CN101658493B - Azithromycin nanostructured lipid carrier and preparation method thereof - Google Patents
Azithromycin nanostructured lipid carrier and preparation method thereof Download PDFInfo
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- CN101658493B CN101658493B CN200910144945XA CN200910144945A CN101658493B CN 101658493 B CN101658493 B CN 101658493B CN 200910144945X A CN200910144945X A CN 200910144945XA CN 200910144945 A CN200910144945 A CN 200910144945A CN 101658493 B CN101658493 B CN 101658493B
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Abstract
The invention discloses an azithromycin nanostructured lipid carrier and a preparation method thereof. The components of the carrier are as follows according to mass percentage: 0.1-1 percent of azithromycin, 20-40 percent of emulsifier, 3-8 percent of lipid materials and the balance of water. The composition has good stability and higher bioavailability, simple and controllable preparation method, and good repeatability, and can be applied to the preparation of azithromycin antibacterials of eye dose.
Description
Technical field
The invention belongs to the carrier system technical field in cosmetics and the food preparation technology, relate to a kind of nano carrier and preparation method thereof, particularly a kind of nano structured lipid carrier composition and method of making the same that comprises the azithromycin active constituents of medicine.
Background technology
Azithromycin (Azithromycin) is a kind of macrolide antibiotics; Can suppress multiple Gram-negative coccus, mycoplasma, chlamydia etc.; Concentration is high in tissue and cell; Can kill intracellular pathogen effectively, respiratory tract, eye, skin soft-tissue infection etc. are all had good efficacy.But stimulating gastrointestinal road during systemic administration, and because blood-aqueous humor barrier, it is low to absorb the drug level that gets into part tissue of eye, is very important so study its dosing eyes system.
More dosing eyes mode is arranged at present, like the eye drop administration, because the effect of ocular movement and nose tear system makes a large amount of drug loss, need multiple dosing every day, dosage is inaccurate, and the intraocular drug fluctuation of concentration is big; Suspension or ointment administration affect one's power of vision again and ocular movement.For overcoming above-mentioned shortcoming, adopt to add hydrophilic gel carbomer (carbomer) increase viscosity, delay the holdup time of medicine, increase absorption; But make blurred vision easily, influence eyelid movement; Or implant long lasting controlled-release administrating system, like Ocusert (pilocarpine release-controlled film), but the patient has foreign body sensation.Ideal dosing eyes system should be able to keep drug depot, discharges medicine for a long time; Can penetrate cornea effectively, arrive each agents area of ophthalmic; Can reduce the part and the whole body toxic and side effects of original medicine; Preparation is transparent, does not influence the normal physiological function of eye.
Medicine combines with carrier, makes the physiological disposition of medicine no longer only depend on the character of medicine itself, and depends on the performance of carrier system to a great extent.The suitable selection of carrier system makes active medicine can controllably reach the release of locality ground according to the special requirement of Drug therapy.Carrier can be divided into nano-carrier, micron-sized microgranule and millimetre-sized embedded type carrier by size.Implant and microgranule size for target administration and intravenous injection is too big.Therefore, nano-medicament carrier receives the extensive attention of research worker in recent years.
Present nano-carrier comprises nanoparticle, nanoemulsions, liposome, nano suspending liquid, solid lipid nanoparticle, nano structured lipid carrier etc.Wherein solid lipid nanoparticle is a kind of medicament carrier system that the eighties of last century the nineties grows up.Solid lipid nanoparticle has following characteristics: the probability that controlled drug release and targeting discharge is realized in (1); (2) improved medicine stability; (3) drug loading is higher; (4) oleophylic and hydrophilic drugs all can facilitate the introduction of; (5) carrier does not have bio-toxicity; (6) avoided the use of organic solvent; (7) can carry out large-scale production and sterilization.Yet, because the single fixedly lipid that solid lipid nanoparticle adopts can form the lipid crystal, limited its medicine carrying ability, and changed, thereby caused process Chinese medicine such as storage to be extruded lattice to perfect cystal, cause the leakage of medicine in storage process; In addition in its aqueous dispersion moisture also than higher.
The medicine relatively poor with other dissolubility is the same, and the typical problem that azithromycin exists is that biological utilisation is spent low and the absorption instability.Do not appear in the newspapers as yet and research and develop about the pharmaceutical carrier of azithromycin at present, Given this present invention carries out the R and D of the nano structured lipid carrier compositions of azithromycin.
Summary of the invention
The object of the invention is to provide the Azithromycin nanostructured lipid carrier that a kind of stability is high, the compatibility is good, has solved azithromycin in the prior art because special physiologic barrier, and the effect of whole body or topical treatment ophthalmic diseases such as is restricted at problem.
In order to solve these problems of the prior art, technical scheme provided by the invention is:
A kind of Azithromycin nanostructured lipid carrier, the said carrier loaded azithromycin medicine that has is characterized in that composition is counted by its percentage by weight in the said nano structured lipid carrier:
Azithromycin 0.1～1%;
Emulsifying agent 20～40%;
All the other are water.
Preferably, composition is counted by its percentage by weight in the said nano structured lipid carrier:
Azithromycin 0.5%;
Emulsifying agent 30%;
Matrix material 5%;
All the other are water.
Preferably, said emulsifying agent is the mixture of polyoxyl stearate and poloxamer.
Preferably, the proportion of said polyoxyl stearate and poloxamer by its percentage by weight count 1: 3～5: 1.
Preferably, said matrix material is selected from least a following chemical compound: glyceryl monostearate, Oleum Ricini, olive oil, glyceryl triacetate.
Preferably, the particle size range of said compositions is at 40-100nm.
Another object of the present invention is to provide a kind of method for preparing said composition, it is characterized in that said method comprising the steps of:
(1) weighing emulsifying agent and matrix material mixing post-heating obtain liquid oil phase after design temperature to fusion in proportion;
(2) an amount of azithromycin of weighing joins in the liquid oil phase, and stirring and dissolving obtains the clarification system;
(3) water that adds an amount of design temperature is in the clarification system, and mix homogeneously carries out obtaining colostrum after mechanical agitation is handled, and said colostrum carries out high pressure homogenize and handles the high pressure homogenize liquid that obtains in suitable pressure limit;
(4) the high pressure homogenize liquid cool to room temperature for preparing is got final product.
Preferably, the mass ratio of matrix material and emulsifying agent is 1: 4～1: 6 in the said method; The mass ratio of said azithromycin and matrix material is 1: 5～1: 10.
Preferably, in the said method design temperature in 60～80 ℃ of scopes; Said pressure limit is between 600～800bar.
Preferably, the cycle-index that high pressure homogenize is handled was in 3～5 times at 5～15 minutes the time that mechanical agitation is handled in the said method.
Application aspect the antimicrobial drug that another object of the present invention is to provide a kind of Azithromycin nanostructured lipid carrier to adopt the dosing eyes mode in preparation.
The present invention selects for use complex lipid as carrier material, is model drug with the insoluble drug azithromycin, and the utilization high pressure homogenization method prepares the azithromycin nano-lipid carrier.Through difference weighing matrix material and emulsifying agent, both mass ratioes, i.e. matrix material: emulsifying agent is 1: 4～1: 6; Complex lipid material and emulsifier post-heating to design temperature T, promptly T=60-80 degree centigrade, are obtained liquid oil phase after the fusion; As carrier loaded material azithromycin, the mass ratio of this material and matrix material is 1: 5～1: 10 by matrix material in weighing.This material is joined in the liquid oil phase, use magnetic agitation that this azithromycin is dissolved fully, must clarify system; To join with the water of design temperature T uniform temp in the above-mentioned clarification system.After water, lipid, emulsifying agent and medicament mixed are even, carry out mechanical agitation and handle; Under 600-800bar, above-mentioned colostrum is carried out the circulation high pressure homogenize; Naturally cool to room temperature, promptly obtain azithromycin lipid nanoparticle dispersion liquid.
With respect to scheme of the prior art, advantage of the present invention is:
1, the Azithromycin nanostructured lipid carrier of the present invention preparation is a kind of fat-soluble pharmaceutical carrier, so fat-soluble medicine can use it as carrier, the pharmaceutical carrier good stability of preparation.
3, present, the method that the preparation of lipid nanoparticle generally adopts high pressure homogenize to handle, the size of the azithromycin lipid nanoparticle that makes is basically at several ten nanometers levels.This preparation process is simple and convenient, and repeatability is high.
Description of drawings
Below in conjunction with accompanying drawing and embodiment the present invention is further described:
Fig. 1 is the method for preparing flow chart of Azithromycin nanostructured lipid carrier of the present invention;
Fig. 2 is the time stability block diagram of Azithromycin nanostructured lipid carrier of the present invention.
The specific embodiment
Below in conjunction with specific embodiment such scheme is further specified.Should be understood that these embodiment are used to the present invention is described and are not limited to limit scope of the present invention.The implementation condition that adopts among the embodiment can be done further adjustment according to the condition of concrete producer, and not marked implementation condition is generally the condition in the normal experiment.
The preparation of embodiment 1 Azithromycin nanostructured lipid carrier
Composite formula:
Method for preparing:
1. take by weighing 21 gram polyoxyl stearate S-40,9 gram poloxamer F-68,2.5 gram glyceryl monostearates and 2.5 gram Oleum Ricini, put into sample cell;
2.75 ℃ heating in water bath adds 0.5 gram azithromycin after it is melted fully again and carries out magnetic agitation, obtains the clarification system;
3. 65 milliliters 75 ℃ distilled water is joined in the above-mentioned clarification system;
4. stirred 15 minutes;
5. under 800bar, above-mentioned colostrum is carried out 3 circulation high pressure homogenize;
6. naturally cool to room temperature, promptly obtain azithromycin lipid nanoparticle dispersion liquid.
The mean diameter that has prepared is 74.5 nanometers, preserves that mean diameter is 75.2 nanometers after 0.5 month
The preparation of embodiment 2 Azithromycin nanostructured lipid carriers
Composite formula:
Method for preparing:
1. take by weighing 16.8 gram polyoxyl stearate S-40,7.2 gram poloxamer F-68,2 gram glyceryl monostearates, 2 gram glyceryl triacetate, put into sample cell;
2.70 ℃ heating in water bath adds 0.4 gram azithromycin after it is melted fully again, obtains the clarification system;
3. 62 milliliters 60 ℃ distilled water is joined in the above-mentioned clarification system;
4. stirred 10 minutes;
5. under 700bar, above-mentioned colostrum is carried out 4 circulation high pressure homogenize.
6. naturally cool to room temperature, promptly get azithromycin lipid nanoparticle dispersion liquid.
The preparation of embodiment 3 Azithromycin nanostructured lipid carriers
Composite formula:
Method for preparing:
1. take by weighing 12.6 gram polyoxyl stearate S-40,5.4 gram poloxamer F-68,1.5 gram glyceryl monostearates, 1.5 gram Oleum Ricini, put into sample cell;
2.70 ℃ heating in water bath adds 0.3 gram azithromycin after it is melted fully again, obtains the clarification system;
3. 79 milliliters 60 ℃ distilled water is joined in the above-mentioned clarification system;
4. stirred 10 minutes;
5. under 600bar, above-mentioned colostrum is carried out 4 circulation high pressure homogenize.
6. naturally cool to room temperature, promptly get azithromycin lipid nanoparticle dispersion liquid.
The stability test of embodiment 4 Azithromycin nanostructured lipid carriers
Comprise:
(1) timely stability test: obtain stability result at short notice through ultracentrifugal method, observe centrifuge tube and wild effects such as layering, deposition whether occur;
(2) time stability test: observation sample place certain intervals after the time outward appearance whether layering, deposition appear, and carry out centrifugal or the particle diameter test;
(3) temperature stabilization property testing: get an amount of Azithromycin nanostructured lipid carrier (AZM-NLC) and be sealed in the bottle, be positioned over respectively under room temperature, 4 ℃, 40 ℃ the condition, carry out stability observing after some days under same time the same terms respectively and measure.
Grain diameter measurement:
The AZM-NLC mean diameter is recorded by PCS, and test angle is 90 degree, and probe temperature is 25 ℃.Whether each sample obtains two parallel results all through a repeated measure, exist than mistake to investigate between the data, and get the meansigma methods of two times result.
Centrifugal stability
Survey its particle size distribution behind the centrifugal 10min of 10000r/min, and with centrifugal before compare, as shown in the table.Can find out that after above-mentioned centrifugal condition was centrifugal, particle diameter had increased about 6nm.Centrifugally do not cause the very variation of big-difference of particle diameter.Explain that the centrifugal stability of AZM-NLC is better.
Time stability
Adopt the time dependent stability of PCS tracking and testing AZM-NLC.Choose the highest AZM-NLC of present load capacity, test its stability.Because time restriction, the test interval is chosen 1 day, 7 days, 15 days after the preparation respectively.Concrete characterization result following table.
Can find out that the AZM-NLC mean diameter change of size in 15 days for preparing with high pressure homogenization method is very little, the PI value is all less than 0.3, and data are reliable, and the AZM-NLC stable existence is described.
As shown in Figure 2, find out that from bar diagram load capacity is that 0.5% AZM-SLN change of size trend is stable, stability is relatively good, particulate coagulation do not occur.
Temperature stability
Test result such as following table:
Different temperatures is preserved AZM-NLC particle diameter test result down
40 ℃ of particle size growth that occur down to a certain degree do not appear than leap ahead it is thus clear that the particle diameter maintenance is stable under low temperature and room temperature state.
Above-mentioned instance only is explanation technical conceive of the present invention and characteristics, and its purpose is to let the people who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalent transformations that spirit is done according to the present invention or modification all should be encompassed within protection scope of the present invention.
Claims (7)
1. Azithromycin nanostructured lipid carrier, the said carrier loaded azithromycin medicine that has is characterized in that composition is counted by its percentage by weight in the said nano structured lipid carrier:
Azithromycin 0.1～1%;
Emulsifying agent 20～40%;
Complex lipid material 3～8%;
All the other are water;
Said matrix material is selected from the chemical compound below at least two kinds: glyceryl monostearate, Oleum Ricini, olive oil, glyceryl triacetate.
2. Azithromycin nanostructured lipid carrier according to claim 1 is characterized in that said emulsifying agent is the mixture of polyoxyl stearate and poloxamer.
3. Azithromycin nanostructured lipid carrier according to claim 2, the proportion that it is characterized in that said polyoxyl stearate and poloxamer by its percentage by weight count 1: 3～5: 1.
4. Azithromycin nanostructured lipid carrier according to claim 1, the particle size range that it is characterized in that said Azithromycin nanostructured lipid carrier is at 40～100nm.
5. method for preparing the described Azithromycin nanostructured lipid carrier of claim 1 is characterized in that said method comprising the steps of:
(1) weighing emulsifying agent and matrix material mixing post-heating obtain liquid oil phase after design temperature to fusion in proportion;
(2) an amount of azithromycin of weighing joins in the liquid oil phase, and stirring and dissolving obtains the clarification system;
(3) water that adds an amount of design temperature is in the clarification system, and mix homogeneously carries out obtaining colostrum after mechanical agitation is handled, and said colostrum carries out high pressure homogenize and handles the high pressure homogenize liquid that obtains in suitable pressure limit;
(4) the high pressure homogenize liquid cool to room temperature for preparing is got final product.
6. according to the method for claim 5, it is characterized in that design temperature is in 60～80 ℃ of scopes in the said method; Said pressure limit is between 600～800bar.
7. according to the method for claim 5, the time that it is characterized in that mechanical agitation processing in the said method, the cycle-index that high pressure homogenize is handled was in 3～5 times at 5～15 minutes.
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| CN101912363A (en) * | 2010-07-29 | 2010-12-15 | 蔡海德 | Dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine |
| CN105476730B (en) * | 2016-01-06 | 2018-01-30 | 中国医科大学附属第四医院 | A kind of medicament nano lipid carrier intraocular lens system and its application |
| CN109381707B (en) * | 2017-08-03 | 2022-02-15 | 沈阳药科大学 | Azithromycin ion pair liposome eye drops and preparation method thereof |
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|---|---|---|---|---|
| CN1490055A (en) * | 2003-08-28 | 2004-04-21 | 东南大学 | Method for preparing nanometre structure medicine |
| CN1621029A (en) * | 2004-10-14 | 2005-06-01 | 东南大学 | Method for preparing ten nanometers level solid lipid nanometer particle |
| US20080102127A1 (en) * | 2006-10-26 | 2008-05-01 | Gao Hai Y | Hybrid lipid-polymer nanoparticulate delivery composition |
| CN101485629A (en) * | 2008-01-16 | 2009-07-22 | 沈阳药科大学 | Drug delivery system and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1490055A (en) * | 2003-08-28 | 2004-04-21 | 东南大学 | Method for preparing nanometre structure medicine |
| CN1621029A (en) * | 2004-10-14 | 2005-06-01 | 东南大学 | Method for preparing ten nanometers level solid lipid nanometer particle |
| US20080102127A1 (en) * | 2006-10-26 | 2008-05-01 | Gao Hai Y | Hybrid lipid-polymer nanoparticulate delivery composition |
| CN101485629A (en) * | 2008-01-16 | 2009-07-22 | 沈阳药科大学 | Drug delivery system and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 张典瑞等.阿奇霉素固态类脂纳米粒的制备及其体外释药特性的研究.《山东大学学报（医学版）》.2003,第41卷(第6期),第701-705页. * |
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