CN106821962A - Amphotericin B cubic liquid crystal gel, cubic liquid crystal nanoparticle and preparation method thereof - Google Patents
Amphotericin B cubic liquid crystal gel, cubic liquid crystal nanoparticle and preparation method thereof Download PDFInfo
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- CN106821962A CN106821962A CN201611185282.2A CN201611185282A CN106821962A CN 106821962 A CN106821962 A CN 106821962A CN 201611185282 A CN201611185282 A CN 201611185282A CN 106821962 A CN106821962 A CN 106821962A
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- amphotericin
- liquid crystal
- cubic liquid
- cubic
- nanoparticle
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- 239000003643 water by type Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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Abstract
The present invention relates to a kind of amphotericin B cubic liquid crystal gel, cubic liquid crystal nanoparticle and preparation method thereof.The amphotericin B cubic liquid crystal gel is mainly prepared from by the raw material of following mass parts:0.1 1 parts of amphotericin B, 0.04 1.7 parts of micellar material, 16 20 parts of liquid crystal material, 0.8 3 parts of stabilizer, 15 25 parts of water;The amphotericin B is 1 with the mass ratio of micellar material:0.3‑2;The liquid crystal material is 9 with the mass ratio of stabilizer:0.4‑1.5.The amphotericin B cubic liquid crystal gel is further prepared into amphotericin B cubic liquid crystal nanoparticle, dissolving barrier and permeability barrier of the amphotericin B during oral administration can be overcome, the stability of amphotericin B is improved, the oral administration biaavailability of amphotericin B is significantly improved.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, more particularly to a kind of amphotericin B cubic liquid crystal gel, nanoparticle and its
Preparation method.
Background technology
Amphotericin B (amphotericin B, AmB) is many alkenes broad-spectrum antifungal antibiotic, tethers mould
A kind of separation product in Streptomyces nodosus nutrient solutions, this macrolide derivatives contain one in molecular structure
Individual nonpolar heptene and a polarity polyalcohol, water insoluble, ethanol, Yi Beiguang, heat and acid destruction.The antibacterial of amphotericin B
Mechanism is:Optionally combined with the ergosterol on fungal cell membrane, fenestra is formed on cell membrane, increased the logical of cell membrane
Permeability, causes various small-molecule substances such as intracellular potassium ion, nucleotides, amino acid to leak outside, and destruction eubolism causes cell
It is dead.
Clinically amphotericin B is main exists in the form of injection.Domestic and international medical personal successively successfully develops
Amphotericin B deoxycholic acid salt injection, amphotericin B lipid complex, amphotericin B colloid dispersion and anphotericin
B liposomes amount to 4 kinds of injections and supply Clinical practice.The appearance of amphotericin B lipid parenteral solution is amphotericin B injection formulation
The important breakthrough obtained in research, to the perfect of early development amphotericin B deoxycholic acid sodium injection, significantly reduces both sexes mould
The infusion reaction and renal toxicity of plain B.But, however it remains certain toxic and side effect and it is expensive the problems such as, so as to limit
Amphotericin B lipid parenteral solution is used in clinical expansion.Therefore, further screening efficiently, the newtype drug of wide spectrum, low toxicity and
It is still a very urgent task that reasonable design medicine formulation solves amphotericin B toxic and side effect
Amphotericin B is administered orally to be had many advantages, such as:Medication under without being instructed in health care professional, patient can be voluntarily
It is convenient to take at home;The problems such as oral administration avoids painful and the transfusion adverse reaction of long term injections, improves patient's
Compliance and the quality of life of raising patient;The amphotericin B research display that is administered orally can keep good anti-true of amphotericin B
Bacterium activity can significantly reduce the toxic and side effect of medicine simultaneously.However, amphotericin B oral absorption faces many technical barriers, grind
Study carefully and make slow progress.The main cause of amphotericin B oral absorption difference is as follows:Amphotericin B belongs under Biopharmaceutics Classification
4th class medicine, solubility is small, poor permeability, there is dissolving barrier and absorption barrier during oral absorption.Additionally, both sexes
Mycin B is sensitive to light and heat, and degradable, oral administration biaavailability is very low.Ground in a series of early stage amphotericin B oral formulations
Study carefully after failure, researcher show that amphotericin B should not prepare the conclusion of oral formulations.
Cubic liquid crystal nanoparticle (Cubosomes) refers to certain density amphipathic lipids material and surfactant-dispersed
Cellular or spongelike structure the nanometer of aquaporin containing co-continuous and closure lipid bilayer is self-assembled into aqueous
Particle.The system is that, with cubic lattice as construction unit, there is small pore passageway (5~10nm) in cubic lattice, contains two
The not connected co-continuous water channel of bar, wherein a water channel leads to outer continuous phase, and another water channel is then closing, doubly-linked
Continue aquaporin and closure lipid bilayer spatially three-dimensional extension, ordered stacks, with three-dimensional, cycle arrangement and minimum table
The tight structure of area feature.
The content of the invention
It is mould for oral both sexes for preparing the invention provides a kind of amphotericin B cubic liquid crystal gel based on this
Plain B cubic liquid crystals nanoparticle, to overcome amphotericin B that barrier and absorption barrier are dissolved present in oral absorption process, carries
The stability of amphotericin B high, to improve its oral administration biaavailability.
Concrete technical scheme is as follows:
A kind of amphotericin B cubic liquid crystal gel, is mainly prepared from by the raw material of following mass parts:
The amphotericin B is 1 with the mass ratio of the micellar material:0.3-2;
The liquid crystal material is 9 with the mass ratio of the stabilizer:0.4-1.5;
The micellar material is selected from NaTDC, polyoxyethylene, polyethylene glycol-chitin copolymer, PVP, imitative thin
At least one in after birth phosphocholine, polyaminoacid, PLA and Poly(D,L-lactide-co-glycolide;The liquid crystal material
It is phytantriol;The stabilizer is poloxamer188.
Wherein in some embodiments, the main raw material system by following mass parts of the amphotericin B cubic liquid crystal gel
It is standby to form:
Wherein in some embodiments, the micellar material is selected from NaTDC, PLA and poly lactic-co-glycolic acid
At least one in copolymer.
Wherein in some embodiments, the amphotericin B is 1 with the mass ratio of the micellar material:0.6-1.3.
Wherein in some embodiments, the amphotericin B is 1 with the mass ratio of the micellar material:0.7-1.0.
Wherein in some embodiments, the liquid crystal material is 9 with the mass ratio of the stabilizer:0.8-1.2.
Wherein in some embodiments, the amphotericin B cubic liquid crystal gel, mainly by the raw material system of following mass parts
It is standby to form:
The amphotericin B is 1 with the mass ratio of the NaTDC:0.7-0.9;
The phytantriol is 9 with the mass ratio of the poloxamer188:0.8-1.2.
Present invention also offers the preparation method of above-mentioned amphotericin B cubic liquid crystal gel.
Concrete technical scheme is as follows:
A kind of preparation method of above-mentioned amphotericin B cubic liquid crystal gel, comprises the following steps:
The preparation of amphotericin B micella:Amphotericin B and micellar material are added in distilled water, concentration is added dropwise is
0.08-0.12mol·L-1Sodium hydroxide solution, it is until amphotericin B is completely dissolved then molten with the phosphoric acid buffer of pH6-6.4
Liquid is diluted, then resulting solution is carried out into freeze-drying, obtains final product the amphotericin B micella;
The preparation of amphotericin B cubic liquid crystal gel:The amphotericin B micella is dissolved in claim any one of 1-6
In described water, the aqueous solution of amphotericin B is obtained;Stabilizer and liquid crystal material heating melting, whirlpool are mixed, added described
The aqueous solution of amphotericin B, whirlpool is mixed, and room temperature is placed, and obtains final product the amphotericin B cubic liquid crystal gel.
Wherein in some embodiments, the temperature of the heating melting is 40-70 DEG C.
Present invention also offers the application of above-mentioned amphotericin B cubic liquid crystal gel.
Concrete technical scheme is as follows:
Application of the above-mentioned amphotericin B cubic liquid crystal gel in amphotericin B cubic liquid crystal nanoparticle is prepared.
Present invention also offers a kind of amphotericin B cubic liquid crystal nanoparticle.
Concrete technical scheme is as follows:
A kind of amphotericin B cubic liquid crystal nanoparticle, is made by above-mentioned amphotericin B cubic liquid crystal gel dispersion in water
It is standby to form.
Present invention also offers a kind of preparation method of amphotericin B cubic liquid crystal nanoparticle.
Concrete technical scheme is as follows:
A kind of preparation method of above-mentioned amphotericin B cubic liquid crystal nanoparticle, comprises the following steps:
Amphotericin B cubic liquid crystal gel is added to the water, ultrasonic disperse is carried out with Ultrasonic cell smash, obtain both sexes
Mycin B cubic liquid crystal coarse dispersion systems;
Amphotericin B cubic liquid crystal coarse dispersion system is carried out high-pressure homogeneous, homogenization pressure is 300-1800bar, circulation
Number of times is 3-13 times, obtains final product the amphotericin B cubic liquid crystal nanoparticle.
Wherein in some embodiments, the homogenization pressure is 1100-1300bar, and cycle-index is 8-10 times.
Wherein in some embodiments, the condition of the ultrasonic disperse is that jitter time is 10-15min, and power is 150-
400w, the working time is 4-6s, and break time is 8-12s.
Amphotericin B cubic liquid crystal gel of the invention, cubic liquid crystal nanoparticle and preparation method thereof have advantages below
And beneficial effect:
The present inventor has found for amphotericin B and micellar material to be prepared into anphotericin by lot of experiments
The cubic liquid crystal gel prepared with special ratios with specific liquid crystal material and stabilizer again after B micellas, can be used to make
The standby amphotericin B cubic liquid crystal nanoparticle that entrapment efficiency is high, particle diameter is smaller and is evenly distributed.Cubic liquid crystal nanoparticle is one
Novel nano Lipid pharmaceutical carrier is planted, its huge film surface area and unique three-dimensional lattice structure have good to the medicine of indissoluble
Good solubilizing effect and sustained release performance.Thus amphotericin B cubic liquid crystal nanoparticle of the invention can overcome and be administered orally
Dissolving barrier and permeability barrier in journey, significantly improve the oral administration biaavailability of amphotericin B.
Drug concentration between the contact area of size of pharmaceutical particles, medicine and dissolution medium, and dissolution layer and medium
Difference is the key parameter for influenceing insoluble drug dissolution rate.Amphotericin B cubic liquid crystal nanoparticle of the invention is mould by both sexes
After plain B is contained into liquid crystal structure, medicine is transformed into unformed molecular state by crystal grain, is uniformly distributed in lipophilic domain,
Co-continuous aquaporin significantly increases the dissolution surface area of amphotericin B with the huge interface area of lipid bilayer.Simultaneously
Amphotericin B has larger solubility in lipophilic domain, and it is poor to form larger drug concentration between dissolution layer and medium, can enter
One step increases the dissolution rate of medicine, effectively overcomes medicine to dissolve barrier.
The unique biology in situ adhesion properties of cubic liquid crystal nanoparticle, can adsorb on intestines and stomach surface, increase medicine and stomach
Enteron aisle action time.Additionally, the lipid bilayer in cubic liquid crystal lattice element has class eucaryotic cell structure, have very strong with cell
Compatibility, gastrointestinal tract epithelial cell can be promoted to absorb the endocytosis of medicine, across small intestine gastrointestinal mucosa barrier, increase medicine
Thing absorbs.The bioadhesive of amphotericin B cubic liquid crystal nanoparticle and the class membrane structure of uniqueness can effectively overcome two
Property the permeability barrier that is administered orally of mycin B.
Amphotericin B is sensitive to light and heat, and degradable, physical and chemical stability is poor.Amphotericin B cube liquid of the invention
The lattice structure of brilliant nanoparticle has very strong protective effect to the amphotericin B for containing, and amphotericin B is contained in a cube liquid
In brilliant nanoparticle three-dimensional network lattice structure, aforementioned stable sex chromosome mosaicism can be efficiently solved.Amphotericin B is contained in liquid crystal
Inside lattice structure, it is possible to reduce medicine connects with external world sexual factor (such as light, heat, soda acid, chemistry and biology enzyme etc.)
Touch, it is to avoid amphotericin B is degraded in solvent medium or organism and loses bioactivity, isolate external world sexual factor pair
Amphotericin B structural damage, effectively keeps amphotericin B structural stability and corresponding pharmacological activity, increases both sexes mould
The stability of plain B.
In addition, amphotericin B cubic liquid crystal nanoparticle of the invention, particle diameter is smaller, and uniform particle diameter is good, is conducive to intestines
Annex in transporte to cells in epithelial cell.
Therefore, amphotericin B cubic liquid crystal nanoparticle of the invention can overcome the dissolving barrier during being administered orally
And permeability barrier, amphotericin B structure and activity are protected, increase the stability of amphotericin B, effectively improve amphotericin B
Oral administration biaavailability.
The oral Relative biological that amphotericin B cubic liquid crystal nanoparticle of the invention significantly improves amphotericin B is utilized
Degree, while amphotericin B can be made slowly to discharge, with 24 hours effects of sustained release, can delay for amphotericin B provides one kind
On The Drug Release, the amphotericin B new oral formulation that absorption is good, bioavilability is high, while nanoparticle solution is also beneficial to mouth
Clothes, it is possible to increase the compliance of patient.
The preparation method process is simple of amphotericin B cubic liquid crystal nanoparticle of the invention, envelop rate is high, makes to prepare
Amphotericin B cubic liquid crystal nanoparticle particle diameter it is small and be evenly distributed, the repeatability of technique is good, and production cost is relatively low, favorably
In industrialized production, have a good application prospect, while being conducive to advancing the industrialization development of liquid crystal nanometer.
Brief description of the drawings
Fig. 1 is amphotericin B cubic liquid crystal nanoparticle preparation flow figure in embodiment 1;
Fig. 2 is amphotericin B cubic liquid crystal nanoparticle freezing transmission electron microscope picture in embodiment 5;
Fig. 3 is amphotericin B cubic liquid crystal nanoparticle SAXS spectrograms in embodiment 5;
Fig. 4 is blank cubic liquid crystal nanoparticle SAXS spectrograms (A in embodiment 5:1200bar, homogeneous 9 times;B:1800bar,
Homogeneous 9 times);
Fig. 5 is stability experiment result (n=of the amphotericin B cubic liquid crystal nanoparticle in simulated intestinal fluid in embodiment 6
6);
Fig. 6 is the In-vitro release curves (n=6) of amphotericin B cubic liquid crystal nanoparticle in embodiment 8;
Fig. 7 be embodiment 9 in amphotericin B it is oral after blood concentration (n=6).
Specific embodiment
Amphotericin B cubic liquid crystal gel of the invention, cubic liquid crystal are received below by way of specific embodiment and accompanying drawing
Grain of rice and preparation method thereof is further described in detail.
Embodiment 1:The preparation of amphotericin B cubic liquid crystal nanoparticle
Referring to Fig. 1, the preparation method of the amphotericin B cubic liquid crystal nanoparticle of the present embodiment comprises the following steps:
The preparation of amphotericin B NaTDC micella:Weigh 0.5g amphotericin Bs bulk drug and 0.41g deoxycholic acids
(mass ratio is 1 to sodium:0.82), it is added in 30mL distilled water, then 0.1molL is added dropwise-1Sodium hydroxide solution, until both sexes are mould
Plain B bulk drugs are completely dissolved, then with the 0.01molL of pH 6.2-1Phosphate buffer solution is diluted to cumulative volume for 100mL.Gained
Solution places lucifuge in freeze drier, and -50 DEG C of condenser temperatures, vacuum obtains final product yellow to freeze 48h under the conditions of 0.1Mbar
Amphotericin B NaTDC micellar powder.Lucifuge, closed, 4 DEG C of Refrigerator stores.
The preparation of amphotericin B cubic liquid crystal gel:Raw material prescription weighs each raw material as shown in table 1, by F127 and phytane
In 100mL plastic centrifuge tubes, 60 DEG C of heating meltings of water-bath mix 30s to triol per 30min whirlpool suspensions device, are added after 1 hour
The aqueous solution of 60 DEG C of amphotericin B NaTDC micella is (with the amphotericin B deoxidation of recipe quantity shown in the water-soluble inducing diaphoresis 1 of 2g
Sodium taurocholate micella, now with the current), whirlpool suspension device mixes 1min, and room temperature places 48h, obtains final product amphotericin B cubic liquid crystal and coagulates
Glue.
The preparation of amphotericin B cubic liquid crystal nanoparticle:Added in gained amphotericin B cubic liquid crystal gel at room temperature
Ultra-pure water ad pond om is 20g, and Ultrasonic cell smash ultrasonic disperse 5min is used after 48h, and ultrasonic power used is 200W, is surpassed
Sound working time 5s, break time 10s obtains amphotericin B cubic liquid crystal coarse dispersion system;Again by amphotericin B cubic liquid crystal
Coarse dispersion system carries out high-pressure homogeneous (homogenization pressure is 1200bar, and homogenization cycles are 9 times) with high pressure homogenizer, obtains final product yellow fraction
The amphotericin B cubic liquid crystal nanoparticle of color.
The raw material prescription of the amphotericin B cubic liquid crystal gel of table 1
Embodiment 2:The preparation of amphotericin B cubic liquid crystal nanoparticle
The preparation method of the amphotericin B cubic liquid crystal nanoparticle of the present embodiment comprises the following steps:
The preparation of amphotericin B micella:Constituted by table 2 Suo Shi, amphotericin B bulk drug and micellar material are weighed, by reality
The method for applying example 1 prepares amphotericin B micella.
The preparation of amphotericin B cubic liquid crystal gel:Each raw material is weighed by the prescription 1-9 in embodiment 1, by embodiment 1
Method prepare.
The preparation of amphotericin B cubic liquid crystal nanoparticle:With embodiment 1
The preparing raw material of the amphotericin B micella of table 2
Comparative example 1
The raw material prescription of the amphotericin B cubic liquid crystal nanoparticle of this comparative example substantially with embodiment 1 in prescription 1-9 phases
Together, difference is that the consumption of F127 is 0.4g.Its preparation method is with embodiment 1.
Comparative example 2
The raw material prescription of the amphotericin B cubic liquid crystal nanoparticle of this comparative example substantially with embodiment 1 in prescription 1-9 phases
Together, difference is without F127.Its preparation method is with embodiment 1.
Comparative example 3
The raw material prescription of the amphotericin B cubic liquid crystal nanoparticle of this comparative example substantially with embodiment 1 in prescription 1-9 phases
Together, difference is that stabilizer used is POLOXAMER 188.Its preparation method is with embodiment 1.
Comparative example 4
The raw material prescription of the amphotericin B cubic liquid crystal nanoparticle of this comparative example substantially with embodiment 1 in prescription 1-9 phases
Together, difference is that liquid crystal material used is two oleic acid sweet acids ester (DGMO).Its preparation method is with embodiment 1.
Embodiment 3
The particle diameter of the amphotericin B cubic liquid crystal nanoparticle prepared to embodiment 1-2 and its comparative example 1-4 and encapsulating
Rate is measured.
Particle Size Determination Method is as follows:After cubic liquid crystal nanoparticle dilutes 100 times with ultra-pure water, take 1mL samples and be added to sample
Product pond, 25 DEG C of balance 1min, dispersion viscosities are 0.8872cPa, and Zetasizer Nano ZS90 determine cubic liquid crystal nanoparticle
Particle size parameters, particle size analyzer software calculates the particle size and polydispersity coefficient (PDI) of cubic liquid crystal nanoparticle.PDI is anti-
The index of particle size distribution range is reflected, the smaller expression particle sizes of PDI are more uniform, integrated distribution, the bigger expression grains of PDI
Sub- size is uneven, significant difference.
Entrapment efficiency determination method:Take 1mL amphotericin B cubic liquid crystal nanoparticle solution ultra-pure waters and be dissolved to 5mL, take
In the super filter tube of YM-100,15000r/min centrifugation 30min collect amphotericin B cubic liquid crystal nanoparticle and lower floor to 0.5mL
Liquid, after being washed with methyl alcohol, dimethyl sulfoxide (DMSO) is dissolved to 5mL, takes 0.2mL methanol constant volumes to 10mL, and high performance liquid chromatography is surveyed
Determine amphotericin B content.
Envelop rate formula:EE%=(Wtotal- Wfree)/Wtotal× 100%.
Wtotal:Amphotericin B dosage;Wfree:Free amphotericin B
High-efficient liquid phase chromatogram condition:Chromatographic column:Phenomenex luna C18 (250x4.6mm, 5 μm), mobile phase:Second
Nitrile:0.01mol pH6.20 phosphate buffer=40:60,35 DEG C of column temperature, Detection wavelength 406nm, flow velocity:1.0mLmin-1,
Sample size:20μL.
Measurement result is as shown in table 3:
The particle diameter and envelop rate of the amphotericin B cubic liquid crystal nanoparticle of table 3
The dissolution rate of amphotericin B is very slow, and dissolution rate turns into limitation amphotericin B deliquescent pass in phosphatide
Key.According to Noyes-Whitney dissolution equations:Dc/dt=DA (Cs-C)/Vh
dc/dt:Dissolution rate, D:The diffusion coefficient of medicine, A:Dissolution interfacial area, Cs:Medicine saturation solubility, C:It is molten
The concentration of medicine, V in liquid:Dissolution medium quality, h:Thickness of diffusion layer.
Understand, the dissolution rate of amphotericin B can be increased by following two aspects:1st, amphotericin B particle diameter is reduced, is increased
Plus drug-eluting surface area A, increase drug-eluting speed;2nd, reduce diameter of carrier, reduce drug diffusion layer thickness h, increase medicine
Thing dissolution rate.The present invention is prepared in the method for amphotericin B cubic liquid crystal nanoparticle, first by NaTDC solubilising both sexes
Mycin B forms micella, and particle diameter drops to nano level micella from the bulky grain of bulk drug, increases dissolution surface area.Secondly, by height
Pressure homogeneous reduces diameter of carrier, reduces drug diffusion thickness degree, accelerates the rate of dissolution of amphotericin B.
Additionally, different size of particle is different in the intake of enterocyte, cause different oral absorption effects.Particle diameter is small
Particle can be by enterocyte phagocytosis transporte to cells, and the big particle of particle diameter is difficult to be phagocytized by cells.
As seen from the results in Table 3:Content with stabilizer increases, and the particle diameter of amphotericin B cubic liquid crystal nanoparticle has one
The trend of individual obvious reduction, meet this patent reduction nanoparticle particle diameter requirement, with reference to comparative example 1-3 it is recognised that with not plus
The prescription of stabilizer is compared, and stabilizer can be substantially reduced nanoparticle particle diameter really, but too high stabiliser content is simultaneously
The rock-steady structure of liquid crystal can be destroyed, particle diameter increase is caused on the contrary, phytantriol is 9 with the optimum quality ratio of F127:1.Additionally, steady
The species for determining agent also has a certain impact, and under similarity condition, stabilizer is bigger for the prescription particle diameter of POLOXAMER 188, envelop rate
It is lower.Dosage does not have fairly obvious influence, difference dispensing to the particle diameter and envelop rate of amphotericin B cubic liquid crystal nanoparticle
The envelop rate of amount has reached 90% or so.In addition, fixed drug content, micellar material is 0.41g (medicine and micella mass ratio
1:0.82) there is the envelop rate of maximum when, when micellar material content is smaller, it is difficult to reach critical micelle concentration, therefore envelop rate is big
It is big to reduce;The micellar material of too high amount can then cause that the micella for preparing is inter-adhesive, or even can destroy the structure of micella, cause
Entrapment efficiency reduction.And the species of micellar material also has an impact to encapsulating effect, but influence, PLGA smaller than the influence of its consumption
Also there is preferable effect with PLA, obtain envelop rate higher.Different liquid crystal materials can also influence nanoparticle particle diameter and encapsulating
Rate, the envelop rate of glyceryl dioleate is relatively low, and particle diameter is larger, and effect is not so good as phytantriol.
Embodiment 4:The influence of homogenization pressure and homogenization cycles to amphotericin B cubic liquid crystal nanoparticle particle diameter
Amphotericin B cubic liquid crystal nanoparticle is prepared by the prescription 1-9 of embodiment 1, preparation method is with embodiment 1, difference
High-pressure homogeneous condition is different, is specifically shown in Table 4.
The particle diameter of amphotericin B cubic liquid crystal nanoparticle manufactured in the present embodiment is determined, assay method is surveyed with embodiment 1
Surely 4 be the results are shown in Table.
Average grain diameter result (table 4) the display amphotericin B cubic liquid crystal nanoparticle that Zetasizer Nano ZS90 are determined
Average grain diameter be not reduces with high-pressure homogeneous pressure increase, but as high-pressure homogeneous pressure increases basic holding not
Become.But PDI is shown and reduce with high-pressure homogeneous pressure increase, and the PDI of cubic liquid crystal nanoparticle is prepared from ultrasonic disperse
0.250 PDI 0.107 for being reduced to the amphotericin B cubic liquid crystal nanoparticle prepared under the conditions of high-pressure homogeneous 9 times of 1200bar.
PDI is the index for reflecting particle size distribution range, and the smaller expression particle sizes of PDI are more uniform, integrated distribution, and PDI gets over
Big expression particle size is uneven, significant difference.The Intensity figures that Zetasizer Nano ZS90 are determined show that high pressure is equal
When matter increases to 1200bar 9 times, amphotericin B cubic liquid crystal nanoparticle has no a micron sized particles, all particles size point
Cloth is in nanometer range.The Intensity figure prompting amphotericin B cubic liquid crystal nanometers that Zetasizer Nano ZS90 are determined
The particle diameter of grain reduces with high-pressure homogeneous pressure increase, when it is high-pressure homogeneous reach certain limit after, the high-pressure homogeneous pressure of increase
Power can not reduce the particle size of amphotericin B cubic liquid crystal nanoparticle.Average grain diameter is an average value of particle size,
Reflection particle fraction information, and PDI, Intensity parameter can comprehensively reflect particle size and the distribution of cubic liquid crystal nanoparticle,
It is thus determined that homogenization pressure 1200bar homogeneous is for 9 times optimal processing condition.
Influence (n=3) of the preparation technology of table 4 to the particle diameter of amphotericin B cubic liquid crystal nanoparticle
Embodiment 5:The sign (Cryo-TEM, SAXS) of amphotericin B cubic liquid crystal nanoparticle liquid crystal structure
Using two prepared in freezing transmission electron microscope (Cryo-TEM) and low-angle scattering of X-rays observation embodiment 1 prescription 1-9
The form and particle size of property mycin B cubic liquid crystal nanoparticles.
Freezing transmission electron microscope.The amphotericin B cubic liquid crystal nanoparticle solution of prescription 1-9 in 4 μ L embodiments 1 is added drop-wise to
On copper mesh, filter paper draws liquid about 3s, until cubic crystal nanoparticle is absorbed and fixed at film is formed on copper mesh completely, uses phosphorus tungsten
After sour negative staining, be put into rapidly it is quick-frozen in liquid ethane, it is quick-frozen after copper mesh be placed on cold-trap, -172 DEG C at transmission electron microscope observing stand
Square liquid crystal nano shape, CCD shoots photo.
Result is shown in Fig. 2, and amphotericin B cubic liquid crystal nanoparticle Ice mapping figure shows average grain diameter in 250nm or so, with
It is basically identical that Zetasizer Nano ZS90 measure particle size;A large amount of orderly cubic liquid crystal nanoparticles, are presented the shape of rounding
Shape, 3, upper right corner bright spot represents cubic liquid crystal internal voids passage in figure, and display nano-particle has typical cubic liquid crystal knot
Structure.
Low-angle scattering of X-rays.By the amphotericin B cube in the cubic liquid crystal nanoparticle of blank and the prescription 1-9 of embodiment 1
Liquid crystal nanoparticle solution is filled into the quartz capillary of diameter 1mm, radiation exposure 60min.Using the small angle X- of Anton Paar
Scatterometer, scattering light source is Cu, and X-ray wavelength is 0.1542nm, and angle of scattering measurement range is q=0.05~6nm-1。
The amphotericin B cubic liquid crystal nanoparticle that result is shown in after Fig. 3 and 4, Fig. 3 display 1200bar homogeneous 9 times existsThere is spectral line peak, corresponding to Miller index h k l=110,111 and 200, show the anphotericin of 60mg
Amphotericin B cubic liquid crystal nanoparticle prepared by B still has Pn3m cubic liquid crystal structures.Amphotericin B cubic liquid crystal nanoparticle
X- small-angle diffractions existThe X- that the peak width of appearance diffraction maximum is significantly greater than the blank cubic liquid crystal nanoparticle in Fig. 4 is small
Angle diffraction existsThere is the peak width of diffraction maximum, and the X- small-angle diffractions of amphotericin B cubic liquid crystal nanoparticle existDiffraction maximum disappear, display amphotericin B participate in influence cubic liquid crystal formation.
Embodiment 6:The intestinal juice stability experiment of amphotericin B cubic liquid crystal nanoparticle
Investigate stability of the amphotericin B cubic liquid crystal nanoparticle in intestinal juice.
The preparation of artificial simulation intestinal juice:Potassium dihydrogen phosphate 6.8g is taken, the 500~800mL that adds water is allowed to dissolve, with 1mol/L's
Sodium hydroxide solution adjusts pH value to 7.5, separately takes pancreatin 10g and adds water and make dissolving in right amount.After two liquid are mixed, plus distilled water is dissolved to
1000mL, obtains final product simulated intestinal fluid, standby.
The amphotericin B cubic liquid crystal nanoparticle solution of the prescription 1-9 of 0.5mL embodiments 1 preparations is accurately measured, manually mould
Intend intestinal juice be settled to 50mL, avoid light place in isothermal vibration device, 37 DEG C of water-baths, shake speed 100r/min.Exist respectively
30min, 60min, 120min, 240min take 0.5ml samples, and methanol dilution is dissolved to 5ml, 0.22 μm of membrane filtration, efficient liquid
Phase chromatographic determination amphotericin B content, method is with embodiment 3.
Amphotericin B NaTDC simulated intestinal fluid experimental comparison group:Amphotericin B NaTDC distilled water is taken to determine
It is molten to 2mgmL-1.Dilution 0.5mL is taken, artificial simulation intestinal juice is dissolved to 50mL, remaining step is ibid.
Result is shown in Fig. 5.Amphotericin B in amphotericin B cubic liquid crystal nanoparticle and amphotericin B NaTDC contains
Amount drops to 81.83 ± 2.51% and 78.56 ± 8.96%, two groups of data respectively in warm bath in simulating simulated intestinal fluid after 0.5 hour
There is no significant difference (P>0.05);But as action time increases to 1 hour, amphotericin B cubic liquid crystal nanoparticle and two
Amphotericin B in property mycin B NaTDCs is respectively 82.40 ± 3.92% and 69.30 ± 6.70% (P<0.05), both sexes
The stability of the amphotericin B in mycin B cubic liquid crystal nanoparticles is apparently higher than control group amphotericin B NaTDC;When
Action time increases to 3 hours, and amphotericin B stability difference is more notable.These results suggest that amphotericin B of the invention
Cubic liquid crystal nanoparticle has the effect of protection amphotericin B in simulated intestinal fluid, it is to avoid the degraded of amphotericin B.
Embodiment 7:The stability of amphotericin B cubic liquid crystal nanoparticle
Prepared amphotericin B cubic liquid crystal nanoparticle in the investigation prescription 1-9 of embodiment 1 and comparative example 1,2 and 3
Stability.Place at room temperature 1 month, sampled 15 days, 30 days respectively, determine the grain of amphotericin B cubic liquid crystal nanoparticle
Footpath and envelop rate.Method is respectively with embodiment 3.
The results are shown in Table 5.Amphotericin B cubic liquid crystal nanoparticle is placed 30 days at room temperature, outward appearance yellow fraction homogeneous solution, not
See aggregation, flocculation, show good physical stability.Result show the 15th day particle diameter of amphotericin B cubic crystal nanoparticle and
Envelop rate is not changed in substantially, and the particle diameter of amphotericin B cubic liquid crystal nanoparticle has slight increase within the 30th day, while envelop rate has
Downward trend.Not plus stabilizer comparative example 2 prepare amphotericin B cubic liquid crystal nanoparticle occurred in that in 30 days it is more tight
The clustering phenomena of weight, because nanoparticle is unstable, therefore also there is obvious decline in envelop rate.The too high contrast of stabiliser content
Also there is the situation that aggregation and envelop rate decline due to cubic liquid crystal structural damage in example 1.Pool Lip river Sa is employed in comparative example 3
Nurse 188 equally can be observed the decline of stability as stabilizer.Amphotericin B cube prepared by embodiment 1-9 and comparative example
The stability result of liquid crystal nanoparticle is consistent with the particle diameter and the result of envelop rate in embodiment 3.
The particle diameter distribution of the amphotericin B cubic liquid crystal nanoparticle of table 5 and envelop rate (n=3)
Embodiment 8:Carry the release in vitro behavior of amphotericin B cubic liquid crystal nanoparticle
The release in vitro for carrying medicine cubic liquid crystal nanoparticle is investigated using Bag filter method.Both sexes in the prescription 1-9 of Example 1
Mycin B cubic liquid crystal nanoparticle 1mL and 0.25% sodium dodecyl sulfate solution 1mL be collectively disposed in bag filter (SMI companies,
Retention relative molecular mass 3500Da), it is placed on after sealing in the 50mL plastic centrifuge tubes of 15mL dissolution mediums.Both sexes are mould
Plain B is water insoluble, and the bakie bar of amphotericin B extracorporeal releasing experiment is met using 0.25% lauryl sodium sulfate dissolution medium
Part.Be subsequently placed in 37 DEG C, in the isothermal vibration device of 100rpm, respectively at 1,2,4,8,12,24,48,72,96h samplings, plastics from
Dissolution medium in heart pipe is all taken out, and adds the fresh dissolution medium of same volume simultaneously.Take the release of different time points 1mL
Medium methyl alcohol is dissolved to 5mL, the amphotericin B content in high effective liquid chromatography for measuring dissolution medium, the same embodiment of condition
3, draw release profiles.
Amphotericin B NaTDC extracorporeal releasing experiment control group:Amphotericin B NaTDC distilled water is taken to determine
It is molten to 2mgmL-1.The dilution 1mL and 0.25% sodium dodecyl sulfate solution 1mL for taking amphotericin B NaTDC are total to
With being placed in bag filter, remaining step is ibid.
Result is shown in Fig. 6.The release in vitro of result display amphotericin B cubic liquid crystal nanoparticle is slow, is within 1 hour 2.64
± 0.61%, 96h are only 12.37 ± 3.87%, and control group amphotericin B NaTDC was in the release in vitro of 1 hour
12.80 ± 2.16%, 96h release in vitro are up to 61.64 ± 3.60%.Amphotericin B cubic liquid crystal nanoparticle release in vitro is notable
Less than amphotericin B NaTDC control group, display medicine is discharged not from nanoparticle, but stomach is passed through together with carrier
The barrier of enteron aisle, be ingested absorption, it is to avoid it discharges in the gastrointestinal tract, meets with degraded or separates out crystal settling.
Embodiment 9:The pharmacokinetic of amphotericin B cubic liquid crystal nanoparticle
Investigate the pharmacokinetic characteristics of amphotericin B cubic liquid crystal nanoparticle prepared by the prescription 1-9 of embodiment 1.Take SD
Male rat, fasting 12h, free water before administration.24 rats are randomly divided into 4 groups:First group of implementation with 10mg/kg dosage
The amphotericin B cubic liquid crystal nanoparticle of the prescription 1-9 of example 1 gives rat oral gavage as experimental group 1;Second group with 20mg/kg agent
The amphotericin B cubic liquid crystal nanoparticle of the prescription 1-9 of embodiment 1 of amount gives rat oral gavage as experimental group 2;3rd group with
The amphotericin B cubic liquid crystal nanoparticle of the comparative example 4 of 10mg/kg dosage gives rat oral gavage as a control group 1;4th group with
The amphotericin B NaTDC of 10mg/kg dosage gives rat oral gavage as a control group 2.1h after administration, 2h, 4h, 8h,
12h, 24h, 48h, 72h, 96h, 120h eye socket take blood about 0.5mL, whole blood be placed in scribble heparin dry centrifuge tube,
8000rpm is centrifuged l0min separated plasmas, and -20 DEG C preserve to analysis measure.The accurate blood plasma 0.1mL that draws is in 1.5mL centrifuge tubes
In, methyl alcohol 100 μ l, vortex mixing 30s are added, the μ l of acetonitrile 100 are added, after vortex mixing 30s, 4 DEG C of refrigerator placement 5min are abundant
Protein precipitation, 16000pm centrifugation 10min, takes the μ l of supernatant 200, and 25 μ l sample introductions are determined.HPLC determines the content of amphotericin B.
HPLC conditions are as follows:Chromatographic column:Phenomenex luna C18 (250x4.6mm, 5 μm), mobile phase:Acetonitrile:
0.01mol/L pH6.2 phosphate buffers 40:60,35 DEG C of column temperature, Detection wavelength 406nm, flow velocity:1.0mLmin-1, sample introduction
Amount:25μl.Plasma drug concentration data is processed using PKSolver V2.1 pharmacokinetics software kit (China Medicine University).
According to blood concentration, calculate amphotericin B it is oral after drug plasma Cmax Cmax, peak time Tmax, eliminate half-life period
t1/2, area under the drug-time curve AUC0-120Deng kinetic parameter.
Pharmacokinetic parameters are shown in Table 6.Plasma concentration curve is shown in Fig. 7.Result shows that blood concentration result shows in SD rat bodies
After the administration of amphotericin B cubic liquid crystal nanoparticles oral compared with the amphotericin B NaTDC control group with dosage, orally
Bioavilability improves 285%.The peak time of amphotericin B is by amphotericin B NaTDC control group mouthful in blood medicine
6.3h after clothes administration brings up to the 26h after the administration of amphotericin B cubic liquid crystal nanoparticles oral.The medicine inspection of amphotericin B blood is surveyed
Time extends to amphotericin B cubic liquid crystal nanoparticle mouthful for 2 days by after amphotericin B NaTDC control group oral administration
5 days after clothes administration, display amphotericin B cubic liquid crystal nanoparticle can stick to gastrointestinal wall and play certain slow releasing function.Two
Property mycin B cubic liquid crystal nanoparticles oral dosage increases to 20mg/kg by 10mg/kg, and blood concentration increase is not obvious.Using two
As liquid crystal material compared with the phytantriol liquid crystal nanoparticle of statistic, its area under the drug-time curve is relatively for olein
Low, peak time also shifts to an earlier date.
Pharmacokinetic parameter (n=6) after the amphotericin B of table 6 is oral
Cmax:Drug plasma Cmax, Tmax:Peak time, t1/2:Eliminate half-life period, AUC0-120:Area under the drug-time curve.
Each technical characteristic of embodiment described above can be combined arbitrarily, to make description succinct, not to above-mentioned reality
Apply all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, the scope of this specification record is all considered to be.
Embodiment described above only expresses several embodiments of the invention, and its description is more specific and detailed, but simultaneously
Can not therefore be construed as limiting the scope of the patent.It should be pointed out that coming for one of ordinary skill in the art
Say, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (10)
1. a kind of amphotericin B cubic liquid crystal gel, it is characterised in that be mainly prepared from by the raw material of following mass parts:
The amphotericin B is 1 with the mass ratio of the micellar material:0.3-2;
The liquid crystal material is 9 with the mass ratio of the stabilizer:0.4-1.5;
The micellar material is selected from NaTDC, polyoxyethylene, polyethylene glycol-chitin copolymer, PVP, imitative cell membrane
At least one in phosphocholine, polyaminoacid, PLA and Poly(D,L-lactide-co-glycolide;The liquid crystal material is plant
Alkane triol;The stabilizer is poloxamer188.
2. amphotericin B cubic liquid crystal gel according to claim 1, it is characterised in that main by following mass parts
Raw material is prepared from:
3. amphotericin B cubic liquid crystal gel according to claim 1, it is characterised in that the micellar material is selected from de-
At least one in oxycholic acid sodium, PLA and Poly(D,L-lactide-co-glycolide.
4. the amphotericin B cubic liquid crystal gel according to claim any one of 1-3, it is characterised in that the both sexes are mould
Plain B is 1 with the mass ratio of the micellar material:0.6-1.3.
5. the amphotericin B cubic liquid crystal gel according to claim any one of 1-3, it is characterised in that the liquid crystal material
Expect that with the mass ratio of the stabilizer be 9:0.8-1.2.
6. the amphotericin B cubic liquid crystal gel according to claim any one of 1-3, it is characterised in that main by following
The raw material of mass parts is prepared from:
The amphotericin B is 1 with the mass ratio of the NaTDC:0.7-0.9;
The phytantriol is 9 with the mass ratio of the poloxamer188:0.8-1.2.
7. the preparation method of the amphotericin B cubic liquid crystal gel described in a kind of any one of claim 1-6, it is characterised in that
Comprise the following steps:
The preparation of amphotericin B micella:Amphotericin B and micellar material are added in distilled water, dropwise addition concentration is 0.08-
0.12mol·L-1Sodium hydroxide solution, it is until amphotericin B is completely dissolved then dilute with the phosphate buffer solution of pH6-6.4
Release, then resulting solution is carried out into freeze-drying, obtain final product the amphotericin B micella;
The preparation of amphotericin B cubic liquid crystal gel:The amphotericin B micella is dissolved in described in claim any one of 1-6
Water in, obtain the aqueous solution of amphotericin B;Stabilizer and liquid crystal material heating melting, whirlpool are mixed, the both sexes are added
The aqueous solution of mycin B, whirlpool is mixed, and room temperature is placed, and obtains final product the amphotericin B cubic liquid crystal gel.
8. the amphotericin B cubic liquid crystal gel described in any one of claim 1-6 is preparing amphotericin B cubic liquid crystal nanometer
Application in grain.
9. a kind of amphotericin B cubic liquid crystal nanoparticle, it is characterised in that the both sexes as described in claim any one of 1-6 are mould
Plain B cubic liquid crystals gel dispersion is prepared from water.
10. the preparation method of the amphotericin B cubic liquid crystal nanoparticle described in a kind of claim 9, it is characterised in that including with
Lower step:
Amphotericin B cubic liquid crystal gel is added to the water, ultrasonic disperse is carried out with Ultrasonic cell smash, obtain anphotericin
B cubic liquid crystal coarse dispersion systems;
Amphotericin B cubic liquid crystal coarse dispersion system is carried out high-pressure homogeneous, homogenization pressure is 300-1800bar, cycle-index
For 3-13 times, the amphotericin B cubic liquid crystal nanoparticle is obtained final product.
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