Novel curcumin self-micellization solid dispersion and preparation method thereof

Abstract

The invention relates to the technical field of food additive preparation, in particular to a novel curcumin self-micellization solid dispersion and a preparation method thereof.The method comprises the steps that F127 and TPGS serve as composite carriers, the composite carriers and curcumin raw material medicine are dissolved in absolute ethyl alcohol, a solvent is removed through rotary evaporation, freeze drying, grinding and sieving are conducted, and the self-micellization solid dispersion is prepared. According to the process, the solubility and the stability of the curcumin are remarkably improved, the prepared solid dispersion has the characteristics of high drug loading capacity, good physical stability and rapid in-vitro dissolution, and in a simulated digestion experiment, the release rates of the curcumin in the oral cavity and gastric juice reach 9.9% and 4.6% respectively and are far superior to those of free curcumin, so that the curcumin solid dispersion can be applied to the oral cavity and the gastric juice of the oral cavity and the gastric juice of the oral cavity and the gastric juice of the oral cavity. Through the synergistic effect of micelle wrapping and the surfactant, drug aggregation is effectively reduced, gastrointestinal adsorption and permeation are enhanced, bioavailability is greatly improved, the curcumin dispersible tablet is suitable for development of various efficient preparations such as oral administration, inhalation and percutaneous absorption, and the key problems that curcumin is poor in dissolubility and low in bioavailability are solved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of food additive preparation, in particular to a novel curcumin self-micellized solid dispersion and a preparation method thereof. BACKGROUND

[0002] As a natural active ingredient, curcumin exhibits a variety of beneficial biological activities, including free radical scavenging, inflammation reduction, bacterial growth inhibition, blood lipid level regulation, immune function enhancement, and protection of gastrointestinal mucosa. Therefore, it has important application potential in the field of medicine. However, due to the poor solubility of curcumin in water, the unstable chemical properties, and the low in vivo absorption and utilization rate, these shortcomings greatly restrict its practical application.

[0003] Solid dispersion technology is a modern preparation method that uniformly disperses poorly soluble active substances in solid carriers in amorphous, molecular or microcrystalline state. This technology effectively improves the solubility characteristics of active ingredients by changing their physical state, thereby significantly improving the bioavailability. Converting curcumin into a solid dispersion for biomedical applications has multiple advantages. Curcumin in the solid dispersion system is in an amorphous state, which significantly increases its effective solubility surface area, thereby improving its solubility. At the same time, this technology can also effectively improve the taste characteristics of curcumin and eliminate its original slight bitterness. From a molecular level, various carrier materials can bind to the phenolic hydroxyl group of curcumin through hydrogen bonding, achieving uniform dispersion of curcumin molecules in the macromolecular matrix and enhancing its solubility.

[0004] Self-micellization refers to the process of amphiphilic molecules (molecules with both hydrophilic and hydrophobic parts) spontaneously aggregating to form micelles in solution. The existing micellar drug loading method still has several key defects, which seriously limit its clinical application effect. First, the traditional micellar drug loading system generally has a low drug loading capacity. Due to the limited capacity of the hydrophobic core, the loading rate of poorly soluble drugs is usually less than 5%. Second, the physical and chemical stability of the micellar system is poor, which is manifested in the high critical micelle concentration (CMC) that causes the micelles to dissociate after blood dilution, and some carrier materials accelerate the degradation of the drug. In addition, the traditional preparation process such as the film hydration method requires high temperature treatment, which not only causes about 15% of the drug to degrade, but also is not suitable for heat-sensitive drugs. Some synthetic carrier materials also have obvious hemolytic risk, and the drug release behavior of conventional micellar systems often shows rapid burst release. The current technology (such as patent CN111991337B) has not achieved the "self-micellization" function, and cannot simultaneously consider high drug loading capacity, slow release characteristics, and gastrointestinal stability. SUMMARY

[0005] Based on the above problems, the application provides a preparation method of high-bioavailability curcumin self-intersecting beam solid dispersion, adopts F127 and TPGS in a specific proportion of 9:1 as a composite carrier, and uses a freeze-drying process to successfully obtain a curcumin solid dispersion with high drug loading and good stability, the solid dispersion has fast in-vitro dissolution and high bioavailability, is suitable for development of various high-efficiency curcumin preparations, and effectively solves the problems of poor curcumin dissolution and low bioavailability.

[0006] The specific preparation method is as follows: curcumin powder and carrier materials are mixed, anhydrous ethanol is added, 40kHZ ultrasonic dissolution is carried out, then 50-65 DEG C, 0.06-0.08 MPa rotary evaporation is carried out for 1-3h to remove the organic solvent, then (-60)-(-80) DEG C freeze drying is carried out for 45-50h, and then grinding through a 40-60 mesh sieve to obtain the curcumin self-micellization solid dispersion.

[0007] Preferably, the ratio of the curcumin powder, the carrier material and the anhydrous ethanol is (9.5-10.5) mg:(133-147) mg:(0.95-1.05) mL.

[0008] Preferably, the carrier material is F127 and TPGS, and the mass ratio is (8-10):1.

[0009] The application has the following advantages: The application adopts F127 and TPGS as a composite carrier material to prepare a curcumin self-micellization solid dispersion system, Pluronic F127 can spontaneously form a micelle structure in an aqueous environment, and can wrap drug molecules in the hydrophobic inner core, so as to significantly improve the solubility of curcumin. As a non-ionic surfactant, the hydrophilic-hydrophobic balance characteristics of the molecular structure of TPGS can effectively reduce the surface free energy of the suspended particles. This double-acting mechanism can not only reduce the aggregation and precipitation phenomenon of the drug in the gastric juice environment, but also significantly enhance the physical stability of the whole delivery system, and significantly improve the water solubility of curcumin.

[0010] The curcumin self-micellization solid dispersion prepared by the application has high embedding rate and solubility, which is improved by 885.23 times, and the self-micellization process significantly improves the thermal stability of curcumin. The drug nanoparticles also improve the solubility of the poorly soluble drug, and enhance the adsorption and penetration of the drug in the gastrointestinal tract, so as to improve the bioavailability. The in-vitro digestion simulation research results show that the free curcumin is hardly released in the oral cavity and gastric juice, and about 9.9% and 4.6% of curcumin in the curcumin self-micellization solid dispersion is observed in the oral cavity and gastric juice, respectively.

[0011] In addition, the prepared curcumin solid dispersion has high drug loading and good stability, and can be used for the development of curcumin oral, inhalation, transdermal absorption and other preparations. BRIEF DESCRIPTION OF DRAWINGS

[0012] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced. Obviously, the drawings in the following description are only a part of the embodiments of the present application, and all other drawings obtained by those skilled in the art without creative labor on the basis of the provided drawings are within the protection scope of the present application.

[0013] Figure 1 Curcumin standard curve.

[0014] Figure 2 Solubility of curcumin and sample of example 1.

[0015] Figure 3 Scanning electron microscope (SEM) analysis, the upper picture is curcumin standard, and the lower picture is curcumin self-micellization solid dispersion.

[0016] Figure 4 Thermogravimetric analysis (TGA) graph, A is curcumin standard, and B is curcumin self-micellization solid dispersion.

[0017] Figure 5 Differential scanning calorimetry (DSC) determination result, A is curcumin standard, and B is curcumin self-micellization solid dispersion.

[0018] Figure 6 Infrared spectrum determination result, A is curcumin standard, and B is curcumin self-micellization solid dispersion.

[0019] Figure 7 Biological accessibility of curcumin standard and sample of example 1 in in-vitro simulated digestion process. DETAILED DESCRIPTION

[0020] The technical solutions in the embodiments of the present application will be described clearly and completely in combination with the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the protection scope of the present application.

[0021] Example 1 Curcumin and F127 in the embodiments of the present application are purchased from Shanghai Maikelin Biochemical Science and Technology Co., Ltd., and TPGS is purchased from Shanghai Yinn Chemical Technology Co., Ltd.

[0022] Take curcumin raw material 150 mg, F127 and TPGS (9:1) mixed, total amount of 2250 mg, put into 50 mL round bottom flask, add 15 mL anhydrous ethanol, then 40kHZ ultrasonic dissolution, then use rotary evaporator 0.08 MPa evaporation at 60℃ for 2h to remove organic solvent, the mixture obtained-60℃ freeze drying 48h, then grinding and crushing, and pass through 60 mesh sieve, get self-micellized solid dispersion.

[0023] Test example 1 Take curcumin standard 10 mg, add anhydrous ethanol to dissolve, dilute to 10 mL, get 1 mg / mL standard solution, take 0.01, 0.02, 0.03, 0.04, 0.05 mL standard solution respectively, dilute to 10 mL, use enzyme marker to measure at wavelength 425 nm, calculate curcumin standard curve, results see Figure 1 .

[0024] As Figure 1 shown, with absorbance as ordinate, concentration as abscissa, get curcumin standard curve y=80.82571x+0.09019(r=0.99555), curcumin concentration in 0.001-0.005 mg / mL and absorbance linear relationship is good.

[0025] Test example 2 (embedding rate) Take 15 mg sample prepared in example 1, mix with 10 mL anhydrous ethanol, constant temperature shaking at 37℃ for 4h, calculate embedding rate according to the following formula.

[0026] E = C 0 / C 1×100%. In the formula, E is embedding rate, %; C 0 is curcumin mass calculated according to absorbance, mg; C 1 is initial added curcumin mass, mg.

[0027] Calculation can get curcumin self-micellized solid dispersion embedding rate (65.34±0.12)%.

[0028] Test example 3 (solubility) Grind the sample prepared in example 1 to fine powder. Accurately weigh a certain amount of sample powder using a high-precision balance, and mix with distilled water to prepare a solution of a certain volume. Use a magnetic stirrer or constant temperature oscillator to stir thoroughly until the solution reaches dissolution equilibrium. Use appropriate filter paper or filter membrane to filter the solution to remove undissolved solid particles. Use enzyme marker to measure the absorbance of the solution. According to the standard curve or regression equation, convert the absorbance to the concentration of curcumin. According to the measured concentration and solution volume, calculate the solubility of the sample powder in water, results seeFigure 2 .

[0029] From Figure 2 it can be seen that the solubility of curcumin in water is increased from (0.03567±0.18) μg / mL to (31.576±0.11) μg / mL, which is increased by 885.23 times after curcumin is prepared into a curcumin self-micellar solid dispersion.

[0030] Test Example 4 (scanning electron microscope analysis) Curcumin standard and the freeze-dried sample of Example 1 are adhered to conductive glue, and after surface gold spraying, SEM is used for observation, and the results are shown in Figure 3 It can be seen that the sample of Example 1 is in a circular and elliptical shape due to adsorption.

[0031] Test Example 5 (thermogravimetric analysis) It is carried out under a dynamic atmosphere of dry nitrogen, the flow rate is 20 mL / min, the temperature is 25-600℃, and the temperature rising rate is 10℃ / min, and the results are shown in Figure 4 It can be seen that curcumin standard is decomposed from 270-410℃, and curcumin self-micellar solid dispersion is decomposed from 370-420℃, and the thermal stability of curcumin self-micellar solid dispersion is more stable than that of curcumin standard.

[0032] Test Example 6 (particle size and Zeta point measurement) Photon correlation spectrum analysis is carried out at 25℃ using a nanoparticle size and Zeta potential analyzer (model Malvern Zetasizer Nano ZS90). Before measurement, the freeze-dried sample is configured into a water solution of one thousandth. Finally, it can be seen that the particle size of curcumin standard is 6579.37 nm, and the Zeta potential is -11.57 mV; the particle size of curcumin self-micellar solid dispersion is 1037.93 nm, and the Zeta potential is -3.15 mV.

[0033] Test Example 7 (differential scanning calorimetry DSC) The program is set to be scanned at 30-250℃, and the temperature rising rate is 20℃ / min, and the results are shown in Figure 5 It can be seen that curcumin standard has one obvious crystal endothermic peak at about 185℃, and curcumin self-micellar solid dispersion has one obvious crystal endothermic peak at about 60℃.

[0034] Test Example 8 (infrared spectrum) Infrared spectrum scanning is carried out in the range of 4000-400 cm -1 , and the results are shown in Figure 6 It can be seen that the characteristic peak of curcumin standard appears at 1708.6 cm -1 , 1326.3 cm -1, 1054.3 cm -1 , 674.3 cm -1 and 493.8 cm -1 ; the characteristic peaks of the curcumin self-micellized solid dispersion appeared at 1858.7 cm -1 , 1706.3 cm -1 , 1396.7 cm -1 , 993.3 cm -1 and 880.7 cm -1 .

[0035] Test Example 9 (in vitro simulated digestion) (1) Simulated oral digestion: 1 g of the sample to be tested was taken and added to 10 mL of simulated oral digestion fluid (containing 100 U / mL of salivary amylase), and incubated at 37°C with shaking at 150 rad / min for 2 min; (2) Simulated gastric digestion: the oral digestion fluid was transferred to 10 mL of simulated gastric fluid (containing 150 U / mL of pepsin), and the pH was adjusted to 3.0 with HCl, and the reaction was continued at 37°C with shaking at 150 rad / min for 1 h; (3) Simulated intestinal digestion: the 20 mL of the gastric digestion fluid after the reaction was completed was adjusted to pH 7.0 with NaOH, and then 20 mL of simulated intestinal fluid (containing 10 mmol / L of bile salts and 250 U / mL of trypsin) was added, the pH was adjusted to 7.0 again, and the incubation was continued at 37°C with shaking at 150 rad / min for 1 h.

[0036] After each digestion stage (oral, gastric, intestinal), the digestion fluid was collected and centrifuged at 8000 rad / min for 10 min, and the supernatant was taken. The content of free curcumin was determined at 425 nm by using an enzyme marker, and the value reflected the amount of curcumin released from the curcumin embedding material, and the release rate was calculated according to the following formula: Curcumin bioavailability (%) = (content of curcumin in the digestion fluid after digestion / total content of curcumin in the digestion fluid) x 100%, and the results are shown in Figure 7 .

[0037] As can be seen from Figure 7 , free curcumin is hardly released in the oral and gastric fluids, and the curcumin in the curcumin self-micellized solid dispersion is observed to be released by about 9.9% and 4.6% in the oral and gastric fluids, respectively. When entering the intestinal digestion stage, the free curcumin is dispersed in the digestion fluid in the form of micelles under the action of ingredients such as bile salts, resulting in a release amount of about 8% in this stage. The curcumin existing in the form of amorphous in the curcumin self-micellized solid dispersion exhibits a release of about 5% under the extraction action of ingredients such as bile salts.

[0038] From the test example 1-9, it can be seen that the curcumin self-micellized solid dispersion system prepared by using Pluronic F127 and TPGS as a composite carrier material has excellent technical effects. Pluronic F127 can spontaneously form a micellar structure in an aqueous environment, and the drug molecules are wrapped in the hydrophobic core, thereby significantly improving the solubility of curcumin. As a non-ionic surfactant, the hydrophilic-hydrophobic balance characteristics of the molecular structure of TPGS can effectively reduce the surface free energy of the suspended particles. This double-acting mechanism not only can reduce the aggregation and precipitation phenomenon of the drug in the gastric juice environment, but also can significantly enhance the physical stability of the whole delivery system, and significantly improve the water solubility of curcumin (885 times).

[0039] The above description of disclosed embodiments enables one of ordinary skill in the art to make or use the application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein can be applied to other embodiments without departing from the spirit or scope of the application. Thus, the present application is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing a novel curcumin self-micellarized solid dispersion, characterized in that, Curcumin powder, carrier material and anhydrous ethanol were mixed and dissolved at a ratio of (9.5-10.5) mg:(133-147) mg:(0.95-1.05) mL, the organic solvent was removed by evaporation, the mixture was freeze-dried and ground to obtain a self-micellarized solid dispersion of curcumin.

2. The method for preparing a novel curcumin self-micellarcitized solid dispersion according to claim 1, characterized in that, The carrier material is F127 and TPGS, with a mass ratio of (8-10):

1.

3. The method for preparing a novel curcumin self-micellarcitized solid dispersion according to claim 1, characterized in that, Rotary evaporation at 50-65℃ and 0.06-0.08MPa for 1-3 hours.

4. The method for preparing a novel curcumin self-micellarcitized solid dispersion according to claim 1, characterized in that, Freeze-dry at (-60)-(-80)℃ for 45-50 hours.

5. Curcumin self-micellarized solid dispersion prepared by the method according to any one of claims 1-4.

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