CN105878194A - Glibenclamide nanocrystal preparation and preparation method thereof - Google Patents
Glibenclamide nanocrystal preparation and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a glibenclamide nanocrystal preparation and a preparation method and belongs to the technical field of pharmaceutical preparations. The glibenclamide nanocrystal preparation is prepared from, by weight, glibenclamide 35%-93%, a stabilizer 2%-7% and a freeze-drying protective agent 28-60%, wherein the ratio of the glibenclamide to the stabilizer is 30:1 to 15:1. The stabilizer is hydroxypropyl methyl cellulose, polyvinylpyrrolidone, poloxamer or a surface active agent. The glibenclamide nanocrystal preparation is controllable in particle size, good in stability and small in side and toxic effect and obviously improves the dissolution and bioavailability of the glibenclamide.
Description
Technical field
The present invention relates to a kind of glibenclamide nano crystallization preparation and preparation method, belong to drug preparation technique neck
Territory.
Background technology
Glibenclamide (Glyburide) is second filial generation sulphanylureas oral antidiabetic drug, chemical entitled N-[2-[4-[[[(hexamethylene
Amino) carbonyl] amino] sulfonyl] phenyl] ethyl]-2-methoxyl group-5-chlorobenzamide, there is dosage little, poison is secondary
Act on little, the advantages such as blood sugar reducing function is stronger.But glibenclamide water solublity is low, and (at 25 DEG C, in water, dissolubility is 0.1
Mg/mL, is insoluble by the definition of Chinese Pharmacopoeia), lipotropy is strong (LogP=4.5), belongs to typical BCSII
Class medicine, its extremely low bioavailability limits its clinical practice.Traditional preparation process is in order to improve lattice row
The dissolution of this urea and bioavailability generally use the measure adding amphipathic adjuvant, but this technique essence be by
Raw material and adjuvant carry out physical mixed, and medicine is still deposited in the mixture with primary crystallization state.Chinese patent
01803639 discloses a kind of glibenclamide and combinations thereof thing, and this application has redefined required glibenclamide chi
Degree scope: the outsifting grain diameter of 25% is positioned at 3-11 micron, the outsifting grain diameter of 50% is positioned at
6-23 micron, the outsifting grain diameter of 75% is positioned at 15-46 micron, but filler in prescription, binding agent,
The a large amount of interpolation of disintegrating agent makes preparation of Chinese medicine content relatively low, is unfavorable for the subsequent process of preparation, and reduces
The compliance that patient takes medicine.
From Ostwald-Freundlich equation, Noyes-Whitney equation, particle diameter reduces the table caused
Area increases, and can improve the dissolution rate of medicine, it is possible to improve drug oral bioavailability further.
Nanocrystal utilizes this principle exactly, and the one of appearance, for insoluble drug, improves oral administration biaavailability
New preparation technique.It is to be dispersed in by medicine in disperse medium (water, aqueous solution or non-aqueous media),
Using surfactant or high molecular polymer as stabilizer, prepared by self-assembling technique or crushing technology
A kind of submicron colloidal dispersion system, its particle diameter is less than 1000nm.The preparation method of nanocrystal mainly has:
Medium milling, microjet method, ultrasound precipitation method, high pressure homogenization method etc..It is unstable that nano suspension belongs to thermodynamics
Determine system, in order to improve its stability, it is to avoid there is the nano-grade medicine aggregation of particles of high surface free energy very
To caking, the selection of stabilizer is most important.During medicament nano, the existence of stabilizer can be effective
Prevent growing up of medicine crystal, prevent the gathering of nano-particle.Generally, stabilizer is divided into two classes: a class is sky
Between stereoscopic stable agent, including polymer stabilizer and surfactant stabilisers；Another kind of is then that electric charge is steady
Determine agent.At present, the stabilizer being applied to glibenclamide mostly is the complex of high molecular polymer and surfactant,
To provide charge stable effect, spatial stability effect respectively and to reduce the effect of particle velocity, prescription forms
Complex.Owing to the mechanism of action of different stabilizers is different, therefore, find and can effectively control particle size range
Stabilizer is to widen this drug-supplying system suitability and the key of range of application.
Summary of the invention
For glibenclamide existing preparation clinical practice limitation, the invention provides a kind of glibenclamide nano junction
Brilliant preparation, by the selection of stabilizer, can prepare the nanocrystal of specified particle diameter scope, it is achieved that particle diameter can
Control.Substantially increase efficiency and the productivity of glibenclamide nanocrystal.
The present invention is realized by following technical scheme:
A kind of glibenclamide nano crystallization preparation, including glibenclamide, stabilizer, freeze drying protectant.By weight
Percentages, comprises: glibenclamide 35%～93%, stabilizer 2%～7%, freeze drying protectant 28～60%.
Wherein glibenclamide with the ratio of stabilizer is: 30:1～15:1.
Wherein, described stabilizer be hydroxypropyl methyl cellulose, polyvinylpyrrolidone class, poloxamer class,
Surfactant-based, selected from HPMC-E5, HPMC-E50, PVP K30, F68, F127, deoxidation gallbladder
Acid sodium, Tween 80, one or more in SDS.
Result shows, when stabilizer is hydroxypropyl methyl cellulose, polyvinylpyrrolidone class, it reduces grain
The effect in footpath is more preferable, when it is HPMC-E5, during HPMC-E50, PVP K30, becomes apparent from.
The preparation method of above-mentioned glibenclamide nanocrystal, comprises the steps:
(1) stabilizer is dissolved in the water, obtains solution A, wherein stabilizer and the w/v of water
0.05%～2.0%；
(2) by glibenclamide in magnetic agitation is scattered in the solution that step (1) obtains, suspension B is obtained, wherein
Glibenclamide is 30:1～15:1 with the weight ratio of stabilizer；
(3) suspension B is joined in the grinding pot containing zirconium dioxide grinding bead, suspension B and zirconium dioxide
The volume ratio of grinding bead is 1:0.5～2；
(4) grinding pot is put into and planetary ball mill grinds 0.4～4h, i.e. obtain nanocrystal suspension；
(5) adding 5% freeze drying protectant in above-mentioned nanocrystal suspension, lyophilizing i.e. obtains glibenclamide nanocrystal
Lyophilized powder.
In above-mentioned steps (1), it is divided into following three classes according to its stablizing effect:
Above-mentioned freeze drying protectant includes mannitol, lactose, glucose, sucrose, trehalose, sorbitol, dextrorotation
One or more in glucosides.
Above-mentioned grinding condition is: the revolution speed of ball mill is 150～300 revs/min, and rotational velocity is 300～600
Rev/min.Milling time is 0.4～4h.
Above-mentioned lyophilization condition is: at lyophilization condition is-80 DEG C～-20 DEG C, and then pre-freeze 4～10h puts
Lyophilizing 15～24h in freeze drying equipment.
The glibenclamide nanocrystal of method gained prepared by the present invention, the dosage form made during its application can be mouth
Take suspension, injection powder pin, inhalation powder spray, tablet, capsule, powder or granule.
The preparation method of the glibenclamide nanocrystal of the present invention, use ball-milling method, first medicine is suspended in dissolved with
In the distilled water of surfactant and (or) macromolecule stabilizer.Then by uniform suspension zirconium dioxide
Grinding bead is ground in planetary ball mill, prepares nanocrystal.Finally, freeze drying protectant joins and receives
In rice crystallization suspension, lyophilised obtain glibenclamide nano junction crystalline flour.The present invention passes through process optimization and prescription
Screening, select suitable stabilizer and grinding condition, can prepare size can control, stability relatively
Good glibenclamide nanocrystal.Its toxic and side effects is little, and stable system.
Glibenclamide nano crystallization preparation of the present invention has the following advantages:
(1) stabilizer and freeze drying protectant used by are the wide variety of adjuvant of field of pharmaceutical preparations, without exempting from
Epidemic disease zest, physiological-toxicity-free, there is good biocompatibility.
(2) according to the effect of reduction nanocrystal particle diameter, stabilizer can be divided three classes.Buckling coefficient agent
Can maintain particle diameter in 150～300nm, ultimate load coefficient agent can maintain particle diameter in 400～600nm,
3rd class stabilizer can maintain particle diameter in 800～900nm.
(3) being tested by In Vitro Dissolution and vivo biodistribution availability is tested, result shows, is ground by ball-milling method
The nanocrystal lyophilized powder obtained after mill and lyophilization and the micron order preparation of prior art
Comparing, dissolution in vitro and vivo biodistribution availability all have and significantly promote.
(4) relative to the drug-supplying system such as liposome, nanoparticle, the drug loading of medicine is high, and toxic and side effects is little,
In clinical heavy dose of application.
Accompanying drawing explanation
Fig. 1 is the embodiment of the present invention 1 gained glibenclamide nanocrystal dynamic light scattering particle size instrument particle size determination knot
Really.
Fig. 2 is the embodiment of the present invention 2 gained glibenclamide nanocrystal dynamic light scattering particle size instrument particle size determination knot
Really.
Fig. 3 is the embodiment of the present invention 3 gained glibenclamide nanocrystal dynamic light scattering particle size instrument particle size determination knot
Really.
Fig. 4 is the embodiment of the present invention 4 gained glibenclamide nanocrystal dynamic light scattering particle size instrument particle size determination knot
Really.
Fig. 5 is the embodiment of the present invention 5 gained glibenclamide nanocrystal dynamic light scattering particle size instrument particle size determination knot
Really.
Fig. 6 is the embodiment of the present invention 5 gained glibenclamide nanocrystal dynamic light scattering particle size instrument particle size determination knot
Really.
Fig. 7 is the embodiment of the present invention 5 gained glibenclamide nanocrystal dynamic light scattering particle size instrument particle size determination knot
Really.
In Fig. 8, (a) is the micron order glibenclamide scanning electron microscope diagram of prior art, (b) average particle
Footpath is the glibenclamide nanocrystal scanning electron microscope diagram of 801nm, and (c) mean diameter is 516nm's
Glibenclamide nanocrystal scanning electron microscope diagram, (d) mean diameter is the glibenclamide nanometer of 193nm
Crystallization scanning electron microscope diagram
Fig. 9 be mean diameter be the micronization Ge Lieben of glibenclamide nanocrystal and the prior art of 193nm
Urea dissolution figure.
Figure 10 be mean diameter be the micronization Ge Lieben of glibenclamide nanocrystal and the prior art of 193nm
Urea vivo biodistribution availability figure.
Detailed description of the invention
Further illustrate the present invention below by the mode of embodiment, but the most therefore invention is limited in described
Among scope of embodiments.
Embodiment 1: the preparation of a kind of glibenclamide nanocrystal suspensoid
First the aqueous phase 10ml of the HPMC-E5 containing 80mg is prepared, by the glibenclamide suspendible of 1500mg
In above-mentioned aqueous phase, and transfer them in ball grinder, be simultaneously introduced 0.1mm zirconia balls abrading-ball 20mL,
Planetary ball mill is utilized to grind 100min.Electronic Speculum result display drug particle is irregularly shaped, and particle diameter is big
Little identical with measurement result.The sucrose of 500mg is added in the glibenclamide nano suspension of above-mentioned preparation,
It is then placed in-80 DEG C～-20 DEG C of refrigerators, pre-freeze 4～10h, is subsequently placed in lyophilizing 15～24h in freeze drying equipment,
Obtaining the glibenclamide nano crystallization preparation of solidification, recording mean diameter after redissolution is 193nm.
Embodiment 2: the preparation of a kind of glibenclamide nanocrystal suspensoid
First the aqueous phase 10ml of the HPMC-E5 containing 40mg is prepared, by the glibenclamide suspendible of 1200mg
In above-mentioned aqueous phase, and transfer them in ball grinder, be simultaneously introduced 0.1mm zirconia balls abrading-ball 20mL,
Planetary ball mill is utilized to grind 100min.Electronic Speculum result display drug particle is irregularly shaped, and particle diameter is big
Little identical with measurement result.The sucrose of 500mg is added in the glibenclamide nano suspension of above-mentioned preparation,
It is then placed in-80 DEG C～-20 DEG C of refrigerators, pre-freeze 4～10h, is subsequently placed in lyophilizing 15～24h in freeze drying equipment,
Obtaining the glibenclamide nano crystallization preparation of solidification, recording mean diameter after redissolution is 206nm
Embodiment 3: the preparation of a kind of glibenclamide nanocrystal suspensoid
First the aqueous phase 10ml of PVP K30 containing 130mg is prepared, by the glibenclamide suspendible of 1200mg
In above-mentioned aqueous phase, and transfer them in ball grinder, be simultaneously introduced 0.1mm zirconia balls abrading-ball 20mL,
Planetary ball mill is utilized to grind 100min.Electronic Speculum result display drug particle is irregularly shaped, and particle diameter is big
Little identical with measurement result.The sucrose of 500mg is added in the glibenclamide nano suspension of above-mentioned preparation,
It is then placed in-80 DEG C～-20 DEG C of refrigerators, pre-freeze 4～10h, is subsequently placed in lyophilizing 15～24h in freeze drying equipment,
Obtaining the glibenclamide nano crystallization preparation of solidification, recording mean diameter after redissolution is 238nm
Embodiment 4: the preparation of a kind of glibenclamide nanocrystal suspensoid
First the aqueous phase 10ml of PVP K30 containing 80mg is prepared, by the glibenclamide suspendible of 1500mg
In above-mentioned aqueous phase, and transfer them in ball grinder, be simultaneously introduced 0.1mm zirconia balls abrading-ball 20mL,
Planetary ball mill is utilized to grind 100min.500 are added in the glibenclamide nano suspension of above-mentioned preparation
The sucrose of mg, is then placed in-80 DEG C～-20 DEG C of refrigerators, pre-freeze 4～10h, is subsequently placed in freeze drying equipment
Middle lyophilizing 15～24h, obtains the glibenclamide nano crystallization preparation of solidification, records mean diameter and be after redissolution
298nm。
Embodiment 5: the preparation of a kind of glibenclamide nanocrystal suspensoid
First prepare the aqueous phase 10ml of the F127 containing 80mg, the glibenclamide of 1500mg is suspended in
State aqueous phase, and transfer them in ball grinder, be simultaneously introduced 0.1mm zirconia balls abrading-ball 20mL, utilize
Planetary ball mill grinds 100min.5% (w/v) is added in the glibenclamide nano suspension of above-mentioned preparation
Sucrose, be then placed in-80 DEG C～-20 DEG C of refrigerators, pre-freeze 4～10h, be subsequently placed in freeze drying equipment and freeze
Dry 15～24h, obtain the glibenclamide nano crystallization preparation of solidification, recording mean diameter after redissolution is 424nm.
Embodiment 6: the preparation of a kind of glibenclamide nanocrystal suspensoid
First prepare the aqueous phase 10ml of the F127 containing 80mg, the glibenclamide of 1500mg is suspended in
State aqueous phase, and transfer them in ball grinder, be simultaneously introduced 0.5mm zirconia balls abrading-ball 20mL, utilize
Planetary ball mill grinds 100min.Electronic Speculum result display drug particle be irregularly shaped, size with
Measurement result is coincide.The sucrose of 500mg is added, then in the glibenclamide nano suspension of above-mentioned preparation
Put into-80 DEG C～-20 DEG C of refrigerators, pre-freeze 4～10h, be subsequently placed in lyophilizing 15～24h in freeze drying equipment,
Obtaining the glibenclamide nano crystallization preparation of solidification, recording mean diameter after redissolution is 516nm.
Embodiment 7: the preparation of a kind of glibenclamide nanocrystal
First prepare the aqueous phase of the Tween 80 containing 80mg, the glibenclamide of 1500mg is suspended in above-mentioned
Aqueous phase, and transfer them in ball grinder, it is simultaneously introduced 0.5mm zirconia balls abrading-ball 20mL, utilizes row
Planetary ball mill grinding 125min.Electronic Speculum result display drug particle is irregularly shaped, size and survey
Amount result is coincide.In the glibenclamide nano suspension of above-mentioned preparation, add the sucrose of 500mg, then put
Enter in-80 DEG C～-20 DEG C of refrigerators, pre-freeze 4～10h, it is subsequently placed in lyophilizing 15～24h in freeze drying equipment, i.e.
The glibenclamide nano crystallization preparation that must solidify, recording mean diameter after redissolution is 801nm..Electronic Speculum result shows
Showing that drug particle is irregularly shaped, size is coincide with measurement result.
Embodiment 8: the external dissolution determination of glibenclamide nanocrystal.
The glibenclamide nanocrystal lyophilized powder of the 193nm prepared by above-described embodiment 1 (is equivalent to Ge Lieben
Urea 2.5mg) and Micronized Glyburide 2.5mg load in No. 00 capsule, according to according to dissolution method (in
State's pharmacopeia two annex XC the second methods of version in 2010), with the pH6.8PBS solution 250mL of 0.3%SDS
For dissolution medium, rotating speed is 75 turns per minute, operates, respectively at 5,10,20,30,45,60min in accordance with the law
Sampling 5mL, filters through 0.45 μm microporous filter membrane, discards just filtrate, takes subsequent filtrate as need testing solution,
Measure concentration.Result such as Fig. 9, shows that, relative to prior art, the dissolution of glibenclamide nanocrystal obtains
To significantly improving.
Embodiment 9: Bioavailability Determination in glibenclamide nanocrystal body.
Use male SD rat (200g～220g) 12, be randomly divided into two groups (n=6), fasting 12h before being administered,
Freely drink water.Two groups of rat gavages respectively give the glibenclamide nanometer of 193nm prepared by above-described embodiment 1
Crystal lyophilized powder and Micronized Glyburide, dosage is 10mg/kg.Respectively at be administered after 0.25,0.5,1,2,
3,4,6,8,12,24,36h take blood 0.3mL in rat eye socket, be placed in the centrifuge tube of heparinization, 10000rpm
Centrifugal 10min, takes upper plasma-20 DEG C and saves backup.Carry out determination of plasma concentration (Figure 10), calculate medicine and move
Learn parameter.The AUC (0-36 hour) of nanometer formulation, CmaxIt is the micronization preparation of prior art the most respectively
6.08 times and 7.79 times.Bioavailability significantly improves, and prompting can adjust stabilizer, and preparation is gone through accordingly
Through the glibenclamide nanocrystal of size, improve oral absorption.
Claims (10)
1. a glibenclamide nano crystallization preparation, it is characterised in that by weight percentage, comprise: glibenclamide 35%～93%, stabilizer 2%～7%, freeze drying protectant 28～60%, wherein glibenclamide with the ratio of stabilizer is: 30:1～15:1.
2. glibenclamide nano crystallization preparation as claimed in claim 1, it is characterised in that: described stabilizer is hydroxypropyl methyl cellulose, polyvinylpyrrolidone class；Preferably HPMC-E5, HPMC-E50, PVP K30, in one or more；Can obviously reduce in 150～300nm.
3. glibenclamide nano crystallization preparation as claimed in claim 1, it is characterised in that: described stabilizer is poloxamer class；Preferably F68, one or both combinations in F127；Can obviously reduce in 400～600nm.
4. glibenclamide nano crystallization preparation as claimed in claim 1, it is characterised in that: described stabilizer is surfactant-based；Preferably NaTDC,
Tween 80, one or more in SDS；Can obviously reduce in 800～900nm.
5. according to the glibenclamide nano crystallization preparation described in Claims 1 to 4 any one, it is characterised in that one or more in mannitol, lactose, glucose, sucrose, trehalose, sorbitol, dextran of described freeze drying protectant.
The preparation method of glibenclamide nano crystallization preparation the most according to claim 1, it is characterised in that step is as follows:
(1) stabilizer of percentage by weight 2%～7% is dissolved in as disperse medium in distilled water, obtains solution A；
(2) by 35%～93% glibenclamide in magnetic agitation is scattered in the Aqueous dispersions medium that step (1) obtains, obtain suspension B；
(3) suspension B is joined in the grinding pot containing zirconium dioxide grinding bead；
(4) grinding pot is put in planetary ball mill, grind, i.e. obtain nanocrystal suspension;
(5) addition 28～the freeze drying protectant of 60% in above-mentioned nanocrystal suspension, lyophilizing i.e. obtains glibenclamide nanocrystal lyophilized powder.
7. the preparation method of glibenclamide nanocrystal as claimed in claim 6, it is characterised in that: in step (1), described stabilizer with the w/v of distilled water is: 0. 5%～2.0%.
8. the preparation method of glibenclamide nanocrystal as claimed in claim 6, it is characterised in that: in step (3), suspension B is 1:0.5～2 with the volume ratio of zirconium dioxide grinding bead.
9. the preparation method of glibenclamide nanocrystal as claimed in claim 6, it is characterised in that: in step (4), ball mill revolves round the sun: 150～300 revs/min, rotation: 300～600 revs/min, milling time: 0.4～4h.
The preparation method of glibenclamide nanocrystal the most according to claim 6, it is characterised in that: in step (5), lyophilization condition is at-80 DEG C～-20 DEG C, pre-freeze 4～10h, is subsequently placed in lyophilizing 15～24h in freeze drying equipment.
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| CN109260159A (en) * | 2018-11-29 | 2019-01-25 | 沈阳药科大学 | A kind of pharmaceutical composition and preparation method thereof containing Idebenone |
| CN109260159B (en) * | 2018-11-29 | 2021-07-23 | 沈阳药科大学 | Idebenone-containing pharmaceutical composition and preparation method thereof |
| CN111759816A (en) * | 2019-04-02 | 2020-10-13 | 北京大学 | Oral solid nano crystal slow-release composition and preparation method thereof |
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Application publication date: 20160824 |