CN114796159A - Gastrodia elata micro-capsule and preparation method and application thereof - Google Patents
Gastrodia elata micro-capsule and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a gastrodia elata microcapsule, and a preparation method and application thereof, and belongs to the technical field of traditional Chinese medicine extraction and preparation. The method adopts a low-temperature high-pressure crushing extraction technology combined with a freeze drying technology to prepare the gastrodia elata extract, and the gastrodia elata freeze-dried powder is prepared into the microcapsule by adopting a high-pressure homogenizing-spray drying technology. Compared with reflux extraction-reduced pressure drying technology, the total yield of the rhizoma gastrodiae freeze-dried powder obtained by the method and the extraction rate of target components are higher than those of the traditional method, and the rhizoma gastrodiae freeze-dried powder has higher oxidation resistance. The microcapsule prepared by adopting the high-pressure homogenizing-spray drying technology has high encapsulation efficiency, high yield and large drug-loading rate, improves the thermal stability of the thermosensitive component in the gastrodia elata after drug loading, has a certain slow release effect, is beneficial to improving the bioavailability of the active component in the gastrodia elata, and provides a basis for the effective utilization of the gastrodia elata and the development of a preparation.
Description
Technical Field
The invention belongs to the technical field of traditional Chinese medicine extraction and preparation, and particularly relates to a gastrodia elata microcapsule as well as a preparation method and application thereof.
Background
Gastrodia elata is a herbaceous plant symbiotic with fungi, has high requirements on growth environment, is fond of humid and cool environment, needs to rely on good mixed wood forest and sufficient moisture, and grows in high-altitude mountain areas (800-2500 m) with more forest lands, the highest temperature is not more than 30 ℃, the air humidity is not less than 50%, the annual precipitation is about 1000mm, and the terrain is preferably selected on shady slopes. The southwest region of China is the main production area of rhizoma gastrodiae, including Guizhou, Yunnan, Sichuan, Shaanxi, Hubei and the like, and the rhizoma gastrodiae is rich in hundreds of chemical components, wherein the active components mainly comprise phenols, glycosides, organic acids, sterols, polysaccharides and the like.
The extraction method of the gastrodia elata mainly comprises a percolation method, a reflux extraction method, an enzymolysis extraction method, an ultrasonic extraction method and a microwave extraction method, the problems of long extraction time, high temperature, easy degradation of thermosensitive components and the like exist in the extraction and separation of the gastrodia elata by the traditional extraction method, and the characteristics of different extraction and separation technologies are shown in table 1.
TABLE 1 Gastrodia elata Blume traditional extraction and separation technique
Compared with the traditional extraction method, the low-temperature high-pressure crushing extraction technology has the advantages of short extraction time, high extraction efficiency and good extraction effect on heat-sensitive components. The principle is that under the condition of low temperature, fluid dynamic high pressure is applied to form instantaneous high pressure, then instantaneous pressure reduction is carried out to generate strong actions of shearing, turbulence, impact and the like, so that material cells are instantaneously expanded and crushed, the contact area of effective components and a solvent is enlarged, the penetration and the release of the components of the solvent are accelerated, and the aim of high-efficiency extraction is fulfilled while the cells are crushed. The high-pressure crushing extraction technology can combine wall breaking and extraction, the whole extraction process is carried out under low-temperature and continuous conditions, compared with the traditional mechanical crushing method, the problems of thermal degradation or inactivation of thermosensitive active ingredients and the like can be avoided, the process is simple, the efficiency and the energy are high, and the production cost can be reduced.
The prior gastrodia elata preparation mainly comprises a monomer component gastrodin preparation in gastrodia elata, is mostly a traditional preparation and comprises tablets, injections, dropping pills, soft capsules and the like. The literature, the preparation of gastrodin sustained release tablets and the research on the in vitro drug release characteristics thereof, adopts an osmotic pump technology and takes cellulose acetate as a coating material to prepare the gastrodin sustained release tablets; the document, polysorbate 80-modified gastrodin liposome preparation research, adopts a film-ultrasonic method to prepare a polysorbate 80-modified gastrodin liposome injection capable of crossing a blood brain barrier; gastrodin nano liposome and nano microsphere preparation research adopts a solvent volatilization-multiple emulsion method to prepare the Gastrodin microsphere. However, the efficacy of traditional Chinese medicines is mostly the result of comprehensive action of multiple components, so that few researches on multi-component preparations of the gastrodia elata extract are carried out at present, and few researches on microcapsules capable of preventing heat-sensitive components from being damaged and lost are carried out. In the literature, "preparation of gastrodia elata extract microcapsules" sodium alginate is used as a wall material, and a dripping method is adopted to prepare the gastrodia elata extract calcium alginate microcapsules with the particle size of 200 microns and the embedding rate of about 48%, so that the problems that the preparation process is long in time consumption and the embedding rate of gastrodin is low exist.
Disclosure of Invention
In order to solve the related problems, the primary object of the present invention is to provide a method for preparing a rhizoma gastrodiae microcapsule.
Another object of the present invention is to provide the microcapsule of gastrodia elata obtained by the above preparation method.
The invention also aims to provide application of the gastrodia elata microcapsules.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for preparing rhizoma Gastrodiae microcapsule comprises the following steps:
step (1): low-temperature high-pressure crushing extraction: adding rhizoma Gastrodiae powder into extraction solvent, uniformly dispersing with high-speed homogenizer, injecting into high-pressure crushing extraction device for crushing and extracting, centrifuging extract, and collecting filtrate; wherein the extraction solvent is ethanol with the volume fraction of 30-70%, the liquid-solid ratio is 10: 1-40: 1, the crushing and extraction temperature is 3-5 ℃, the pressure is 50-200 MPa, and the times are 1-4;
step (2): and (3) freeze drying: freeze-drying the filtrate obtained in the step (1) to constant weight to obtain rhizoma gastrodiae extract freeze-dried powder;
and (3): high pressure homogenization-spray drying method for preparing the microcapsule: adding wall materials and an emulsifier into water, uniformly stirring, and adding the freeze-dried powder of the gastrodia elata extract obtained in the step (2) as a core material; stirring at high speed with a high speed dispersion machine, homogenizing with a high pressure homogenizer to obtain rhizoma Gastrodiae homogeneous solution, and spray drying to obtain rhizoma Gastrodiae microcapsule.
Further, the rotating speed of the high-speed refiner in the step (1) is 10000r/min, and the time for uniform dispersion is 2 min.
Further, the rotation speed of the centrifugation in the step (1) is 4000r, and the time is 5 min.
Further, the extraction solvent in the step (1) is ethanol with the volume fraction of 50%, the liquid-solid ratio is 30:1, the crushing and extraction temperature is 4 ℃, and the pressure is 100 MPa.
Further, in the gastrodia elata extract freeze-dried powder in the step (3), the content of the gastrodin in percentage by mass is 0.281%, the content of the parahydroxybenzyl alcohol in percentage by mass is 1.509%, the content of the barbaloside E in percentage by mass is 0.964%, the content of the barbaloside B in percentage by mass is 0.717%, the content of the barbaloside C in percentage by mass is 0.123%, and the content of the barbaloside A in percentage by mass is 2.422%.
Further, the wall material in the step (3) is a composite wall material composed of Soy Protein Isolate (SPI) and Maltodextrin (MD), and the mass ratio of the soy protein isolate to the maltodextrin is 0.5: 1-2.5: 1, preferably 1: 1.
Further, the emulsifier in the step (3) is monoglyceride.
Further, the mass concentration of the wall material in the step (3) is 2-10%, the mass concentration of the emulsifier is 0.6-0.8%, and the mass ratio of the wall material to the core material is 3: 1-7: 1; preferably, the mass concentration of the wall material is 8%, the mass concentration of the emulsifier is 0.67%, and the mass ratio of the wall material to the core material is 7: 1.
Further, the feeding speed of the spray drying in the step (3) is 10-30% of the maximum feeding speed, and the maximum feeding speed is 1.5 mL/min.
Further, the rotation speed of the high-speed dispersion machine in the step (3) is 10000r/min, and the high-speed stirring is carried out for 2 min.
Further, the pressure of the high-pressure homogenizer in the step (3) is 50 MPa.
A rhizoma Gastrodiae microcapsule is prepared by the above preparation method.
Furthermore, the particle size distribution of the gastrodia elata microcapsules is 1-10 microns, the encapsulation rate reaches 87.48%, the yield reaches 75.96%, and the drug loading rate reaches 15.46%.
The rhizoma Gastrodiae microcapsule can be used for preparing intestinal tract release medicine.
Compared with the prior art, the invention has the following advantages and effects:
the invention discloses a preparation method of a rhizoma gastrodiae microcapsule, which is characterized in that a rhizoma gastrodiae extract is prepared by adopting a low-temperature high-pressure crushing extraction technology and a freeze drying technology, and the rhizoma gastrodiae freeze-dried powder is prepared into the microcapsule by adopting a high-pressure homogenization-spray drying technology. Compared with reflux extraction-reduced pressure drying technology, the total yield of the rhizoma gastrodiae freeze-dried powder obtained by the method and the extraction rate of target components are higher than those of the traditional method, and the rhizoma gastrodiae freeze-dried powder has higher oxidation resistance; the microcapsule prepared by adopting the high-pressure homogenizing-spray drying technology has high encapsulation efficiency, high yield and large drug-loading rate, improves the thermal stability of the thermosensitive component in the gastrodia elata after drug loading, has a certain slow release effect, is beneficial to improving the bioavailability of the active component in the gastrodia elata, and provides a basis for the effective utilization of the gastrodia elata and the development of a preparation.
Drawings
FIG. 1 is a graph showing the results of a study on the influence of ethanol concentration on the extraction rate of 6 index components in Gastrodia elata Blume;
FIG. 2 is a graph showing the results of a study on the influence of liquid-solid ratio on the extraction rate of 6 index components in Gastrodia elata Blume;
FIG. 3 is a graph showing the results of the study on the effect of extraction pressure on the extraction rate of 6 index components in Gastrodia elata Blume;
FIG. 4 is a graph showing the results of the study on the influence of the extraction frequency on the extraction rate of 6 index components in Gastrodia elata Blume;
FIG. 5 is a graph showing the results of the study of antioxidant ability of the extract obtained by heating and refluxing the extract and the extract obtained by crushing the extract at low temperature and high pressure; wherein, a is DPPH free radical scavenging test result, b is FRAP test result, c is ABTS free radical scavenging test result;
FIG. 6 is a scanning electron micrograph of different samples; wherein A is maltodextrin, B is soybean protein isolate, C is rhizoma Gastrodiae lyophilized powder, D is physical mixture, and E is rhizoma Gastrodiae extract microcapsule;
FIG. 7 is a distribution diagram of microcapsule particle size;
FIG. 8 is a Fourier infrared spectrum;
FIG. 9 is an X-ray diffraction spectrum; wherein, a is rhizoma gastrodiae extract freeze-dried powder, b is rhizoma gastrodiae extract microcapsule, c is soybean protein isolate, and d is maltodextrin;
FIG. 10 is a thermogravimetric analysis (TG) plot; wherein, a is rhizoma gastrodiae extract freeze-dried powder, b is maltodextrin, c is soybean protein isolate, and d is a rhizoma gastrodiae extract microcapsule;
FIG. 11 is a Differential Scanning Calorimetry (DSC) chart;
FIG. 12 is a graph showing the relative content of the micro-capsules of Gastrodia elata extract and the physical mixture at different temperatures; wherein A is 40 ℃, B is 60 ℃ and C is 80 ℃;
FIG. 13 is the in vitro dissolution curve of lyophilized powder and microcapsule of rhizoma Gastrodiae low temperature extract.
Detailed Description
The present invention will be further specifically illustrated by the following examples for better understanding, but the present invention is not to be construed as being limited thereto, and certain insubstantial modifications and adaptations of the invention by those skilled in the art based on the foregoing disclosure are intended to be included within the scope of the invention.
The component detection and analysis method related in the embodiment of the invention comprises the following steps:
(1) chromatographic conditions
A chromatographic column: phenomenex Luna C18(250 mm. times.4.6 mm, 5 μm); mobile phase: acetonitrile (A) -0.1% phosphoric acid water (B), gradient elution (0-5 min, 3.0% A, 5-15 min, 3.0-5.0% A, 15-22 min, 5.0% A, 22-25 min, 5.0-10.1% A, 25-35 min, 10.1-10.2% A, 35-45 min, 10.2-14.0% A, 45-52 min, 14.0% A, 52-55 min, 14.0-16.5% A, 55-63 min, 16.5-17.5% A, 63-65 min, 17.5-20.0% A, 65-70 min, 20.0% A); flow rate: 1.0 mL/min; detection wavelength: 220 nm; column temperature: 35 ℃; sample introduction amount: 4 μ L.
(2) Preparation of control solutions
Accurately weighing appropriate amount of gastrodin, p-hydroxybenzyl alcohol, barban glycoside E, barban glycoside B, barban glycoside C and barban glycoside A reference substances, adding 30% chromatographic grade acetonitrile solution to prepare mixed reference substance solutions with the concentrations of 0.0830, 0.0694, 0.0845, 0.0760, 0.0273 and 0.2070 mg/mL respectively, and filtering with a 0.45 mu m microporous filter membrane for later use.
(3) Preparation of test solution
Weighing appropriate amount of rhizoma Gastrodiae lyophilized powder or microcapsule, placing in 50mL conical flask with plug, adding appropriate amount of methanol, ultrasonic treating for 40min (40kHZ, 250W), cooling, weighing, supplementing with methanol to lose weight, and shaking.
(4) Linear relationship and range
Preparing mixed reference substance solutions with different concentrations, determining peak areas by adopting the chromatographic conditions, drawing standard curves by taking the mass of each reference substance as a horizontal coordinate and the corresponding peak area value as a vertical coordinate, wherein the results of regression equations, correlation coefficients, linear ranges, quantitative limits and detection limits of each standard curve are shown in a table 2. The results show that the linear relationship of the 6 index components in the corresponding range is good.
Table 26 linear equations, correlation coefficients and linear ranges of index components
Example 1: crushing and extracting at low temperature and high pressure
1. Effect of ethanol concentration
Solvent properties play a crucial role in the extraction process, which is influenced by solvent polarity, solution viscosity and surface tension, and a single solvent (water) may not be effective in extracting all the desired components. Therefore, organic solvents are used to increase extraction efficiency. Green solvent ethanol water solution is selected as extraction solvent. The results are shown in FIG. 1. As the ethanol concentration increased from 10% to 50%, the extraction rate of the target compound increased.
2. Influence of liquid-solid ratio
The results are shown in FIG. 2. When the liquid-solid ratio is increased from 10:1 to 30:1, the total extraction yield of the target compound is improved. After that, the extraction rate decreases as the liquid-solid ratio increases. The trend of each single component is basically the same.
3. Influence of extraction pressure
The results are shown in FIG. 3. As the extraction pressure is increased from 50MPa to 200MPa, the sum of the extraction rates of the target compounds is increased and then decreased, and the difference of the sum of the extraction rates is not large. The change trends of the extraction rates of the gastrodin, the parahydroxybenzyl alcohol, the barban glycoside E, the barban glycoside C and the barban glycoside A are basically the same.
4. Influence of extraction times
The results are shown in FIG. 4. With the increase of the times of low-temperature and high-pressure crushing extraction, the total extraction rate of the target compounds in the gastrodia elata gradually decreases, probably because the extraction times increase, the extraction solution has loss, and the change trend of each single component is basically the same.
5. Low-temperature high-pressure crushing extraction response surface test
According to the single-factor results, the influence of the ethanol concentration, the feed-liquid ratio and the extraction pressure on the extraction of the target components of the gastrodia elata is large, a Box-Behnken (BBD) design method is adopted for the three factors, and the yield of the six components is used as a response value to optimize.
And determining the influence of different independent variables on the extraction of the target components of the gastrodia elata and the comprehensive effect of the independent variables by adopting a three-level three-factor BBD design. As shown in table 3, the selected independent variable is ethanol concentration (X1); liquid-to-solid ratio (X2); the extraction pressure (X3) and the third order multiplication levels of these variables are-1, 0 and +1, respectively, low, medium and high levels, respectively. Dependent variables are the extraction rates of target compounds including gastrodin (Y1), p-hydroxybenzyl alcohol (Y2), barban E (Y3), barban B (Y4), barban C (Y5) and barban A (Y6).
TABLE 3 response surface analysis factors and horizon table
The optimum operating parameters shown in Table 4 were obtained according to the BBD test described above. In order to facilitate the practical operation, the four target compounds are crushed and extracted at low temperature and high pressure under the conditions that the ethanol concentration is 50%, the liquid-solid ratio is 30:1 and the extraction pressure is 100 MPa. The optimum conditions were used in the following experiments.
Table 4 optimal extraction conditions and extraction rates of target compounds determined by BBD test
The above optimum process conditions were verified and the results are shown in table 5. The sum of the extraction rates of the 6 index components is 1.599%, wherein the extraction rates of the gastrodin, the parahydroxybenzyl alcohol, the barban glycoside E, the barban glycoside B, the barban glycoside C and the barban glycoside A are respectively 0.068%, 0.497%, 0.249%, 0.161%, 0.036% and 0.588%, and the theoretical optimization value is not obviously different, which indicates that the created response surface model has good fitting degree and is suitable for optimization of the extraction process of the 6 effective components in the gastrodia elata.
Table 5 verifies the test results
Freeze-drying the low-temperature high-pressure crushing extraction filtrate at the temperature of-80 ℃, and drying to constant weight to obtain the freeze-dried powder of the gastrodia elata extract.
Comparative example 1: low-temperature high-pressure crushing extraction is compared with the traditional method
1. Comparison of extraction Rate
Low temperature high pressure crushing extraction method (method 1): the low-temperature high-pressure crushing extraction (the temperature is 4 ℃ and the time is 5min), centrifugation, freeze drying of filtrate and drying to constant weight are carried out according to the method of the invention, thus obtaining the low-temperature high-pressure crushing extract of the gastrodia elata.
Heating reflux extraction method (method 2): referring to the method of rhizoma Gastrodiae content determination method in Chinese pharmacopoeia, weighing 2g rhizoma Gastrodiae powder, placing in a conical flask, adding 50mL diluted ethanol solution, weighing, heating and refluxing for 3h (temperature 80 deg.C, time 180min), cooling, weighing again, adding diluted ethanol to balance weight, filtering, and collecting filtrate. And (3) carrying out vacuum rotary evaporation drying on the reflux extracting solution at 90 ℃ under the condition of 0.08MPa, and drying to constant weight to obtain the traditional reflux extract of the gastrodia elata.
TABLE 6 comparison of different extraction methods
As shown in table 6, the extraction rate of gastrodine, p-hydroxybenzyl alcohol, barban glycoside E, barban glycoside B, barban glycoside C and barban glycoside a by low-temperature high-pressure crushing is higher than that of the conventional reflux extraction. The barban glycosides compound is a thermally unstable compound and can be degraded at high temperature, and the traditional reflux extraction method needs longer extraction time and higher extraction temperature and is not suitable for extracting the thermally unstable compound. In addition, the extraction time of low-temperature high-pressure crushing is only about 10min, which is far lower than the extraction time (3h) of the traditional reflux extraction, and the transfer rate is reduced because of great loss generated by overlong extraction time. Therefore, compared with the traditional extraction method, the method has greater development potential and application value.
2. Comparison of antioxidant Capacity
(1) DPPH free radical scavenging assay: the antioxidant activity was evaluated by the stable scavenging of DPPH free radicals. After mixing 0.1mL of the sample solution with 1.4mL of ethanol, DPPH (0.04mg/mL, 1mL) was added. The reaction was carried out in the dark for 60min, and the absorbance of the sample solution was measured at 517nm using an ultraviolet spectrophotometer. The DPPH clearance is calculated as follows:
greater DPPH clearance, IC 50 Lower value indicates higher antioxidant capacity, and IC of the extract is crushed at low temperature and high pressure 50 IC value of 7.455mg/mL, less than heated reflux extract 50 The value (7.792mg/mL), combined with the results in a of FIG. 5, indicates that the DPPH radical scavenging ability of the low temperature and high pressure disrupted extract is stronger than that of the heat-refluxed extract.
(2) FRAP test: and (3) uniformly mixing 8mL of LTPTZ diluent with 0.8mL of TPTZ solution, adding 0.8mL of detection buffer solution to obtain FRAP working solution, and incubating at 37 ℃ for later use. 27.9mg of FeSO are weighed out 4 ·7H 2 O, dissolved and diluted to 1ml, at which point the concentration is 100 mM. Taking a proper amount of 100mM FeSO 4 The solution was diluted to 0.15, 0.3, 0.6, 0.9, 1.2 and 1.5 mM. A standard curve of FeSO4 was plotted with molar concentration (mM, x) as abscissa and absorbance (y) as ordinate. The results show that FeSO 4 The linear regression equation shows a good linear relation in the range of 0.15-1.5 mM: 0.3321x +0.0489 (r) 2 ＝0.9993)
Sample solutions of different concentrations (1, 6, 8, 10, 20, 30mg/mL) were mixed with FRAP working solution and incubated at 37 ℃ for 5 min. Absorbance was measured at 593nm using a microplate reader. Final total antioxidant capacity of the sample as FeSO 4 Equivalent concentration (FRAP value). The higher the FRAP value, the stronger the oxidation resistance, the FRAP value of the low temperature high pressure crushing extract is 0.082mmol/g which is larger than the FRAP value of the heating reflux extract is 0.074mmol/g, and the higher the total oxidation resistance can be obtained from b in figure 5.
(3) ABTS free radical scavenging assay: and uniformly mixing 0.2mL of ABTS solution and 0.2mL of oxidant solution to obtain ABTS working mother liquor, and storing the ABTS working mother liquor at room temperature in a dark place for 12 hours. 0.1mL of ABTS working mother liquor is taken and diluted to 50mL by 80% ethanol solution to obtain ABTS working liquor. Samples of different concentrations (1, 6, 8, 10, 20, 30mg/mL) were mixed with ABTS working solution and incubated at 37 ℃ for 5 min. The absorbance was measured at 734nm with a microplate reader. The formula for ABTS clearance is as follows:
the greater the ABTS clearance, the greater the antioxidant capacity, and it can be seen from c in FIG. 5 that the extract obtained by crushing at low temperature and high pressure has the greater antioxidant capacity, its IC 50 A value of 1.984mg/mL less than the IC of the heated reflux extract 50 The value (7.437mg/mL) was therefore higher for the ABTS free radical scavenging ability of the low temperature high pressure disruption extract.
TABLE 7 free radical scavenging Activity of conventional reflux extract and Low temperature high pressure disruption extract
As shown in Table 7, the low temperature and high pressure cracked extract had higher antioxidant capacity including DPPH radical scavenging ability, FRAP iron ion reducing ability and ABTS total antioxidant capacity as compared to the heat-refluxed extract. This may be related to the higher content of barusine glycosides in the low temperature high pressure crushed extract of Gastrodia elata.
Example 2: research on micro-capsules of freeze-dried powder extracted from gastrodia elata
1. Effect of wall material concentration on microencapsulation formation
Fixing the ratio of MD to SPI to 1:1, using 1.0g of monoglyceride, and mixing the core materials in a ratio of 5:1, homogenizing at 50MPa for 10min at a feeding rate of 15%, and respectively selecting wall material concentrations of 2%, 4%, 6%, 8% and 10% to prepare the microcapsule. The encapsulation efficiency, the yield and the drug-loading rate of the microcapsules are respectively measured and calculated. As can be seen from table 8, the encapsulation efficiency and yield of the microcapsules tended to increase and decrease with increasing wall material concentration, and the encapsulation efficiency and yield were the highest when the wall material concentration was 6%.
Table 8 effect of wall material concentration on microcapsules
2. Influence of wall material ratio on microcapsule formation
The concentration of the fixed wall material is 6%, the dosage of the monoglyceride is 1.0g, and the ratio of the core material to the core material is 5:1, homogenizing at 50MPa for 10min, feeding at 15%, and selecting MD: SPI of 0.5:1 and 1: 1. 1.5: 1. 2: 1. 2.5:1, preparing the microcapsule. The encapsulation efficiency, the yield and the drug-loading rate of the microcapsules are respectively measured and calculated. As can be seen from table 9, with the increase of the wall material concentration, the encapsulation efficiency and the yield of the microcapsules tend to increase and decrease, when the wall material ratio is 1: when 1, the encapsulation efficiency and the yield are highest.
Table 9 effect of wall material formulation ratio on microcapsules
3. Influence of core material ratio on microcapsule formation
The concentration of the fixed wall material is 6 percent, and the ratio of the MD to the SPI is 1:1, 1.0g of monoglyceride, 50MPa of homogenization pressure, 10min of homogenization time and 15% of feeding rate, wherein the core material ratio is respectively selected to be 3:1,4: 1. 5: 1. 6: 1. 7:1, preparing the microcapsule. The encapsulation efficiency, the yield and the drug-loading rate of the microcapsules are respectively measured and calculated. As can be seen from table 10, as the core material ratio increases, the encapsulation ratio of the microcapsules increases first and then substantially balances, and the yield tends to increase first and then decrease, when the core material ratio is 5: the yield was highest at 1 hour.
TABLE 10 influence of core ratio on microcapsules
4. Effect of feed rate on microencapsulation
The concentration of the fixed wall material is 6 percent, and the ratio of the MD to the SPI is 1:1, core material ratio of 5:1, 1.0g of monoglyceride, 50MPa of homogenizing pressure and 10min of homogenizing time, wherein the feeding rates are respectively 10%, 15%, 20%, 25% and 30%, and the microcapsules are prepared. The encapsulation efficiency, the yield and the drug-loading rate of the microcapsules are respectively measured and calculated. As can be seen from table 11, the encapsulation efficiency and yield of the microcapsules tended to increase and decrease with increasing core material ratio, and were the highest when the feed rate was 15%.
TABLE 11 Effect of feed rate on microcapsules
5. Orthogonal testing of microcapsule preparation Process
(1) Design of orthogonal experiments
According to the previous single-factor experiment result, 3 factors of wall material concentration (A), wall material proportion (B) and core material ratio (C) are selected, 3 levels are respectively selected according to L 9 (3 4 ) Orthogonal table is used for orthogonal experimental design, and the encapsulation efficiency, yield and drug loading capacity are used as evaluation indexes. The factor levels, orthogonality test conditions and results are shown in Table 12 and ANOVA is shown in Table 13. As can be seen from Table 12, the influence sequence of the respective factors on the fine powder production process is A > C > B. The calculation results of the encapsulation efficiency and the yield are integrated, and the optimal preparation process is determined to be A 3 B 2 C 3 . Namely 8 percent of wall material concentration, and the wall material ratio MD is that SPI is 1:1, core material ratio 7: 1.
TABLE 12 orthogonal test conditions and results of rhizoma Gastrodiae extract microcapsule preparation process
TABLE 13 analysis of variance
F 0.05 (2,2)＝19.00
(2) Verification of test results
Three batches of rhizoma gastrodiae microcapsule powder are prepared according to the optimal preparation process, the prediction result is verified, and the experimental conditions and the results are shown in table 14.
Table 14 verifies the test results
From table 13, it can be seen that the micro-encapsulation efficiency of the gastrodia elata extract reaches 87.48%, the yield reaches 75.96%, and the drug loading rate reaches 15.46%.
Example 3: appearance and structure representation of gastrodia elata extract microcapsule
1. Microcapsule morphology and particle size
And (3) carrying out vacuum ion gold spraying on a small amount of rhizoma gastrodiae extract microcapsule powder samples and rhizoma gastrodiae freeze-dried samples, and then putting the samples into a scanning electron microscope for imaging observation to obtain a scanning electron microscope image shown in figure 6. The observation of electron microscope pictures shows that rhizoma gastrodiae freeze-dried samples are in amorphous blocky structures and are different in size before being prepared into the micro-capsule powder, and the rhizoma gastrodiae extract micro-capsules are spherical, stable in shape, smooth and round in surface and beneficial to the dispersion of the powder. As can be seen from the particle size distribution curve of fig. 7, the particle size distribution of the gastrodia elata extract microcapsules prepared under the optimal process conforms to the normal distribution, and the corresponding particle size is 4.356 μm when the cumulative particle size distribution percentage of the microcapsules reaches 0.5, which indicates that the prepared microcapsules have uniform particle size distribution.
2. Characterization result of infrared spectrum
The infrared spectroscopy is one of important methods for identifying the types and structures of compounds, and the research respectively weighs a proper amount of rhizoma gastrodiae freeze-dried powder, maltodextrin, soybean protein isolate and rhizoma gastrodiae extract microcapsules, measures the components at room temperature by a Fourier transform infrared spectrometer, and scans the scanning range of 400-4000 cm- -1 The spectrogram is shown in FIG. 8. Fourier transform infrared spectroscopy (FTIR) graphs are mainly used to confirm the presence of gastrodia elata extract, maltodextrin and soy protein isolate and to study the possible interactions between them. The rhizoma gastrodiae extract microcapsule and the auxiliary material thereof are 3700-3100 cm -1 The interval has a wide and strong peak which is the stretching vibration peak of the O-H bond. The curve of the freeze-dried powder and the micro-capsules of the rhizoma gastrodiae extract is 1700-1600cm -1 The interval is bimodal (the peak in the rhizoma Gastrodiae extract microcapsule is 1654 cm) -1 And 1731cm peak -1 Rhizoma Gastrodiae extract jellyPeak 1614cm in dry powder -1 And 1723cm -1 ) It is the characteristic peak of Gastrodia elata Blume. 1200-1000cm in the micro-capsule curve of the rhizoma gastrodiae extract -1 The absorption peak in the interval is more variable and stronger than the absorption peak in the area in the curves of the raw materials and the auxiliary materials, and is caused by the increase of the number of hydroxyl groups after the covalent bonding of the soybean protein isolate and the maltodextrin. These results demonstrate that the gastrodia elata extract was successfully loaded into the microcapsules.
3. Result of X-ray diffraction
The X-ray diffraction spectrum (XRD) patterns of rhizoma Gastrodiae lyophilized powder, maltodextrin, soybean protein isolate and rhizoma Gastrodiae extract microcapsule are shown in FIG. 9. The crystal structures of the gastrodia elata extract freeze-dried powder and the auxiliary materials are obviously changed to the structure of the microcapsule, the raw material medicines and the auxiliary materials are dispersive diffraction peaks, and a new characteristic peak appears at 21.3 in an XRD (X-ray diffraction) diagram of the microcapsule, so that weak correlation effect is generated between the raw material medicines and the auxiliary materials, and the change of the crystal form is caused.
4. TG/DSC thermal analysis
TG/DSC measurement of the rhizoma Gastrodiae lyophilized powder, maltodextrin, soybean protein isolate, and rhizoma Gastrodiae extract microcapsule is shown in figure 10 and figure 11. The freeze-dried powder of the gastrodia tuber extract is gasified from 120 ℃ to about 200 ℃. The soy protein isolate and maltodextrin are gasified from 230 ℃ to about 335 ℃ completely. The rhizoma Gastrodiae extract is encapsulated with adjuvants to form microcapsule, and the gasification temperature is raised to 190 deg.C to enhance thermal stability.
5. Heat stability test of rhizoma Gastrodiae extract microcapsule
In order to determine the stability of the rhizoma gastrodiae extract in the rhizoma gastrodiae extract microcapsule under the high temperature condition, a proper amount of the rhizoma gastrodiae extract microcapsule and three parts of the physical mixture are weighed and respectively placed in a glass dish, the glass dish is placed for 10 days at the temperature of 40 ℃, 60 ℃ and 80 ℃, the content of 6 index components in the rhizoma gastrodiae extract microcapsule is respectively measured by sampling at 0 th, 1 th, 2 th, 4 th, 6 th, 8 th, 12 th, 20 th, 24 th, 28 th, 32 th, 36 th, 42 th, 54 th, 96 th, 144 th and 240 th hours, and a thermal stability release curve is drawn, wherein the result is shown in figure 12, and a, b and c are respectively at the temperature of 40 ℃, 60 ℃ and 80 ℃.
In fig. 12, a shows that the relative content of the physical mixture decreases rapidly after 24 hours, the relative content of the gastrodia elata extract in the gastrodia elata extract microcapsules is 80.37% at 54 hours, the relative content of the gastrodia elata extract in the gastrodia elata extract microcapsules is less than 70%, and the relative content of the gastrodia elata extract in the gastrodia elata extract microcapsules is 74.97% at 240 hours and 59.89% in the physical mixture. In fig. 12 b, the decrease curve of the relative content of the gastrodia elata extract microcapsules is more gradual than the curve of the physical mixture, the relative content of the gastrodia elata extract in the gastrodia elata extract microcapsules is 85.97% in 36h, the relative content of the gastrodia elata extract in the physical mixture is 71.04%, the relative content of the gastrodia elata extract in the gastrodia elata extract microcapsules is 62.76% in 240h, and the relative content of the gastrodia elata extract in the gastrodia elata extract microcapsules is 51.22% in the physical mixture. In fig. 12 c, the decrease degree of the rhizoma gastrodiae extract in the rhizoma gastrodiae extract microcapsule and the physical mixture is more obvious than that at 40 ℃ and 60 ℃, and the relative content of the rhizoma gastrodiae extract in the rhizoma gastrodiae extract microcapsule is 57.91% and the relative content of the rhizoma gastrodiae extract in the latter is 40.76% at 240 h.
In summary, at three temperatures, inclusion of the gastrodia elata extract into the microcapsules can significantly improve the stability of the gastrodia elata extract compared to untreated physical mixtures, but too high temperatures have a certain effect on the stability of the gastrodia elata extract in the gastrodia elata extract microcapsules, and therefore high temperature conditions should be avoided during storage.
6. In vitro dissolution property of rhizoma Gastrodiae extract microcapsule
(1) Preparation of dissolution media
In order to simulate the dissolution of the rhizoma gastrodiae extract microcapsules in human bodies, artificial intestinal juice is selected as a dissolution medium. Weighing 3.4g of monopotassium phosphate, adding a proper amount of purified water, and adjusting the pH to 6.8 by adopting 0.1mol/L sodium hydroxide solution; and adding a proper amount of purified water into another 5g of trypsin, stirring until the trypsin is completely dissolved, mixing the two solutions, adding the mixed solution into a 500mL volumetric flask, and adding the purified water to a constant volume to obtain the artificial intestinal juice.
(2) Determination of dissolution of microcapsules
Weighing 200mg of rhizoma gastrodiae low-temperature extract freeze-dried powder and 2g of rhizoma gastrodiae extract microcapsule, precisely weighing, adding into 500mL of artificial intestinal juice, performing constant-temperature water bath at 37 ℃, rotating at 50r/min, sampling 1mL at 0.02, 0.05, 0.08, 0.12, 0.25, 0.75, 1.5, 2.0, 4.0, 6.0 and 8.0h respectively, simultaneously supplementing 1mL of artificial intestinal juice, and performing sample injection determination according to chromatographic conditions. The cumulative elution amount (Q) was calculated according to the following formula:
w represents the total mass (mg) of the microcapsules; DL represents the content of the effective ingredient in the microcapsule; cn represents the concentration of the drug (mg/mL) in the sample taken at the nth sampling time point; ci represents the concentration of the drug in the sampled drug (mg/mL) at the ith sampling time point; v represents total dissolution medium volume (mL); vi represents the sample volume (mL) at the ith sampling time.
The in vitro dissolution curve of the rhizoma Gastrodiae extract microcapsule is shown in FIG. 13, the 10min accumulated dissolution of the lyophilized powder of rhizoma Gastrodiae extract reaches more than 90%, and the release is basically complete; the gastrodia elata extract microcapsule has an accumulative dissolution rate of 80% within 1.5h, an accumulative dissolution rate of more than 90% within 2h, a high drug release rate in the early stage and a low release rate in the later stage.
The dissolution curves of the gastrodia elata extract microcapsules are subjected to model fitting, and as can be seen from table 15, correlation coefficients of zero-order, Higuchi and Weibull fitting equations of the dissolution curves of the gastrodia elata extract in the microcapsules are 0.9361, 0.9910 and 0.9949 respectively, so that the in-vitro dissolution fitting of the gastrodia elata extract microcapsules is more consistent with a Weibull model. The Weibull model is more applied to the evaluation of the drug dissolution curve, can successfully describe various dissolution curves, has sensitive parameters to the release reaction of the dissolution curve, can enable the quantification of the result to be more accurate, and better analyzes and explains data ] . The dissolution curve of the gastrodia elata extract microcapsule conforms to a Weibull model, so that the dissolution process of the gastrodia elata extract conforms to a diffusion drug release mechanism, and the gastrodia elata extract microcapsule can be used for predicting the in-vivo dissolution effect of the gastrodia elata extract microcapsule.
The combination of the in vitro dissolution curve and the in vitro dissolution model fitting result shows that the gastrodia elata extract microcapsule has a certain slow release effect, the release is complete basically within 2 hours, the problem of fast release of the gastrodia elata extract is effectively solved, and the bioavailability of active ingredients in the gastrodia elata can be improved.
TABLE 15 in vitro dissolution fitting results of rhizoma Gastrodiae extract in the microcapsules
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A preparation method of a rhizoma gastrodiae microcapsule is characterized by comprising the following steps: the method comprises the following steps:
step (1): low-temperature high-pressure crushing extraction: adding rhizoma Gastrodiae powder into extraction solvent, uniformly dispersing with high-speed homogenizer, injecting into high-pressure crushing extraction device for crushing and extracting, centrifuging extract, and collecting filtrate; wherein the extraction solvent is ethanol with the volume fraction of 30-70%, the liquid-solid ratio is 10: 1-40: 1, the crushing and extraction temperature is 3-5 ℃, the pressure is 50-200 MPa, and the times are 1-4;
step (2): and (3) freeze drying: freeze-drying the filtrate obtained in the step (1) to constant weight to obtain rhizoma gastrodiae extract freeze-dried powder;
and (3): high pressure homogenization-spray drying method for preparing the microcapsule: adding wall materials and an emulsifier into water, uniformly stirring, and adding the freeze-dried powder of the gastrodia elata extract obtained in the step (2) as a core material; stirring at high speed with a high speed dispersion machine, homogenizing with a high pressure homogenizer to obtain rhizoma Gastrodiae homogeneous solution, and spray drying to obtain rhizoma Gastrodiae extract microcapsule.
2. The method for preparing rhizoma Gastrodiae microcapsule according to claim 1, wherein:
in the step (1), the extraction solvent is ethanol with the volume fraction of 50%, the liquid-solid ratio is 30:1, the crushing and extraction temperature is 4 ℃, and the pressure is 100 MPa.
3. The method for preparing the rhizoma gastrodiae microcapsule according to claim 1 or 2, characterized in that:
the wall material in the step (3) is a composite wall material consisting of soybean protein isolate and maltodextrin, and the mass ratio of the soybean protein isolate to the maltodextrin is 0.5: 1-2.5: 1;
the emulsifier in the step (3) is monoglyceride.
4. A method for preparing rhizoma Gastrodiae microcapsule according to claim 3, wherein:
the mass concentration of the wall material in the step (3) is 2-10%, the mass concentration of the emulsifier is 0.6-0.8%, and the mass ratio of the wall material to the core material is 3: 1-7: 1;
the feeding speed of the spray drying in the step (3) is 10-30% of the maximum feeding speed, and the maximum feeding speed is 1.5 mL/min.
5. The method for preparing rhizoma Gastrodiae microcapsule according to claim 3, wherein:
the mass ratio of the soybean protein isolate to the maltodextrin is 1: 1;
the mass concentration of the wall material in the step (3) is 8%, the mass concentration of the emulsifier is 0.67%, and the mass ratio of the wall material to the core material is 7: 1.
6. The method for preparing the rhizoma gastrodiae microcapsule according to claim 1 or 2, characterized in that:
the rotating speed of the high-speed refiner in the step (1) is 10000r/min, and the time for uniform dispersion is 2 min;
the rotation speed of the centrifugation in the step (1) is 4000r, and the time is 5 min.
7. The method for preparing the rhizoma gastrodiae microcapsule according to claim 1 or 2, characterized in that:
the rotating speed of the high-speed dispersion machine in the step (3) is 10000r/min, and the high-speed stirring is carried out for 2 min;
the pressure of the high-pressure homogenizer in the step (3) is 50 MPa.
8. The method for preparing the rhizoma gastrodiae microcapsule according to claim 1 or 2, characterized in that:
in the gastrodia elata extract freeze-dried powder in the step (3), the content of the gastrodin in percentage by mass is 0.281%, the content of the parahydroxybenzyl alcohol in percentage by mass is 1.509%, the content of the barban E in percentage by mass is 0.964%, the content of the barban B in percentage by mass is 0.717%, the content of the barban C in percentage by mass is 0.123%, and the content of the barban A in percentage by mass is 2.422%.
9. A rhizoma gastrodiae microcapsule is characterized in that: the preparation method of any one of claims 1 to 8, wherein the gastrodia elata microcapsules have the particle size distribution of 1-10 μm, the encapsulation efficiency is 87.48%, the yield is 75.96%, and the drug loading rate is 15.46%.
10. Use of the rhizoma gastrodiae microcapsules described in claim 9 for the preparation of enteric release drugs.
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