEDDS also has advantages such as taking convenience, simple, the suitable large-scale production of preparation.And SMEDDS is suitable for use as the carrier of lipotropy, low, the difficult absorption of dissolubility, facile hydrolysis medicine.Owing in preparation process, can avoid illumination or can in system, add antioxidant, thereby SMEDDS also can be used as the carrier of the medicine that needs lucifuge or easy oxidation.The spontaneous medicine carrying emulsion that is dispersed into O/W type, particle diameter less than 100nm of gastro-intestinal Fluid is met in the oral back of medicine carrying SMEDDS under physiology body temperature and gastrointestinal motility effect, at gastrointestinal tract evenly, distribute fast, increased drug solubility.
The preparation of at present relevant 5-fluorouracil all is only limited to the injectable powder of being made by common nano-scale freeze-dried powder, the oral formulations of rarer 5-fluorouracil.The someone has declared the Chinese patent of the floating in stomach delay two-layer release-controlled tablet of 5-fluorouracil in recent years, and is external also relevant for the report of 5-fluorouracil self emulsifying Emulsion, still do not have the document of the self-emulsifying nano-scale of 5-fluorouracil to disclose as yet.
(3) summary of the invention
The object of the present invention is to provide a kind of emulsifying nano-scale freeze-dried powder dispersion height, good stability can improve the bioavailability of 5-fluorouracil effectively, improves 5-fluorouracil self-emulsifying nano-scale freeze-dried powder of curative effect of medication and preparation method thereof.
5-fluorouracil self-emulsifying nano-scale freeze-dried powder of the present invention comprises: activated feedstock 5-fluorouracil medicated powder, oil phase, emulsifying agent, and natural polyanion carrier sodium alginate and natural polycation carrier chitosan, its weight proportion of composing is 1: 10-13: 2.5-3.5: 0.13-0.15: 0.11-0.13.
5-fluorouracil self-emulsifying nano-scale freeze-dried powder of the present invention also comprises some technical characterictics like this:
1, the weight ratio of described oil phase and emulsifying agent is 3: 1-4: 1, and oil phase is an ethyl oleate, emulsifying agent is a lecithin;
2, described natural polyanion carrier is a sodium alginate, and natural polycation carrier is a chitosan, and its weight ratio is 1.25: 1-1.5: 1.
The preparation method of 5-fluorouracil self-emulsifying nano-scale freeze-dried powder of the present invention is: 5-fluorouracil medicated powder is mixed with the 5-fluorouracil aqueous solution that concentration is 6mg/ml with distilled water, add emulsifying agent and natural polyanion carrier, being stirred to reaction finishes, this mixed liquor is injected oil phase, stir into 5-fluorouracil w/o type Emulsion, add again and left standstill one hour after calcium chloride solution fully stirs, get subnatant and add natural polycation carrier solution stirring one hour, with this solution lyophilization, promptly get the 5-fluorouracil self-emulsifying nano-scale freeze-dried powder.This self-emulsifying nano-scale freeze-dried powder dispersion height, good stability can improve the bioavailability of 5-fluorouracil effectively, improves the curative effect of medicine.
The preparation method of 5-fluorouracil self-emulsifying nano-scale freeze-dried powder of the present invention also has some technical characterictics like this:
1.5-the preparation of fluorouracil w/o type Emulsion:
Get emulsifier lecithin 0.4g, 5-fluorouracil aqueous solution (6mg/ml) 20ml, at 25-30 ℃, being stirred to lecithin under 1000-1200-1500 rev/min the condition dissolves fully, splash into the natural polyanion carrier sodium alginate soln 2.5ml of 6mg/ml again with the speed of 2ml/min, continue to stir 10 minutes with above-mentioned identical preparation condition, this mixed liquor slowly is injected in the 1.2-1.6g oil phase ethyl oleate, the mass ratio of emulsifier lecithin and oil phase ethyl oleate is 1: 3-1: 4, at 25-30 ℃, stir under 1200-1500 rev/min the condition and promptly got 5-fluorouracil w/o type Emulsion in 10-15 minute;
2. the preparation of self-emulsifying nano-scale freeze-dried powder:
At 25-30 ℃, under 1200-1500 rev/min the condition calcium chloride solution 15-20ml of 60mg/ml is splashed in the 5-fluorouracil W/O Emulsion with the speed of 2ml/min, the volume ratio of 5-fluorouracil w/o type Emulsion and calcium chloride solution is 4: 3-1: 1, stirred 10-15 minute, this mixed liquor is changed in the separatory funnel, left standstill one hour, get subnatant, under above-mentioned identical stirring condition, splash into 1% 1.6mg/ml acetic acid solution 7.6ml of chitosan with the speed of 2ml/min, stirred one hour, lyophilization promptly gets lyophilized powder.
The investigation index of 5-fluorouracil self-emulsifying nano-scale freeze-dried powder:
(1) self emulsifying speed
With a fixed rotating speed but the minimum stirring paddle of shearing force be contained in the glass self emulsifying pond of containing water, put into a small amount of lyophilized powder, by nephelometer, scattered intensity in the whole emulsion process is measured.Scattered light intensity reaches peaked time t at 50%, 90% o'clock
50And t
90Can be used as relative emulsification times.
(2) particle diameter of nanoparticle
Form the size of emulsion droplet behind the employing transmission electron microscope method mensuration formation self emulsifying, generally should be less than 5 μ m.
(3) envelop rate and drug loading:
Precision takes by weighing the 5-fluorouracil 0.4g that is dried to constant weight, with the dissolve with hydrochloric acid solution of 0.1mol/L and be diluted to 100mL, the accurate 1mL that draws places the 25mL volumetric flask, hydrochloric acid with 0.1mol/L is diluted to scale, draws 0.5,1 respectively, 1.5,2,2.5mL is diluted to 25mL, measures trap A value in 265nm wavelength place.With mass concentration ρ trap A is carried out linear regression, get standard curve equation: C=51.875A+0.0334 (r=0.9998)
The lyophilized powder 80mg that makes is placed volumetric flask, with the dissolving with hydrochloric acid of 0.1mol/L, filter, filtrate is settled to 1000mL, measures its ultraviolet absorptivity, has tried to achieve actual concentrations according to standard curve, calculates drug loading and envelop rate by following formula:
We can further make all kinds of solid preparations by the 5-Fu self emulsifying lyophilized powder that above technology makes, and as tablet, capsule etc. have improved the compliance that the patient takes medicine.The patient is when taking 5-Fu self-emulsification solid preparation, but this dosage form gastric in the short time self emulsifying become microemulsion, medicine just with the form of nanoparticle adhere to each organ mucosa on, because nanoparticle can be engulfed as foreign body by the macrophage misidentification in vivo the time, therefore help to improve the absorption and the therapeutic effect of medicine.
(4) description of drawings
Fig. 1 is the preparation flow figure of 5-fluorouracil self-emulsifying nano-scale freeze-dried powder.
(5) specific embodiment
Further describe the specific embodiment of the present invention below in conjunction with embodiment:
Embodiment 1:
The preparation method of 5-fluorouracil W/O Emulsion is in the present embodiment: get lecithin 0.4g, 5-fluorouracil aqueous solution (6mg/ml) 20ml, at 25-30 ℃, being stirred to lecithin under 1200-1500 rev/min the condition dissolves fully, speed with 2ml/min splashes into sodium alginate soln (6mg/ml) 2.5ml again, continue to stir 10 minutes with above-mentioned identical preparation condition, this mixed liquor slowly is injected in the 1.2g ethyl oleate, at 25-30 ℃, stir under 1200-1500 rev/min the condition and promptly got Emulsion in 10 minutes.
The preparation method of self-emulsifying nano-scale freeze-dried powder is: at 25-30 ℃, with calcium chloride solution (60mg/ml) 20ml, splash in the 5-fluorouracil W/O Emulsion under 1200-1500 rev/min the condition, stirred 10 minutes with the speed of 2ml/min, this mixed liquor is changed in the separatory funnel, left standstill one hour, and got subnatant, under above-mentioned identical stirring condition, splash into 1% acetic acid solution (1.6mg/ml) 7.6ml of chitosan with the speed of 2ml/min, stirred one hour, lyophilization promptly gets lyophilized powder.
The investigation index of 5-fluorouracil self-emulsifying nano-scale freeze-dried powder:
(1) self emulsifying speed
With a fixed rotating speed but the minimum stirring paddle of shearing force be contained in the glass self emulsifying pond of containing water, put into the 70mg lyophilized powder, by nephelometer, scattered intensity in the whole emulsion process is measured.t
50＝5min，t
90＝16.5min。
(2) particle diameter of nanoparticle
Adopt transmission electron microscope method to measure and form the emulsion droplet that forms behind the self emulsifying, most of emulsion droplet becomes the sphere of rule, smooth surface, and the quantity meansigma methods of particle diameter is 220.2nm.
(3) envelop rate and drug loading:
Precision takes by weighing the 5-fluorouracil 0.4g that is dried to constant weight, with the dissolve with hydrochloric acid solution of 0.1mol/L and be diluted to 100mL, the accurate 1mL that draws places the 25mL volumetric flask, hydrochloric acid with 0.1mol/L is diluted to scale, draws 0.5,1 respectively, 1.5,2,2.5mL is diluted to 25mL, measures trap A value in 265nm wavelength place.With mass concentration ρ trap A is carried out linear regression, get standard curve equation: C=51.875A+0.0334 (r=0.9998)
The lyophilized powder 80mg that makes is placed volumetric flask,, filter with the dissolving with hydrochloric acid of 0.1mol/L, filtrate is settled to 1000mL, and measuring its ultraviolet absorptivity is 0.847, has tried to achieve actual concentrations according to standard curve, by formula the computational envelope rate is 64.9%, and drug loading is 18.53%.
Embodiment 2:
The preparation method of 5-fluorouracil W/O Emulsion is in the present embodiment: get lecithin 0.4g, 5-fluorouracil aqueous solution (6mg/ml) 20ml, at 25-30 ℃, being stirred to lecithin under 1000-1500 rev/min the condition dissolves fully, speed with 2ml/min splashes into sodium alginate soln (6mg/ml) 2.5ml again, continue to stir 10 minutes with above-mentioned identical preparation condition, this mixed liquor slowly is injected in the 1.6g ethyl oleate, at 25-30 ℃, stir under 1200-1500 rev/min the condition and promptly got Emulsion in 10 minutes.
The preparation method of self-emulsifying nano-scale freeze-dried powder is: at 25-30 ℃, with calcium chloride solution (60mg/ml) 20ml, splash in the 5-fluorouracil W/O Emulsion under 1200-1500 rev/min the condition, stirred 10 minutes with the speed of 2ml/min, this mixed liquor is changed in the separatory funnel, left standstill one hour, and got subnatant, under above-mentioned identical stirring condition, splash into 1% acetic acid solution (1.6mg/ml) 7.6ml of chitosan with the speed of 2ml/min, stirred one hour, lyophilization promptly gets lyophilized powder.
The investigation index of 5-fluorouracil self-emulsifying nano-scale freeze-dried powder:
(1) self emulsifying speed
With a fixed rotating speed but the minimum stirring paddle of shearing force be contained in the glass self emulsifying pond of containing water, put into the 70mg lyophilized powder, by nephelometer, scattered intensity in the whole emulsion process is measured.t
50＝4.5min，t
90＝15min。
(2) particle diameter of nanoparticle
Adopt transmission electron microscope method to measure and form the emulsion droplet that forms behind the self emulsifying, most of emulsion droplet becomes the sphere of rule, smooth surface, and the quantity meansigma methods of particle diameter is 220.2nm.
(3) envelop rate and drug loading:
Precision takes by weighing the 5-fluorouracil 0.4g that is dried to constant weight, with the dissolve with hydrochloric acid solution of 0.1mol/L and be diluted to 100mL, the accurate 1mL that draws places the 25mL volumetric flask, hydrochloric acid with 0.1mol/L is diluted to scale, draws 0.5,1 respectively, 1.5,2,2.5mL is diluted to 25mL, measures trap A value in 265nm wavelength place.With mass concentration ρ trap A is carried out linear regression, get standard curve equation: C=51.875A+0.0334 (r=0.9998)
The lyophilized powder 80mg that makes is placed volumetric flask,, filter with the dissolving with hydrochloric acid of 0.1mol/L, filtrate is settled to 1000mL, and measuring its ultraviolet absorptivity is 0.845, has tried to achieve actual concentrations according to standard curve, by formula the computational envelope rate is 64.7%, and drug loading is 18.49%.
Claims (3)
1. the preparation method of a 5-fluorouracil self-emulsifying nano-scale freeze-dried powder, the preparation process that it is characterized in that self-emulsifying nano-scale freeze-dried powder is: at 25-30 ℃, under 1200-1500 rev/min the condition calcium chloride solution 15-20ml of 60mg/ml is splashed in the 5-fluorouracil w/o type Emulsion with the speed of 2ml/min, the volume ratio of 5-fluorouracil w/o type Emulsion and calcium chloride solution is 4: 3-1: 1, stirred 10-15 minute, this mixed liquor is changed in the separatory funnel, left standstill one hour, get subnatant, under above-mentioned identical stirring condition, splash into the speed of 2ml/min and to contain the acetic acid solution 7.6ml that mass fraction is 1% chitosan, acetic acid concentration is 1.6mg/ml in the described acetic acid solution, stirred one hour, lyophilization promptly gets lyophilized powder; The preparation method of wherein said 5-fluorouracil w/o type Emulsion is: get emulsifier lecithin 0.4g, the 5-fluorouracil aqueous solution 20ml of 6mg/ml, at 25-30 ℃, being stirred to lecithin under 1000-1200-1500 rev/min the condition dissolves fully, splash into the natural polyanion carrier sodium alginate soln 2.5ml of 6mg/ml again with the speed of 2ml/min, continue to stir 10 minutes with above-mentioned identical preparation condition, this mixed liquor slowly is injected in the 1.2-1.6g oil phase ethyl oleate, the mass ratio of emulsifier lecithin and oil phase ethyl oleate is 1: 3-1: 4, at 25-30 ℃, stir under 1200-1500 rev/min the condition and promptly got 5-fluorouracil w/o type Emulsion in 10-15 minute.
2. the preparation method of a kind of 5-fluorouracil self-emulsifying nano-scale freeze-dried powder according to claim 1 is characterized in that freeze temperature is-45～-55 ℃.
3. one kind according to the prepared 5-fluorouracil self-emulsifying nano-scale freeze-dried powder of the described preparation method of claim 1.
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| CN1621042A (en) * | 2003-11-25 | 2005-06-01 | 范敏华 | Freeze dried powder injection of cytarabine and its preparation process |
| CN1813752A (en) * | 2005-11-17 | 2006-08-09 | 中国人民解放军第二军医大学 | Fluorouracial nano particle formulation and its preparing method |
| CN101053553A (en) * | 2007-03-16 | 2007-10-17 | 吉林大学 | Biodegradable fluorourcacil polyester medicine-carried nanospheres and its preparation method |
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| CN1621042A (en) * | 2003-11-25 | 2005-06-01 | 范敏华 | Freeze dried powder injection of cytarabine and its preparation process |
| CN1813752A (en) * | 2005-11-17 | 2006-08-09 | 中国人民解放军第二军医大学 | Fluorouracial nano particle formulation and its preparing method |
| CN101053553A (en) * | 2007-03-16 | 2007-10-17 | 吉林大学 | Biodegradable fluorourcacil polyester medicine-carried nanospheres and its preparation method |
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