CN106860425A - A kind of chloramphenicol solid lipid nano granule - Google Patents
A kind of chloramphenicol solid lipid nano granule Download PDFInfo
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Abstract
The invention discloses a kind of chloramphenicol solid lipid nano granule, it is characterised in that the chloramphenicol solid lipid nano granule, including the following raw material component：1 part, matrix material 9-20 parts, emulsifying agent 5-12 parts of chloramphenicol.The chloramphenicol solid lipid nano granule can be by emulsifying, and -- any one method is prepared in the precipitation method prepare, emulsify and volatilize -- prepared by low temperature curing methods, film -- dispersion method preparation, hot melt dispersion method preparation; process is simple; it is adapted to large-scale production, wide market.
Description
Technical field
The invention belongs to field of medicine preparations, and in particular to a kind of chloramphenicol solid lipid nano granule and preparation method thereof.
Background technology
Solid lipid nano granule (solid lip idnanoparticles, SLN) it is the submicron delivery system of new generation that grows up early 1990s, it is usually used in ointment bases in pharmaceutic adjuvant, oneself starts to be applied to the research of the oral sustained-release preparation of matrix type in recent years.SLN is carrier with natural or synthetic solid-state lipoid, such as stearic acid, lecithin, triacylglycerol, and medicine is wrapped in lipoid core the micelle drug delivery system for being made particle diameter about 50-1000nm.Similar to emulsion, liposome, SLN is mainly used in wrapping up insoluble drug, can be used to being injected intravenously, local administration, is administered orally and various methods of administration such as percutaneous dosing, is also used as the carrier of targeting positioning and controlled-release function.Due to its nano level characteristic, therefore SLN is different from the advantage that common suspension ability injection has following liposomes, emulsion and high molecular polymer nanoparticle concurrently:(1) SLN is low using Lipotoxicity, and biocompatibility is high, degradable in vivo, will not produce accumulation；(2) the class vinegar core of solid-state or semisolid makes SLN have the advantages that controlled release, avoids drug degradation and leakage, good targeting；In addition, SLN can carry out industrialized production using high pressure homogenization method or micro emulsion method；The water separate system of SLN, with long-term physical and chemical stability, also can be made solid pharmaceutical preparation through autoclaving or radiation sterilization by lyophilized or spray drying.
Because solid lipid nano granule has targeting, slow controlled release, bioavilability is high, good biocompatibility, the features such as toxicity is low and increases packaging medicine stability, having research confirms, after medicine is made solid lipid nano granule, insoluble drug solubility and bioavilability can be dramatically increased, promote drug substance stable, reduce the excitant of medicine, salt down the bad stink of lid medicine, make liquid drug powdered, therefore solid lipid nano granule technology is development novel pharmaceutical formulation, novel formulation provides effective means, its application in following medicament has good and wide prospect.Chloramphenicol is phthalein amine alcohol class antibiotic, very strong antibacterial efficacy is shown to streptococcus pneumonia, micrococcus scarlatinae, viridans streptococci, and have certain antibacterial action to corynebacterium diphtheriae, mycoplasma, Chlamydia, mycobacterium and some anaerobic bacterias, it is broad-spectrum antibacterial medicine, clinical practice is extensive, but it is slightly soluble in water, and dissolution rate is low, bioavilability is low, therefore being made into solid lipid nano granule has important clinical meaning.Conventional solid lipid nano granule preparation method has high pressure homogenization method, ultrasonic dispersion, micro emulsion method and solvent evaporation method etc. at present.Therefore, will be made lipid nano particle preparation for chloramphenicol can improve its bioavilability, reduce allergic reaction and itself toxic and side effect, reach long-acting, efficient, safety, the purpose of low toxicity, and the research and development of the formulation will bring glad tidings for patient.
The content of the invention
The present invention is intended to provide a kind of chloramphenicol solid lipid nano granule and preparation method thereof.
For achieving the above object, a kind of chloramphenicol solid lipid nano granule of the invention, specific embodiment is：
A kind of chloramphenicol solid lipid nano granule of the present invention, it is characterised in that the chloramphenicol solid lipid nano granule, including the following raw material component：1 part, matrix material 9-20 parts, emulsifying agent 5-12 parts of chloramphenicol.Described matrix material is stearic acid, glycerin monostearate, bi-tristearin, glyceryl tristearate, myristin, monopalmitin, double tripalmitins, tripalmitin, single Compritol 888 ATO, double Compritol 888 ATOs, tribehenin acid glyceride, laurin, triglyceride, three octanoic acids, certain herbaceous plants with big flowers acid glyceride or its mixture.Described emulsifying agent is selected from soybean lecithin, egg yolk lecithin, hydrogenated soy phosphatidyl choline and hydrogenated yolk lecithin or its mixture.The surfactant is selected from enuatrol, Tween 80, polysorbas20, HS15, Pluronic F68 and pluronic F127.The solvent is selected from one kind and its mixed solvent in chloroform, ether, ethanol, methyl alcohol, acetic acid ethyl ester, dichloromethane, acetone.
A kind of chloramphenicol solid lipid nano granule of the present invention, the preparation method is any one in following several method：
Method one：Prepared by emulsification -- the precipitation method, weigh the chloramphenicol of formula ratio, matrix material, fat-soluble emulsifier and be dissolved in organic solvent and obtain organic phase；Weigh water soluble emulsifier it is soluble in water water phase；Organic phase is mutually separately heated to mutually synthermal with water, and organic phase is mixed with water into conjunction under stirring, is then evaporated under reduced pressure and removes organic solvent, then carries out ultrasonic or high-pressure homogeneous treatment, you can obtain chloramphenicol solid lipid nano granule；Or
Method two：Emulsification volatilization -- prepared by low temperature curing methods, will chloramphenicol, matrix material, fat-soluble emulsifier be dissolved in organic solvent in proportion and obtain organic phase；Weigh water soluble emulsifier it is soluble in water water phase；Organic phase is mutually separately heated to mutually synthermal with water, organic phase is mixed with water conjunction under stirring, it is evaporated under reduced pressure and removes organic solvent, and concentrate system, concentrate is mixed in rapidly in 2-50 times of 0-4 DEG C of water at low temperature of volume, stirring cooling, then can carry out ultrasonic or high-pressure homogeneous treatment and obtain chloramphenicol solid lipid nano granule；Or
Method three：It is prepared by film -- dispersion method, the chloramphenicol of recipe quantity, matrix material, fat-soluble emulsion is weighed to be dissolved in organic solvent, the evaporated under reduced pressure film forming in water-bath at 20-60 DEG C, adds the aqueous solution containing water-soluble emulsifying agent, and ultrasonic or high-pressure homogeneous treatment obtains final product chloramphenicol solid lipid nano granule；Or
Method four：Prepared by hot melt dispersion method, weigh chloramphenicol, matrix material, fat-soluble emulsifier and melting is heated at 60-90 DEG C, as oil phase；It is heated to mutually synthermal being water phase by water soluble emulsifier is soluble in water；Oil phase, water are mixed under agitation, through ultrasonic or high-pressure homogeneous treatment, i.e., chloramphenicol solid lipid nano granule processed.
Above-mentioned preparation method, wherein organic phase and water phase temperature are 20-80 DEG C, and preferable temperature is 60-80 DEG C；Particle diameter is reduced using ultrasonic or high-pressure homogeneous technique, it is characterised in that ultrasonic power is 100-1200W, and ultrasonic time is 10-40min；High-pressure homogeneous pressure is 10000-25000psi, and high-pressure homogeneous number of times is 3-10 times.
Beneficial effect of the present invention：
1. the present invention is chloramphenicol solid lipid nano granule, and, in 220-240 nm, release is good, improves the curative effect of medication of chloramphenicol for average grain diameter.
2. invention formulation envelop rate is good, is adapted to industrialized production.
Brief description of the drawings
Fig. 1：Consubstantiality lipid nano particle In-vitro release curves prepared by commercially available chloramphenicol ophthalmic solution and the embodiment of the present invention 2；
Fig. 2：Chloramphenicol solid lipid nano granule particle diameter.
Specific embodiment
Example below is only to further illustrate the present invention, scope that the invention is not limited in any way.
Embodiment 1Take 200mg chloramphenicol, 2400mg bi-tristearins, 1200mg egg yolk lecithins and be dissolved in 20 m1 ethanol, ultrasonic dissolution is simultaneously heated to (80 ± 2) DEG C composition organic phase.Separately take 1200mg
Pluronic F68 is added in 30ml distilled waters, and ultrasound makes it fully dissolve, and constitutes water phase.Organic phase is slowly injected into the thermostatted water phase of (80 scholar 2) DEG C of 1000 r/min stirrings and forms colostrum, continue stir about 2-3h, made organic solvent evaporating completely and system is concentrated into about 5ml.The translucent emulsion of gained is quickly mixed in 20 m1 frozen water phases of another 0-5 DEG C of 1000r/min stirrings; continue to stir 2 hours, then newborn even 5 times (homogenization pressure is 15000psi) obtains final product chloramphenicol solid lipid nano granule suspension in high pressure homogenizer.
Embodiment 2Weigh during the mono- Compritol 888 ATO of 100mg chloramphenicol, 1500mg, 1000mg egg yolk lecithins add 50m1 conical flask with cover, plus 10 ml alcohol solvents, ultrasound makes it fully dissolve and is heated to 70 DEG C of composition organic phases.Separately take 150mg pluronics F127 to be dissolved in 35m1 redistilled waters, constitute water phase.During organic phase is slowly injected into 70 DEG C of water phases that 1000r/min is stirred with syringe, continue to stir 2-3h, form translucent O/W types nanoemulsion, (0-5 DEG C of a certain amount of dispersed phase is poured into rapidly）, it is consistent with above-mentioned water phase composition) in, continue to stir solidification 2h, that is, obtain CAP-SLN that is translucent, showing light blue opalescence.CAP-SLN is crossed into 0.45 μm of miillpore filter, nitrogen charging is preserved, obtain chloramphenicol solid lipid nano granule suspension, its average grain diameter is 245nm, and in 500 below nm, narrow particle size distribution shows that solid lipid nano granule size is more equal to 90% particle
Embodiment 3Weigh 100mg chloramphenicol, 1200mg stearic acid, 1400mg egg yolk lecithins, be dissolved in the ethanol of 20m1, the evaporated under reduced pressure at 50 DEG C, form lipid film, add the Tween-80 of 25m1（0.5%）, ultrasonic disperse 30min (ultrasonic power 600W) obtains final product chloramphenicol solid lipid nano granule suspension.
Embodiment 4Take 50mg chloramphenicol, 500mg glycerin monostearates, 300mg egg yolk lecithins to be placed in 25 mI round-bottomed flasks, it is fully melted in heating in the water bath with thermostatic control of (75 scholar 2) DEG C, constitute oil phase；It is another to take 16mgF68 and be dissolved in 10m1 water, heating water bath to organic phase identical temperature, constitute water phase.Oil phase is injected in water phase under 1000r/min stirrings, 4h is stirred, temperature is maintained at (75 scholar 2) DEG C, form O/W type colostrums.Gained emulsion is quickly mixed in 0 ~ 20 DEG C of 10ml water in the case where (1000 r/min) is stirred, continues to stir 2h, then in ultrasonically treated 40min under 1200W power, obtain final product chloramphenicol solid lipid nano granule suspension.
Embodiment 5Weigh during 150mg chloramphenicol, 2250mg glyceryl tristearates, 1500mg hydrogenated yolk lecithins add 100m1 conical flask with cover, plus 15 ml alcohol solvents, ultrasound makes it fully dissolve and is heated to 70 DEG C of composition organic phases.Separately take 225mg Tween 80s to be dissolved in 52.5m1 redistilled waters, constitute water phase.During organic phase is slowly injected into 70 DEG C of water phases that 1000r/min is stirred with syringe, continue to stir 2-3h, form translucent O/W types nanoemulsion, (0-5 DEG C of a certain amount of dispersed phase is poured into rapidly）, it is consistent with above-mentioned water phase composition) in, continue to stir solidification 2h, that is, obtain chloramphenicol solid lipid nano granule that is translucent, showing light blue opalescence.
Embodiment 6Take 80mg chloramphenicol, 960mg myristins, 480mg soybean lecithins and be dissolved in 8 m1 ethanol, ultrasonic dissolution is simultaneously heated to (80 ± 2) DEG C composition organic phase.Separately take 480mg
Enuatrol is added in 12ml distilled waters, and ultrasound makes it fully dissolve, and constitutes water phase.Organic phase is slowly injected into the thermostatted water phase of (80 scholar 2) DEG C of 1000 r/min stirrings and forms colostrum, continue stir about 2-3h, made organic solvent evaporating completely and system is concentrated into about 5ml.The translucent emulsion of gained is quickly mixed in 20 m1 frozen water phases of another 0-5 DEG C of 1000r/min stirrings; continue to stir 2 hours, then newborn even 5 times (homogenization pressure is 15000psi) obtains final product chloramphenicol solid lipid nano granule suspension in high pressure homogenizer.
Embodiment 7Weigh 150mg chloramphenicol, 1800mg stearic acid, 2100mg egg yolk lecithins, be dissolved in the dichloromethane of 30m1, the evaporated under reduced pressure at 50 DEG C, form lipid film, add the Tween-80 of 37.5m1（0.5%）, ultrasonic disperse 30min (ultrasonic power 600W) obtains final product chloramphenicol solid lipid nano granule suspension.
Embodiment 8Weigh during the mono- Compritol 888 ATO of 120mg chloramphenicol, 1800mg, 1200mg hydrogenated soy phosphatidyl cholines add 50m1 conical flask with cover, plus 12ml alcohol solvents, ultrasound makes it fully dissolve and is heated to 80 DEG C of composition organic phases.Separately take 150mg pluronics F127 to be dissolved in 35m1 redistilled waters, constitute water phase.During organic phase is slowly injected into 70 DEG C of water phases that 1000r/min is stirred with syringe, continue to stir 2-3h, form translucent O/W types nanoemulsion, (0-5 DEG C of a certain amount of dispersed phase is poured into rapidly）, it is consistent with above-mentioned water phase composition) in, continue to stir solidification 2h, that is, obtain CAP-SLN that is translucent, showing light blue opalescence.CAP-SLN is crossed into 0.45 μm of miillpore filter, nitrogen charging is preserved, and obtains solid lipid nano granule suspension.
Experimental example
Below by the various determination experiments of the chloramphenicol solid lipid nano granule prepared to embodiment of the present invention 1-8, the advantage of chloramphenicol lipid nano particle provided by the present invention is further illustrated.
The measure of chloramphenicol solid lipid nano granule envelop rate：
Experimental example 1The chloramphenicol solid lipid nano granule suspension 1mL for preparing in example 2 adds super filter tube (retaining molecular weight 3KDa), in 4000 × g, centrifugal ultrafiltration 30min at 4 DEG C, pipette filtrate, HPLC is analyzed, and records peak area, and the amount (W) of free drug is calculated by external standard method；Mycin solid lipid nano granule suspension 1mL prepared by another Example 2, is placed in 5mL volumetric flasks, and methanol constant volume shakes up, HPLC analyses, records peak area, and calculate total dose by external standard method（W0)。
Envelop rate %=(1-W/W0) ×100。
Wherein, HPLC analysis conditions：Agilent 1100；Chromatographic column:ZORBAX SB-C18 (250mm × 4. 6mm, 5 μm)；Mobile phase：Second eyeball-water (35：65, v/v)；Detection wavelength：248nm；Column temperature：250℃；Flow velocity：1.0ml/min.
The mycin solid lipid nano granule grain envelop rate of preparation is 87.63 %.
Experimental example 2By embodiment 1,3-8 prepares chloramphenicol solid lipid nano granule, respectively according to the same procedure described in experimental example 1, determines its envelop rate, and measurement result see the table below：
The extracorporeal releasing test of chloramphenicol solid lipid nano granule
Experimental example 3
Precision measures the CAP-SLN of 5.0ml, (molecular cut off is fastened for two ends with fine rule to be put into the bag filter that has pre-processed, it is 7.4 to be put into the pH of intraocular in the stripping rotor equipped with 150m1 dissolution mediums, and ocular is 34 DEG C, and the release in vitro condition for using is that dissolution medium is pH7.4.According to phosphate buffer, bath temperature is 34 DEG C, and rotating speed is 1 00r/min.Respectively at 0.5,1,2,4,8,12,24,48h sampling 5ml is filtered with 0.45 μm of miillpore filter, is determined with HPLC, and the dissolution medium that same volume is added after liquid is taken every time.Precision measures the commercially available chloramphenicol ophthalmic solution of 1.0m1, is measured in the same method its release in vitro.
Using the concentration of each sub-sampling Chlorine in Solution mycin solid lipid nano granule of high effective liquid chromatography for measuring, assay method is as follows：High performance liquid chromatograph：Agilent 1100；Chromatographic column：ZODiamonsil
C1g(4.6mmX200mm, Sam)；Mobile phase：The potassium dihydrogen phosphate of methyl alcohol -0.34% (45：55, V/V)；Detection wavelength：278nm；Column temperature:300℃；Flow velocity:1.
0m1/minx
Consubstantiality lipid nano particle In-vitro release curves prepared by commercially available chloramphenicol ophthalmic solution and the embodiment of the present invention 2 are shown in accompanying drawing 1.Result is visible：Chloramphenicol ophthalmic solution release in vitro only has 10% within 8 hours, and the release in vitro of chloramphenicol solid lipid nano granule of the invention is then more than 50%, thus the release in vitro of chloramphenicol solid lipid nano granule of the invention is greatly increased.
Experimental example 4
Embodiment 1 will be prepared, 3-8 obtains chloramphenicol solid lipid nano granule, respectively according to the same procedure described in experimental example 3, carries out extracorporeal releasing test, and result of the test see the table below shown：
Particle size determination
Experimental example 5
Chloramphenicol solid lipid nano granule suspension 1ml prepared by Example 2, with 10 times of distilled water diluting, with NICOMP
380ZLS particle size determination instrument determines its particle diameter.Result is shown in accompanying drawing 2.As can be seen that the average grain diameter of the chloramphenicol solid lipid nano granule of the preparation of embodiment 2 is 225 nm.
Experimental example 6
Embodiment 1 will be prepared, 3-8 obtains chloramphenicol solid lipid nano granule, respectively according to the same procedure described in embodiment 5, determines its particle diameter, and measurement result see the table below shown：
Claims (8)
1. a kind of chloramphenicol solid lipid nano granule, it is characterised in that the chloramphenicol solid lipid nano granule, including the following raw material component：1 part, matrix material 9-20 parts, emulsifying agent 5-12 parts of chloramphenicol.
2. chloramphenicol solid lipid nano granule according to claim 1, characterized in that, described matrix material is stearic acid, glycerin monostearate, bi-tristearin, glyceryl tristearate, myristin, monopalmitin, double tripalmitins, tripalmitin, single Compritol 888 ATO, double Compritol 888 ATOs, tribehenin acid glyceride, laurin, triglyceride, three octanoic acids, certain herbaceous plants with big flowers acid glyceride or its mixture.
3. chloramphenicol solid lipid nano granule according to claim 1, it is characterised in that described emulsifying agent is selected from soybean lecithin, egg yolk lecithin, hydrogenated soy phosphatidyl choline and hydrogenated yolk lecithin or its mixture.
4. chloramphenicol solid lipid nano granule according to claim 1, it is characterised in that the surfactant is selected from enuatrol, Tween 80, polysorbas20, HS15, Pluronic F68 and pluronic F127.
5. chloramphenicol solid lipid nano granule according to claim 1, it is characterised in that the solvent is selected from one kind and its mixed solvent in chloroform, ether, ethanol, methyl alcohol, acetic acid ethyl ester, dichloromethane, acetone.
6. a kind of chloramphenicol solid lipid nano granule according to claim 1, it is characterised in that the preparation method is any one in following several method：
Method one：Prepared by emulsification -- the precipitation method, weigh the chloramphenicol of formula ratio, matrix material, fat-soluble emulsifier and be dissolved in organic solvent and obtain organic phase；Weigh water soluble emulsifier it is soluble in water water phase；Organic phase is mutually separately heated to mutually synthermal with water, and organic phase is mixed with water into conjunction under stirring, is then evaporated under reduced pressure and removes organic solvent, then carries out ultrasonic or high-pressure homogeneous treatment, you can obtain chloramphenicol solid lipid nano granule；Or
Method two：Emulsification volatilization -- prepared by low temperature curing methods, will chloramphenicol, matrix material, fat-soluble emulsifier be dissolved in organic solvent in proportion and obtain organic phase；Weigh water soluble emulsifier it is soluble in water water phase；Organic phase is mutually separately heated to mutually synthermal with water, organic phase is mixed with water conjunction under stirring, it is evaporated under reduced pressure and removes organic solvent, and concentrate system, concentrate is mixed in rapidly in 2-50 times of 0-4 DEG C of water at low temperature of volume, stirring cooling, then can carry out ultrasonic or high-pressure homogeneous treatment and obtain chloramphenicol solid lipid nano granule；Or
Method three：It is prepared by film -- dispersion method, the chloramphenicol of recipe quantity, matrix material, fat-soluble emulsion is weighed to be dissolved in organic solvent, the evaporated under reduced pressure film forming in water-bath at 20-60 DEG C, adds the aqueous solution containing water-soluble emulsifying agent, and ultrasonic or high-pressure homogeneous treatment obtains final product chloramphenicol solid lipid nano granule；Or
Method four：Prepared by hot melt dispersion method, weigh chloramphenicol, matrix material, fat-soluble emulsifier and melting is heated at 60-90 DEG C, as oil phase；It is heated to mutually synthermal being water phase by water soluble emulsifier is soluble in water；Oil phase, water are mixed under agitation, through ultrasonic or high-pressure homogeneous treatment, i.e., chloramphenicol solid lipid nano granule processed.
7. preparation method according to claim 6, it is characterised in that wherein organic phase and water phase temperature are 20-80 DEG C, and preferable temperature is 60-80 DEG C.
8. the chloramphenicol solid lipid nano granule according to claim 1-7, particle diameter is reduced using ultrasonic or high-pressure homogeneous technique, it is characterised in that ultrasonic power is 100-1 200W, and ultrasonic time is 10-40min；High-pressure homogeneous pressure is 10000-25000psi, and high-pressure homogeneous number of times is 3-10 times.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108158994A (en) * | 2018-01-22 | 2018-06-15 | 咸阳职业技术学院 | A kind of compound aureomycin and chloramphenicol nanoemulsions and its preparation method and application |
| CN110376100A (en) * | 2019-07-30 | 2019-10-25 | 浙江省肿瘤医院 | A kind of solid lipid nano granule control release performance test macro |
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| CN101590018A (en) * | 2008-05-27 | 2009-12-02 | 中国科学院上海药物研究所 | Etoposide solid lipid nanoparticle and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108158994A (en) * | 2018-01-22 | 2018-06-15 | 咸阳职业技术学院 | A kind of compound aureomycin and chloramphenicol nanoemulsions and its preparation method and application |
| CN110376100A (en) * | 2019-07-30 | 2019-10-25 | 浙江省肿瘤医院 | A kind of solid lipid nano granule control release performance test macro |
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