CN110075071A - A kind of preparation method of curcumin solid dispersion - Google Patents
A kind of preparation method of curcumin solid dispersion Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N25/00—Investigating or analyzing materials by the use of thermal means
- G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
Abstract
The invention belongs to field of pharmaceutical chemistry technology, disclose a kind of preparation method of curcumin solid dispersion, include the following steps: step 1: the foundation of curcumin detection method；Step 2: the preparation of curcumin solid dispersion；Step 3: response phase method optimization experiment；Step 4: the in-vitro evaluation of curcumin solid dispersion.The preparation method of curcumin solid dispersion of the present invention, select inorganic solvent, solvent method and the precipitation method are combined, utilize molecular self-assembling, cluster, aggregation in acid condition, form bright yellow precipitate, carry out the preparation of solid dispersions, organic solvent residual bring medication toxic side effect is avoided, solves the problems, such as to prepare curcumin solid dispersion using organic solvent method in the prior art there are dissolvent residuals.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, in particular to a kind of preparation method of curcumin solid dispersion.
Background technique
Solid dispersion technology is improve water-insoluble or insoluble drug dispersion degree, solubility and bioavilability effective
One of approach.When prepared by solid dispersions, carrier material should be selected according to drug and support, preparation purpose etc..Solid point
Discrete material has water-soluble, 3 major class of slightly solubility and enteric solubility.Suitable carrier material and preparation method is selected to carry out solid dispersion
The preparation of body is to improve the most effective approach of drug bioavailability.
Curcumin solid dispersion can increase the water solubility of curcumin, because curcumin is in solid dispersions without fixed
Type form exists, and can increase specific surface area when dissolution；Carrier material can form hydrogen with the phenolic hydroxyl group of curcumin molecule simultaneously
Key is scattered in curcumin molecule in macromolecular by hydrogen bond, due to the hydrophily of carrier material, disperses conducive to increasing in its water
Property or dissolubility.Curcumin solid dispersion is prepared using organic solvent method, can be improved curcumin dissolution rate and solubility, but
There are problems that dissolvent residual.
Drug compatible with carrier is the premise to form stabilization of solid dispersion.Water is the good solvent of pectin, and pectin, which removes, to be had
Outside the good aqueous solubility and compatibility of conventional carriers, itself also has many physiological activity, passes through the hydrophilic group in pectin molecule
Solubilized effect plays to curcumin in group, to improve dispersion degree or solubility in drug water.The preparation method of solid dispersions at present
Mostly based on single method.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation method of curcumin solid dispersion, present invention selection is inorganic molten
Agent combines solvent method and the precipitation method, and using molecular self-assembling, cluster, aggregation, it is heavy to form glassy yellow in acid condition
It forms sediment, carries out the preparation of solid dispersions, avoid organic solvent residual bring medication toxic side effect, solve in the prior art
Preparing curcumin solid dispersion using organic solvent method has that dissolvent residual has dissolvent residual.
To achieve the above object, the invention provides the following technical scheme:
A kind of preparation method of curcumin solid dispersion, includes the following steps:
S1: the foundation of curcumin detection method
S2: the preparation of curcumin solid dispersion
Experiment combines solvent method and the precipitation method, using molecular self-assembling, carries out the preparation of solid dispersions；
S3: response phase method optimization experiment
It is soft using Design-Expert8.0 according to Box-Behnken experimental design principles on the basis of experiment of single factor
Part, the horizontal totally 29 groups of experiments of 4 factor of design 3 carry out response surface experiment；
S4: the in-vitro evaluation of curcumin solid dispersion.
Further, S1 further includes following steps:
S101: the measurement of drugloading rate and encapsulation rate；
S102: stability experiment
Quantitative curcumin is accurately weighed, is dissolved in the NaOH solution that concentration is 0.1,0.5,1.0 and 5.0% respectively, in
Its absorbance is surveyed in the sampling of same time point；
S103: the drafting of standard curve；
S104: Precision Experiment
The curcumin aqueous slkali for preparing basic, normal, high three kinds of concentration respectively, its suction is surveyed in different time points sampling in 3 hours
Luminosity, each sample are measured in parallel three times.
Further, S4 further includes following steps:
S401: Thermal characteristic analysis (DSC)
Solid dispersions 3~the 5mg of sample balanced in drier for 24 hours accurately is weighed, is encapsulated in aluminum pot with holes；Without
The aluminum pot of sample is as reference；
S402:X- Diffraction Patterns analyze (XRD)
Solid dispersions are directly compacted in sample cell, using progress XRD survey under Cu-K alpha ray (λ=0.154nm)
Examination；
S403: scanning electron microscope analysis (SEM)
First conducting resinl is pasted on copper sample stage, then drying solid dispersion is dispelled with rubber pipette bulb and is distributed in conduction
On glue, on metal spraying platform after metal spraying 5min, it is placed in the observation that sample room carries out × 1000 times of micromorphologies；
S404: tablets in vitro experiment.
Further, S103 further includes following steps:
S1031: the determination of Detection wavelength；
S1032: the foundation of standard curve；
Further, S404 further includes following steps:
S4041: the preparation of simulated body fluid: simulated body fluid is prepared using the phosphate buffer (PBS) of different pH；
S4042: the determination of Detection wavelength: using the PBS buffer solution of blank solid dispersions and ethyl alcohol as reference, 300~
Scanning, determines that maximum absorption wavelength λ max is 427nm in 700nm wave-length coverage；
S4043: the foundation of standard curve: using the establishment step of step S1032, solvent is 75% ethyl alcohol, obtains standard
Curvilinear equation；
S4044: the measurement of curcumin Accumulation dissolution.
Compared with prior art, the beneficial effects of the present invention are: the preparation of curcumin solid dispersion proposed by the present invention
Method selects inorganic solvent, solvent method and the precipitation method is combined, using molecular self-assembling, cluster, poly- in acid condition
Collection forms bright yellow precipitate, carries out the preparation of solid dispersions, avoid organic solvent residual bring medication toxic side effect,
It solves the problems, such as to prepare curcumin solid dispersion using organic solvent method in the prior art there are solvents there are dissolvent residual
The problem of residual.
Detailed description of the invention
Fig. 1 is preparation flow figure of the invention；
Fig. 2 is the present invention using without seeing the solid dispersions of flavine as scanning curve figure in blank control wave-length coverage；
Fig. 3 is the present invention using the PBS buffer solution of blank solid dispersions and ethyl alcohol as scanning figure within the scope of reference wavelength；
Fig. 4 is pectin of the present invention and curcumin with comparison encapsulation rate and carrying drug ratio influence schematic diagram；
Fig. 5 is CaCl of the present invention2Influence of the concentration to solid dispersions is that conspicuousness influences schematic diagram；
Fig. 6 is influence schematic diagram of the reaction time of the invention to solid dispersions；
Fig. 7 is the situation of change schematic diagram of encapsulation rate of the present invention and drugloading rate with solvent strength；
Fig. 8 is the influence schematic diagram of reaction temperature of the invention to solid dispersions；
Fig. 9 is the Thermal Properties differential scanning calorimetry schematic diagram of curcumin solid dispersion of the present invention；
Figure 10 is X-ray powder diffraction schematic diagram of the present invention；
Figure 11 is the topography scan Electronic Speculum schematic diagram under the different acceleration voltages of the present invention to curcumin solid dispersion particle；
Figure 12 is EM elemental analysis result schematic diagram of the invention；
Figure 13 is drug accumulation release of the present invention, draws its graph of relation between the time；
Figure 14 is release behavior figure of the curcumin dispersion of the present invention in simulation gastro-intestinal Fluid.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other
Embodiment shall fall within the protection scope of the present invention.
Refering to fig. 1, a kind of preparation method of curcumin solid dispersion, includes the following steps:
Step 3: the foundation of curcumin detection method
The measurement of 3.1 drugloading rates and encapsulation rate
RE=MAQ/MTQ× 100% (1)
L=MAQ/MWP× 100% (2)
In formula: REFor encapsulation rate (%)；L is drugloading rate (%)；MAQFor the drug quality (mg) for being loaded into pectin；MTQFor investment
The quality (mg) of drug；MWPFor solid dispersions gross mass (mg)；
3.2 stability experiment
Quantitative curcumin is accurately weighed, is dissolved in the NaOH solution that concentration is 0.1,0.5,1.0 and 5.0% respectively, in
Its absorbance is surveyed in the sampling of same time point, final to determine that amplitude of variation is minimum, high stability according to absorbance change curve
0.5%NaOH solution carries out the measurement of turmeric cellulose content in dispersion；
The drafting of 3.3 standard curves；
(1) determination of Detection wavelength: to be free of the solid dispersions for seeing flavine as blank control, in 300~700nm wave
(such as Fig. 2) is scanned in long range, determines that maximum absorption wavelength λ max is 469nm.
(2) foundation of standard curve: precision weighs 5.0mg curcumin standard items, is placed in 100mL brown volumetric flask, adds
0.5%NaOH solution dissolves and is settled to graduation mark.Precision pipettes 0.5,1.0,1.5,2.0,2.5mL standard solutions and is placed in
In 25mL brown volumetric flask, lye is added to be settled to graduation mark, shaken up, its absorbance is surveyed at 469nm.It is with concentration C (μ g/mL)
Abscissa, absorbance A are ordinate, draw standard curve, and carry out linear regression.Obtain calibration curve equation are as follows: A=
0.1424C+0.0016, wherein r=0.9999.The result shows that curcumin exists well in 1.0~5.0 μ g/mL concentration ranges
Linear relationship.
3.4 Precision Experiment
Since curcumin exists in lye with unstable enol form, in order to ensure the accuracy of measured value, match respectively
The curcumin aqueous slkali (respectively 2.0 μ g/mL, 5.0 μ g/mL and 20.0 μ g/mL) for making basic, normal, high three kinds of concentration, at 3 hours
Its absorbance is surveyed in interior different time points (interval 30min) sampling, and each sample is measured in parallel three times, in minute, precision
RSD be respectively 3.41%, 3.39% and 3.31%.Since absorbance of the curcumin in lye can reduce at any time, in order to
Reduce evaluated error as far as possible, experimental implementation completes the measurement of absorbance as far as possible within half an hour.
Step 2: the preparation of curcumin solid dispersion
Experiment combines solvent method and the precipitation method, and using molecular self-assembling, cluster, aggregation, are formed in acid condition
Bright yellow precipitate carries out the preparation of solid dispersions, and experiment is with curcumin and pectin proportion, CaCl2Concentration, temperature, the time and
Solvent strength is investigation factor, using encapsulation rate and drugloading rate as index；
Step 3: response phase method optimization experiment
On the basis of experiment of single factor, according to Box-Behnken experimental design principles, CaCl is chosen in experiment2Concentration (X1)、
Reaction time (X2), solvent strength (X3) and reaction temperature (X4) it is independent variable, with drugloading rate (Y1) and encapsulation rate (Y2) be
Response is designed the horizontal totally 29 groups of experiments of 4 factor 3 and is carried out response surface experiment using Design-Expert8.0 software.
Step 4: the in-vitro evaluation of curcumin solid dispersion；
4.1 Thermal characteristic analysis (DSC)
Referring to the method measurement of Chuah A M etc..Accurately weigh the solid dispersions sample 3 balanced in drier for 24 hours
~5mg is encapsulated in aluminum pot with holes；Without sample aluminum pot as reference.N is set2Flow velocity is 150 μm of L/min, temperature model
0~300 DEG C is enclosed, the rate of heat addition is 10 DEG C/min.
4.2 X-ray diffraction signature analysis (XRD)
Solid dispersions are directly compacted in sample cell, using progress XRD survey under Cu-K alpha ray (λ=0.154nm)
Examination.Sweep 2 θ of scanning speed/min, 5~80 ° of diffraction angular region, using continuous scanning mode.
4.3 scanning electron microscope analysis (SEM)
First conducting resinl is pasted on copper sample stage, then drying solid dispersion is dispelled with rubber pipette bulb and is distributed in conduction
On glue, on metal spraying platform after metal spraying 5min, it is placed in the observation that sample room carries out × 1000 times of micromorphologies.
The experiment of 4.4 tablets in vitro
(1) preparation of simulated body fluid: simulated body fluid uses phosphate buffer (the phosphate buffer of different pH
Saline, PBS) it is prepared.
(2) determination of Detection wavelength: using the PBS buffer solution of blank solid dispersions and ethyl alcohol as reference, 300~
(such as Fig. 3) is scanned in 700nm wave-length coverage, determines that maximum absorption wavelength λ max is 427nm.
(3) foundation of standard curve: for method with 3.3 (2), solvent is 75% ethyl alcohol.Obtain calibration curve equation are as follows: A=
0.1424C-0.0018, wherein r=0.9999.The result shows that curcumin exists well in 1.0~5.0 μ g/mL concentration ranges
Linear relationship.
(4) measurement of curcumin Accumulation dissolution
Solid dispersions 10.0mg is weighed, is respectively placed in the brown drug release bottle equipped with 30mL dissolution medium, is placed in temperature
It is, according to certain drug release time interval, to sample 5mL in the thermostatic control oscillator vibration of 100r/min, mend simultaneously for 37 DEG C, revolving speed
The simulated body fluid for adding isothermal, isometric corresponding pH, to maintain the constant of medium volume, by spectrophotometry, to correspond to blank
Solid dispersions are reference, measure turmeric cellulose content in dissolution medium at 427nm, calculate Accumulation dissolution by (3) formula, draw not
With drug Accumulation dissolution in dissolution medium and the graph of relation between the time:
In formula: Re% is Accumulation dissolution；cnFor dissolution medium drug concentration after n-th sampling；V0For dissolution medium
Volume；ViFor the volume of every sub-sampling；ciDissolution medium drug concentration when replacing is sampled for i-th；M is that drug contains in sample
Amount.
Step 5: carrying out result and analysis
5.1 pectin and curcumin are with the influence for comparing solid dispersions
Pectin and curcumin are with the conspicuousness for comparing encapsulation rate (0.01 < p < 0.05) and carrying drug ratio (p > 0.05) influence
It is different.As shown in figure 4, the variation tendency for first increasing and reducing afterwards is presented in encapsulation rate and drugloading rate with the increase of material medicine proportion；By
In the complexity of pectin molecule self structure, and there is higher molecular weight, tests within the scope of the dosage of setting, encapsulation rate and load medicine
The amplitude of variation of amount is smaller.Since pectin is poly- negative acidic polysaccharose, drug-loading mechanism includes physics cladding and two kinds of Electrostatic Absorption.
It is chemically reacted in lye with NaOH or even chain rupture occurs for intramolecule, after reaction terminates acidified processing, low concentration fruit
Carboxylic acid ion concentration in xanthan molecule reduces, and causes to reduce with the intermolecular suction-operated of curcumin；And pectin-the calcium formed
Effective cross-linked network structure area is less, reduces pectin to the coating function of curcumin.With the increase of concentration of pectin, effective fruit
Glue-calcium three-dimensional crosslinked network structure increases, and the suction-operated enhancing between drug and carrier promotes drugloading rate and encapsulation rate to mention
It is high；When expecting medicine proportion is 3.0: 1, with Ca2+Between form stable network cross-linked structure, and in pectin molecule carboxyl proton
It is most strong to change effect, forms strong intermolecular hydrogen bonding active force, shows as encapsulation rate and drugloading rate respectively reaches maximum value 42.70%
With 6.70%.With further increasing for concentration of pectin, intermolecular repulsion effect enhancing, not with the pectin molecule of calcium ion crosslinking
Increase, causes the decline of drugloading rate and encapsulation rate.
5.2 CaCl2Influence of the concentration to solid dispersions
CaCl2Influence of the concentration to solid dispersions is that conspicuousness influences (0.01 < p < 0.05).As shown in figure 5, with
CaCl2Concentration increases, and the variation tendency for first increasing and reducing afterwards is presented in encapsulation rate and drugloading rate.Work as Ca2+When concentration is lower, formed
Pectin-calcium cross-linked network structure it is less；Work as Ca2+When concentration reaches a certain concentration, it is capable of forming stable pectin-calcium bridging
" egg-box " structural area, causes encapsulation rate and drugloading rate to reach maximum value；Work as Ca2+Concentration further increases, stable " egg-box "
Network structure is destroyed, and forms more fine and close unstable three-dimensional network cross-linked structure, encapsulation rate and drugloading rate decline therewith.
Influence of 5.3 reaction time to solid dispersions
Influence of the reaction time to solid dispersions has extremely significant property (p < 0.01).As shown in fig. 6, the first two hour
Interior, the two is kept approximately constant, and encapsulation rate and drugloading rate respectively reach 65% and 10% or more；It continues growing, encapsulates at any time
Downward trend is presented in rate and drugloading rate, and downward trend is obvious.Since mixing time is longer, pectin molecule may cause substantially
Chain rupture is spent, effective pectin-calcium cross-linked network structure area is formed and reduces；And pectin molecule is chemically reacted with lye, is caused
The protonation of carboxyl reduces, and the electrostatic repulsion enhancing between strand shows as the decline of encapsulation rate and drugloading rate.
Influence of 5.4 solvent strengths to solid dispersions
Influence of the solvent strength to solid dispersions has extremely significant property (p < 0.01).Encapsulation rate and drugloading rate are with solvent
For the situation of change of concentration as shown in fig. 7, increasing with solvent strength, the variation tendency of first increases and then decreases is presented in the two；When molten
When agent concentration is 0.60%, encapsulation rate and drugloading rate respectively reach maximum value 66.48% and 10.32%.NaOH concentration can be right
The structure and segment size of pectin molecule make a big impact[179], when concentration of lye is lower, pectin molecule chain is mostly with coherent condition
In the presence of formation " egg-box " bridge crosslinking structure is less, causes encapsulation rate and drugloading rate lower.When concentration of lye increases to greater than
When 0.60%, it may cause pectin molecule chain and be broken, long-chain becomes short chain, or even influences the variation of molecular structure, causes
Make to be formed more loose three-dimensional net structure；Meanwhile higher concentration of lye can make more Na+With in pectin molecule-
COOH-Assembled by electrostatic attraction, to reduce suction-operated of the pectin molecule to drug, factors above is made jointly
With causing encapsulation rate and drugloading rate to reduce.
Influence of 5.5 reaction temperatures to solid dispersions
Influence of the reaction temperature to solid dispersions has extremely significant property (p < 0.01).Such as Fig. 8, when temperature is 50 DEG C,
Encapsulation rate and drugloading rate are maximum value；It when temperature is less than 50 DEG C, is increased with temperature, encapsulation rate and drugloading rate are in that increase becomes
Gesture, encapsulation rate amplification are small compared with drugloading rate；It when temperature is greater than 50 DEG C, is increased with temperature, decreasing trend, encapsulation rate drop is presented in the two
Width is obvious.The dispersity of pectin molecule chain is mainly affected by temperature, and when the temperature is low, pectin molecule is to assemble, roll up shape
State exists, and effective " egg-box " bridging area of formation is less, causes encapsulation rate and drugloading rate not high；When temperature is higher, pectin point
Subchain, due to the collective effect of stirring and solvent, causes strand chain rupture probability to increase to unfold state presence, and molecular weight reduces,
The region of combining closely of pectin is further destroyed, encapsulation rate and the drugloading rate decline of solid dispersions.
5.5 parameter optimization
Test the CaCl of setting2Four concentration, reaction time, solvent strength and reaction temperature factors are to drugloading rate and encapsulating
2 response indexs of rate have different influences, need to comprehensively consider influence of each factor to two indexs, can be only achieved drugloading rate and packet
The all good preparation effect of envelope rate.Quadratic regression is carried out to 2 response indexs by Design Expert8.0 Data Analysis Software
Optimization Solution obtains the optimized parameter of each index are as follows: CaCl2Concentration 3.66g/L, time 1.62h, solvent strength 0.69%, temperature
49.04 DEG C of degree.Prediction is under this condition, the encapsulation rate and drugloading rate of curcumin are respectively 69.50% and 11.48%.It is further
The confidence level for verifying this model is operated in combination with actual controllability, is modified to Optimal Parameters: CaCl2Concentration 3.7g/
L, time 100min, solvent strength 0.69%, temperature 50 C.With this condition, pass through parallel laboratory test three times, the solid point of preparation
The encapsulation rate and drugloading rate of granular media are respectively 67.17% and 11.40%.Experiment value and predicted value the result shows that, the model
Confidence level is good, and Optimal Parameters can be used for pectin polysaccharide and prepare curcumin solid dispersion.
5.7 dsc analysis
In order to study the hot property of curcumin solid dispersion, differential scanning calorimetry (DSC) analysis has been carried out to it.Figure
9 show that curcumin reference substance occurs a single highly endothermic peak (melting hump) at 183 DEG C, and the thermal map mould of its dispersion
Formula varies widely, and the melting hump of curcumin completely disappears in dispersion microparticle system, can only find 75 DEG C and 138 DEG C two
A weak unformed endothermic peak.The above results show between curcumin and carrier molecule that interaction forms heat and unit coexists；Ginger
Flavine is not present in solid dispersions in a manner of crystal, is scattered in carrier with high energy amorphous state or molecular state
In.
5.8 XRD analysis
Drug in solid dispersions generally exists with molecular forms, when drug is loaded on carrier with molecular forms,
The drug with certain crystal form can be made to become unformed.XRD result further demonstrates the solid-state of curcumin in dispersions
Matter.X-ray powder diffraction figure 10 shows that crystalline state curcumin reference substance is that there are strong crystal to spread out between 10~50 ° of ranges in 2 θ
Penetrate peak；Pectin is amorphous polymer, and diffracting spectrum does not have apparent crystal diffraction peak.In the diffraction pattern of dispersion,
Curcumin crystal form diffraction maximum disappears, and speculates that the dispersity of curcumin in co-precipitate may be by Pectin polymers physics and chemistry accordingly
Matter influences, and after forming unformed co-precipitate during preparing dispersion, main ingredient is scattered in nothing with unformed or molecular forms
In the Pectin polymers of sizing.This illustrates that the curcumin in solid dispersions is to exist as an amorphous form, the result and DSC
As a result consistent.
5.9 scanning electron microscope analysis
× 1000 times of scanning electron microscopic observations have been carried out to the pattern of curcumin solid dispersion particle under different acceleration voltages,
As shown in figure 11.Strong combine between curcumin and pectin inhibits curcumin to be assembled into orderly crystal structure, so as to cause
Amorphous formation.Therefore, SEM result is consistent with the result of above-mentioned XRD and DSC.SEM elemental analysis result (Figure 12) confirms
Alkali soluble agent and hydrochloric acid occur neutralization reaction and form inorganic salts NaCl, show this experimental method it is possible to prevente effectively from organic solvent
It remains to passing medicine safety bring adverse effect.
5.10 tablets in vitro is tested
(1) in different pH medium release measurement
Curcumin solid dispersion is placed in the dissolution medium of different pH value, measures curcumin in different time medium
Concentration calculates drug accumulation release, draws its relation curve between the time, as shown in figure 13.With dissolution medium pH value
Increase, the Accumulation dissolution of curcumin increases in same time；In entire drug release process, burst release behavior is not shown.It is real
Test the result shows that, the curcumin solid dispersion prepared using pectin as carrier has pH sensibility.Pectin is poly- negative electrolyte,
When low pH, due to the carboxyl height protonation in pectin molecule, the constraint of strong electrostatic force, so that curcumin is not easy to release
It puts, the Accumulation dissolution of 12h is 20% or so；With the increase of dissolution medium pH, in pectin molecule, the protonation of carboxyl is not
Disconnected to weaken, gradually to unfold state presence degradation in various degree occurs for strand, and the electrostatic force of drug molecule drops in carrier
It is low, so that curcumin release increases.In addition, in the dissolution medium of pH7.40, with the further extension of release time, accumulation
Release also fails to reach absolutely.This is because the carboxyl on pectin molecule chain does not ionize completely, by hydrogen bond to turmeric
The constraint effect of element fails to completely eliminate, therefore cannot release the drug completely.
(2) measurement of release in gastro-intestinal Fluid is simulated
Curcumin solid dispersion is placed in the simulated body fluid of gastric juice, intestinal fluid and colonic fluid, referring to drug in stomach and intestine
The general action time in liquid makes curcumin dispersion release the drug in each simulated body fluid under the conditions of isothermal vibration, calculates cumulative release
Degree, Figure 14 are release behavior of the curcumin dispersion in simulation gastro-intestinal Fluid.In the drug release process of simulate the gastric juice 2h, curcumin
Accumulation dissolution is lower than 20%；In drug release process in simulated intestinal fluid 3h, the drug release of continuation part；Into colonic simulated fluid
In, burst drug release occurs, the Accumulation dissolution of 7h nearly reaches 80%, shows certain colon specific feature, machine
Managing the pectin macromolecular being in dispersion has sensibility to the pH of dissolution medium to the electrostatic force of curcumin molecule.Acid
The strong electrostatic interaction of pectin molecule, makes curcumin in dispersion be not easy to discharge under the conditions of property；Increase with pH, drug matrices structure
Corrosion, curcumin burst size increase；After reaching colon, under the action of pectase, pectin-calcium cross-linked network disintegrates, drug bone
The further corrosion of frame, dissolves out drug largely.
In conclusion the preparation method of curcumin solid dispersion proposed by the present invention, the present invention selects inorganic solvent, will
Solvent method and the precipitation method combine, and using molecular self-assembling, cluster, aggregation, form bright yellow precipitate in acid condition, carry out
The preparation of solid dispersions avoids organic solvent residual bring medication toxic side effect, and solving to use in the prior art has
Solvent method, which prepares curcumin solid dispersion, has that dissolvent residual has dissolvent residual.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art within the technical scope of the present disclosure, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (5)
1. a kind of preparation method of curcumin solid dispersion, which comprises the steps of:
S1: the foundation of curcumin detection method
S2: the preparation of curcumin solid dispersion
Experiment combines solvent method and the precipitation method, using molecular self-assembling, carries out the preparation of solid dispersions；
S3: response phase method optimization experiment
On the basis of experiment of single factor, according to Box-Behnken experimental design principles, using Design-Expert8.0 software,
It designs the horizontal totally 29 groups of experiments of 4 factor 3 and carries out response surface experiment；
S4: the in-vitro evaluation of curcumin solid dispersion.
2. a kind of preparation method of curcumin solid dispersion according to claim 1, which is characterized in that S1 further include as
Lower step:
S101: the measurement of drugloading rate and encapsulation rate；
S102: stability experiment
Quantitative curcumin is accurately weighed, is dissolved in the NaOH solution that concentration is 0.1,0.5,1.0 and 5.0% respectively, Yu Xiangtong
Point in time sampling surveys its absorbance；
S103: the drafting of standard curve；
S104: Precision Experiment
The curcumin aqueous slkali for preparing basic, normal, high three kinds of concentration respectively, its absorbance is surveyed in different time points sampling in 3 hours,
Each sample is measured in parallel three times.
3. a kind of preparation method of curcumin solid dispersion according to claim 1, which is characterized in that S4 further include as
Lower step:
S401: Thermal characteristic analysis (DSC)
Solid dispersions 3~the 5mg of sample balanced in drier for 24 hours accurately is weighed, is encapsulated in aluminum pot with holes；Without sample
Aluminum pot as reference；
S402:X- Diffraction Patterns analyze (XRD)
Solid dispersions are directly compacted in sample cell, using progress XRD test under Cu-K alpha ray (λ=0.154nm)；
S403: scanning electron microscope analysis (SEM)
First conducting resinl is pasted on copper sample stage, then drying solid dispersion is dispelled with rubber pipette bulb and is distributed in conducting resinl
On, on metal spraying platform after metal spraying 5min, it is placed in the observation that sample room carries out × 1000 times of micromorphologies；
S404: tablets in vitro experiment.
4. a kind of preparation method of curcumin solid dispersion according to claim 2, which is characterized in that S103 further includes
Following steps:
S1031: the determination of Detection wavelength；
S1032: the foundation of standard curve.
5. a kind of preparation method of curcumin solid dispersion according to claim 3, which is characterized in that S404 further includes
Following steps:
S4041: the preparation of simulated body fluid: simulated body fluid is prepared using the phosphate buffer (PBS) of different pH；
S4042: the determination of Detection wavelength: using the PBS buffer solution of blank solid dispersions and ethyl alcohol as reference, in 300~700nm
Scanning, determines that maximum absorption wavelength λ max is 427nm in wave-length coverage；
S4043: the foundation of standard curve: using the establishment step of step S1032, solvent is 75% ethyl alcohol, obtains standard curve
Equation；
S4044: the measurement of curcumin Accumulation dissolution.
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