A preparation method of angelica volatile oil microcapsules

Abstract

The invention provides a method for preparing angelica volatile oil capsules, comprising the following steps: preparing a gelatin solution and a gum arabic solution respectively; compounding and forming capsules: mixing angelica volatile oil and gelatin solution and dispersing them into an emulsion, adding the gum arabic solution thereto, stirring evenly and adjusting the pH value; and adding a formaldehyde aqueous solution for solidification. The method of the invention improves the stability of the drug, and slows down the oxidation and deterioration of the capsule core caused by the influence of light, moisture and heat. The strong odor of the drug is masked, and the odor becomes lighter after being prepared into microcapsules, which can improve the compliance of patients with medication. The liquid drug is solidified, which is convenient for storage, transportation and development. The gastric irritation of the drug is avoided. The drug can be slowly and controlled released, and the onset time of its active ingredient is increased. As a preparation intermediate, the microcapsule can be further developed into different dosage forms such as tablets, capsules, injections, patches and ophthalmic preparations, thereby providing a reference for the development of new angelica oil drugs.

Description

Technical Field

[0001] The invention relates to a method for preparing angelica volatile oil microcapsules. Background Art

[0002] Angelica sinensis is the dried root of Angelica sinensis (Oliv.) Diels., a perennial herb belonging to the Apiaceae family. It has the effects of promoting blood circulation and replenishing blood, replenishing qi and regulating menstruation, moistening dryness and lubricating the intestines. It is a commonly used blood tonic and gynecological medicine in traditional Chinese medicine, and is known as "Nine out of Ten Prescriptions are Angelica". Angelica volatile oil is a volatile oil extracted from the dried root of Angelica sinensis by steam distillation or supercritical extraction, and has a special and strong smell. Angelica volatile oil, as the main active ingredient of Angelica sinensis, has pharmacological effects such as dilating blood vessels, promoting skin penetration, analgesia and anti-inflammatory. Angelica volatile oil is an oily liquid, which is inconvenient to prepare, and has strong volatility and photosensitivity. It is easy to lose during preparation and storage, which has a great impact on the stability of its preparation. In order to solve this problem, microencapsulation technology is now often used to make Angelica volatile oil into microcapsules to avoid it from being adversely affected by the external environment, thereby prolonging the effectiveness of its chemical components.

[0003] Microcapsules refer to drug-depot-type microcapsules that use high-molecular natural or synthetic materials to encapsulate solid drugs or liquid drugs. Because their particle size is between 1 and 250 μm, which is micron-level, they are called microcapsules. Commonly used microencapsulation methods include spray drying, single coagulation, and complex coagulation. In the spray drying method, the capsule core and capsule material solution are first dispersed as an emulsifier, and then the emulsion is atomized into small droplets by an atomizer. During the thermal movement, the water evaporates and finally solid microcapsule powder is obtained. This method is simple to operate and suitable for large-scale production, but it is not suitable for thermally unstable substances such as volatile oils. High temperature will inactivate heat-sensitive active ingredients, and the solvent of the microcapsules prepared by spray drying evaporates in a short time, and cracks are easy to appear on the capsule wall, and the density cannot be guaranteed. It is not suitable for the preparation of Angelica volatile oil microcapsules. The single coagulation method is to disperse the capsule core in the capsule material solution, and then add a flocculant to reduce the solubility of the system, so that the capsule material and the capsule core are precipitated from the solution together into capsules. The complex coacervation method is to adjust the pH or temperature of the reaction system to make the polymer materials with opposite charges have electrostatic effects, and then cross-link to form microcapsules. Generally, the complex coacervation method is often used to prepare hydrophobic capsule cores and is widely used in the preparation of volatile oil microencapsulation. Studies have shown that under the optimal preparation conditions, the microcapsules prepared by the complex coacervation method have better appearance and smaller particle size. Although the drug loading is slightly lower than that of the microcapsules prepared by the single coacervation method, the encapsulation rate is higher. Compared with the single coacervation method, the success rate of preparing microcapsules by the complex coacervation method is higher. Summary of the invention

[0004] In order to solve the problems existing in the prior art, the present invention provides a method for preparing angelica volatile oil microcapsules. Due to the heat sensitivity and instability of Chinese medicine volatile oil, the present invention prepares angelica volatile oil microcapsules by complex coacervation for the first time, providing a reference for further preparation development of angelica volatile oil.

[0005] The present invention provides a method for preparing angelica volatile oil capsules, comprising the following steps:

[0006] (1) preparing a gelatin solution and a gum arabic solution respectively;

[0007] (2) Complex coagulation capsule formation: Angelica volatile oil and gelatin solution are mixed and dispersed into an emulsion, and the gum arabic solution is added thereto, stirred evenly and the pH value is adjusted to 4.2-4.8;

[0008] (3) adding a curing agent for curing; the curing agent is a formaldehyde aqueous solution.

[0009] As a preferred embodiment, in step (1), the concentration of the gelatin solution is 1-3wt%; preferably, the concentration of the gelatin solution is 3wt%.

[0010] As a preferred embodiment, in step (1), the concentration of the gum arabic solution is 0.5-1.5wt%; preferably, the concentration of the gum arabic solution is 1wt%.

[0011] As a preferred embodiment, in step (2), the angelica volatile oil is 30-40% of the total weight of the gelatin and gum arabic.

[0012] As a preferred embodiment, in step (2), the pH value is adjusted to 4.2.

[0013] As a preferred embodiment, in step (2), the temperature during capsule formation is 20-60°C; preferably, the temperature is 40°C.

[0014] As a preferred embodiment, in step (2), the stirring speed during capsule formation is 400-600 r / min; preferably, the stirring speed during capsule formation is 600 r / min.

[0015] As a preferred embodiment, in step (3), before solidification, the solution is further cooled to below 10° C. and the pH value is adjusted to 8 to 9; and / or

[0016] The curing agent is a 37% formaldehyde aqueous solution; the ratio of the angelica volatile oil to the 37% formaldehyde aqueous solution is: 0.45g: 3-7ml; preferably, the ratio of the angelica volatile oil to the 37% formaldehyde aqueous solution is: 0.45g: 5ml; and / or

[0017] The curing time is 30 to 60 minutes; preferably, the curing time is 30 minutes.

[0018] The invention also provides a medicine, which comprises the angelica volatile oil capsule prepared by the method.

[0019] As a preferred embodiment, the dosage form of the drug is tablets, capsules, injections, patches or ophthalmic preparations.

[0020] By using the method of the present invention, it can be seen that the volatile oil of Angelica sinensis is well wrapped in the capsule material. Advantages:

[0021] (1) Improve drug stability and slow down the oxidative deterioration of the capsule core caused by light, moisture and heat.

[0022] (2) Mask the strong odor of the drug. After being made into microcapsules, the odor becomes lighter, which can improve patient compliance with medication.

[0023] (3) Solidify liquid drugs for easy storage, transportation and development.

[0024] (4) Avoid drug gastric irritation. Oral administration of certain drugs can cause nausea and vomiting or be directly metabolized by the liver, with low bioavailability. Microencapsulation can prevent drug inactivation in the gastrointestinal tract and reduce gastrointestinal irritation.

[0025] (5) It can achieve slow and controlled release of drugs, thereby increasing the onset time of its active ingredients. As a preparation intermediate, microcapsules can be further developed into different dosage forms such as tablets, capsules, injections, patches and ophthalmic preparations, thereby providing a reference for the development of new drugs for angelica oil. DETAILED DESCRIPTION

[0026] The following examples are provided for a better understanding of the present invention, but are not intended to limit the present invention. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are purchased from conventional biochemical reagent companies unless otherwise specified. The quantitative tests in the following examples are repeated three times, and the results are averaged. In the present invention, "wt%" means weight percentage.

[0027] The invention selects gelatin-arabic gum as wall material and angelica volatile oil as capsule core, prepares angelica volatile oil microcapsules by complex coacervation method, and investigates the preparation method of angelica volatile oil microcapsules by taking encapsulation rate as index.

[0028] 1. Instruments and reagents

[0029] 1.1 Instruments

[0030] Table 1 Experimental instruments

[0031]

[0032] 1.2 Reagents and test drugs

[0033] Angelica volatile oil (provided by Lanzhou Heshengtang Pharmaceutical Co., Ltd., extracted by supercritical CO2); gelatin (Rosselot Gelatin Co., Ltd., batch number: 3093949); gum arabic (Shanghai MacLean Biochemical Technology Co., Ltd., batch number: C13452597); methanol and acetonitrile were all chromatographically pure and purchased from Merck & Co., Ltd.; other reagents such as glacial acetic acid, formaldehyde aqueous solution, anhydrous ethanol and sodium hydroxide were all analytically pure and purchased from Sinopharm Chemical Reagent Co., Ltd.; water was ultrapure water.

[0034] 2 Study on microcapsule forming method

[0035] 2.1 Single factor experiment

[0036] The effects of eight factors including gelatin concentration, gum arabic concentration, amount of volatile oil added, pH, encapsulation temperature, stirring speed, amount of curing agent and curing time on the morphology or encapsulation efficiency and drug loading of angelica oil microcapsules were investigated.

[0037] 2.1.1 Selection of emulsifier

[0038] Weigh appropriate amounts of angelica oil and add them to 50 mL of 1.5% gelatin solution and gum arabic solution preheated to 40°C, stir at 10,000 rpm with a high-speed homogenizer for 3 min, and let the emulsion stand to observe its morphology.

[0039] The results showed that gelatin had a better effect as an emulsifier, with uniform emulsion droplets and no stratification. This indicated that gelatin had a better emulsifying ability than gum arabic for angelica oil, so gelatin was selected as an emulsifier and stirred at high speed for 3 minutes.

[0040] 2.1.2 Preliminary preparation of Angelica volatile oil microcapsules

[0041] Microcapsules were prepared as follows:

[0042] (1) Weigh 1.5 g of gelatin, soak it in a small amount of purified water, add 50 ml of purified water after it swells, stir and dissolve in a 60°C water bath to prepare a 3 wt% gelatin solution for later use. Dry the gum arabic in an oven at 80°C for 1 h to remove the oxidase therein, take 0.5 g of the dried gum arabic and add 50 ml of purified water to prepare a 1 wt% solution.

[0043] (2) Add 0.45 g of Angelica volatile oil to 50 ml of gelatin solution preheated to 40°C, and disperse at 13,000 rpm for 3 min to form an emulsion; add 50 ml of gum arabic solution preheated to the same temperature, stir evenly with magnetic stirring at 40°C, and stir at a speed of 600 r / min. Adjust the pH to 4.2 with 10% by volume acetic acid, and continue stirring at the constant temperature for 20 min.

[0044] (3) Add twice the volume of purified water at 30°C, stir and wait for it to cool naturally to room temperature, place in an ice water bath, stir and cool to below 10°C, add 10wt% NaOH solution to adjust the pH value of the system to 8-9, add 5ml 37% formaldehyde aqueous solution to solidify for 30min. Let it stand for sedimentation, pour off the supernatant, centrifuge, wash with purified water until there is no aldehyde smell, place in a freeze dryer and dry in vacuum at low temperature to obtain Angelica volatile oil microcapsules.

[0045] 2.1.3 Gelatin solution concentration

[0046] Microcapsules were prepared according to the method under "2.1.2", and then gelatin solutions were prepared with concentrations of 1wt%, 2wt%, 3wt%, 4wt%, and 5wt%, respectively. Other conditions remained unchanged, and the effect of different gelatin solution concentrations on the microcapsule encapsulation rate of Angelica volatile oil was investigated. The results are shown in Table 2.

[0047] Table 2 Effects of different gelatin concentrations on Angelica volatile oil microcapsules

[0048]

[0049] Note: - indicates no encapsulation and no sedimentation.

[0050] The results showed that as the concentration of gelatin solution continued to increase, the encapsulation rate showed a trend of first increasing and then decreasing. When the concentration of gelatin solution was 2wt%, the encapsulation rate and yield were the highest. As the concentration of the solution increased, the viscosity of the system increased, resulting in the adhesion between microcapsules. The freeze-dried samples were not in powder form, making it difficult to carry out subsequent work. When the solution concentration was 5wt%, there was no sedimentation and no microcapsules were formed. Therefore, a gelatin solution with a concentration of 1wt% to 3wt% was selected for subsequent investigation.

[0051] 2.1.4 Gum Arabic Solution Concentration

[0052] Microcapsules were prepared according to the method under "2.1.2", with a gelatin solution concentration of 2wt%, and then arabic gum solutions with concentrations of 0.5wt%, 1wt%, 1.5wt%, 2wt%, 2.5wt%, and 3wt% were prepared respectively. Other conditions remained unchanged, and the effect of arabic gum solution concentration on the microcapsulation efficiency of Angelica volatile oil was investigated. The results are shown in Table 3.

[0053] Table 3 Effects of different gum arabic concentrations on Angelica volatile oil microcapsules

[0054]

[0055] The results showed that as the concentration of gum arabic solution continued to increase, the encapsulation rate showed a trend of first increasing and then decreasing. The encapsulation rate was the highest when the concentration of gum arabic solution was 1wt%. The wall material concentration was too low, and the yield of microcapsules was low. As the concentration of the gum solution increased, the efficiency of the interaction between the two also increased. However, if the mass fraction of the wall material was too large, the encapsulation rate of the microcapsules would decrease instead. This was because the free diffusion of the polymer chains in the complex coacervation reaction was inhibited, making the capsule shell thickness uneven, and at the same time reducing the utilization rate of the capsule material, resulting in a decrease in the encapsulation rate. Therefore, a gum arabic solution with a concentration of 0.5wt% to 1.5wt% was selected for subsequent investigation.

[0056] 2.1.5 Addition amount of angelica volatile oil

[0057] Microcapsules were prepared according to the method under "2.1.2". The concentration of the gum arabic solution was 1wt%, and 20%, 30%, 40%, 50%, and 60% of the wall material weight (gelatin + gum arabic) of Angelica sinensis volatile oil were added to the 2wt% gelatin solution, i.e., 0.3g, 0.45g, 0.6g, 0.75g, and 0.9g Angelica sinensis volatile oil. The other conditions remained unchanged, and the effect of the dosage on the microcapsule encapsulation efficiency was investigated. The results are shown in Table 4.

[0058] Table 4 Effects of different volatile oil addition amounts on Angelica volatile oil microcapsules

[0059]

[0060] The results showed that with the increase of the amount of angelica volatile oil added, the microcapsule encapsulation rate gradually increased. However, the trend of the encapsulation rate increase gradually slowed down. And during the experiment, it was found that when the amount of angelica oil added was too much, the supernatant after sedimentation was yellow, which might be because the unencapsulated volatile oil floated in it, causing waste. The concentration and proportion of the capsule material remained unchanged. Excessive addition of volatile oil would result in a thinner microcapsule shell with a poor shape and a long strip, making the quality of the microcapsule unstable and easy to break during the subsequent drying process. After comprehensive consideration, the amount of volatile oil added was selected to be 0.45g, that is, the ratio of capsule core: wall material was 30%.

[0061] 2.1.6 pH

[0062] Microcapsules were prepared according to the process under "2.1.2", with a gelatin solution concentration of 2wt%, a gum arabic solution concentration of 1wt%, and 0.5g of Angelica sinensis volatile oil. The pH of the complex coacervation reaction was adjusted to 3.7, 4.0, 4.2, 4.5, 4.8, and 5.0, respectively, and other conditions remained unchanged. The effect of different pH values ​​on the microcapsule encapsulation efficiency was investigated. The results are shown in Table 5.

[0063] Table 5 Effects of different pH values ​​on Angelica volatile oil microcapsules

[0064]

[0065] Note: - indicates no encapsulation and no sedimentation.

[0066] The principle of the complex coacervation reaction is that the capsule materials with opposite charges cross-link with each other through electrostatic interaction to form microcapsules. Gum arabic is a polysaccharide with carboxyl and carboxylate ions on its molecular chain and carries a negative charge. Gelatin belongs to the category of protein macromolecules. It contains amino groups, carboxyl groups and their corresponding dissociated groups ammonium ions and carboxylate ions in aqueous solution. When the pH value of the gelatin solution is lower than the isoelectric point, the number of ammonium ions is greater than that of carboxylate ions and carries a positive charge. The amount of ions in the solution is affected by the pH value, so the pH value of the complex coacervation reaction has a greater influence on the formation of microcapsules. The results show that microcapsules are not formed at pH values ​​of 3.7 and 5.0, while the effect on microcapsules is relatively stable between 4.0 and 4.8, and the encapsulation rate is the highest at 4.5, so the pH value of 4.2 to 4.8 was selected for subsequent investigation.

[0067] 2.1.7 Capsule temperature

[0068] Microcapsules were prepared according to the process under "2.1.2", with a gelatin solution concentration of 2wt%, a gum arabic solution concentration of 1wt%, 0.5g of volatile oil of Angelica sinensis, a pH of 4 for the complex coacervation reaction, and encapsulation temperatures of 20, 30, 40, 50, and 60°C, respectively. Other conditions remained unchanged, and the effect of encapsulation temperature on microcapsule encapsulation efficiency was investigated. The results are shown in Table 6.

[0069] Table 6 Effects of different encapsulation temperatures on Angelica volatile oil microcapsules

[0070]

[0071]

[0072] Note: - indicates no encapsulation and no sedimentation.

[0073] The encapsulation temperature will affect the movement of solution molecules. At a low temperature, the movement speed of emulsion molecules and wall material molecules will slow down, and complete microcapsules cannot be formed. When the temperature is too high, the molecules will move violently, the size of microcapsules will be uneven, and it may cause the isomerization of the effective components of angelica volatile oil. The results show that the encapsulation temperature has little effect on the encapsulation rate of microcapsules, and the encapsulation rate is the highest at 40°C, so the complex coagulation temperature is selected as 40°C.

[0074] 2.1.8 Stirring speed (stirring speed during the entire reaction process)

[0075] Microcapsules were prepared according to the process under "2.1.2", with a gelatin solution concentration of 2wt%, a gum arabic solution concentration of 1wt%, 0.5g of volatile oil of Angelica sinensis, a pH of 4 for the complex coacervation reaction, a complex coacervation temperature of 40°C, and stirring speeds of 200, 400, 600, 800, and 1000 r / min, respectively. Other conditions remained unchanged, and the effect of stirring speed on microcapsule encapsulation efficiency was investigated. The results are shown in Table 7.

[0076] Table 7 Effect of different stirring speeds on Angelica volatile oil microcapsules

[0077]

[0078] The stirring speed will affect the dispersion of Angelica volatile oil-gelatin emulsion and gum arabic solution. If the stirring speed is too low, the solution will be unevenly dispersed, affecting the formation of microcapsules. If the speed is too high, the microcapsules may rupture and affect the encapsulation rate. The results show that when the stirring speed is 200r / min, the encapsulation rate is low, and it is found during the experiment that the microcapsules will adhere to the bottom of the container after sedimentation under this condition, affecting the uniformity of dispersion; when the stirring speed is between 400 and 600r / min, the encapsulation rate first increases and then decreases, reaching the highest at 600r / min, so the stirring speed is selected to be 600r / min.

[0079] 2.1.9 Curing agent dosage

[0080] Microcapsules were prepared according to the process under "2.1.2", with a gelatin solution concentration of 2wt%, a gum arabic solution concentration of 1wt%, 0.5g of angelica volatile oil, a pH of 4 for the complex coagulation reaction, a complex coagulation temperature of 40°C, a stirring speed of 600r / min, and 3, 4, 5, 6, and 7ml of a 37wt% formaldehyde aqueous solution of a curing agent were added respectively, with other conditions unchanged, to investigate the effect of the amount of curing agent on the encapsulation efficiency of the microcapsules. The results are shown in Table 8.

[0081] Table 8 Effect of different curing agent dosage on Angelica volatile oil microcapsules

[0082]

[0083]

[0084] Gelatin and gum arabic solution condense into capsules under the action of electrostatics, but this process is reversible. After adding the curing agent formaldehyde, it reacts with gelatin to form an amine-aldehyde condensation reaction, and the gelatin molecules are cross-linked into a network structure, so that the formed microcapsules maintain their shape and are irreversible. Therefore, the amount of curing agent added will affect the stability of the microcapsule morphology, which may affect the encapsulation effect. The results show that the encapsulation rate does not change significantly when the curing agent dosage is 3-7ml, but it generally shows a trend of first increasing and then decreasing. The highest value is when the amount added is 5ml, so 5ml of 37% formaldehyde aqueous solution of curing agent is selected.

[0085] 2.1.10 Curing time

[0086] Microcapsules were prepared according to the process under "2.1.2". The concentration of gelatin solution was 2wt%, the concentration of gum arabic solution was 1wt%, the volatile oil of Angelica sinensis was 0.5g, the pH of the complex coacervation reaction was 4, the complex coacervation temperature was 40℃, the stirring speed was 600r / min, the curing agent was formaldehyde 4ml, and the curing time was set to 15, 30, 45, 60, and 75min respectively. Other conditions remained unchanged. The effect of curing time on the encapsulation efficiency of the microcapsules was investigated. The results are shown in Table 9.

[0087] Table 9 Effects of different solidification times on Angelica volatile oil microcapsules

[0088]

[0089] The experimental results show that the encapsulation rate is low when the curing time is 15 minutes. This may be due to insufficient curing time, the condensation reaction is not complete, and the microencapsulation reversal phenomenon occurs. When the reaction is 75 minutes, the encapsulation rate is also low. It may be that the long curing time will cause the microcapsule wall material to become hard and brittle, and break during the stirring process. The encapsulation rate is high and does not change much when the curing time is within the range of 30 to 60 minutes, indicating that it has been completely condensed. It reaches the highest at 45 minutes, but the trend of increasing encapsulation rate is not obvious compared with 30 minutes. Based on the comprehensive consideration of encapsulation rate and time cost, the curing time is finally determined to be 30 minutes.

[0090] In summary, the concentration of gelatin solution, the concentration of gum arabic solution and pH value have a great influence on the preparation of angelica oil microcapsules by complex coacervation method, and these three factors will be further investigated.

[0091] 2.2 Optimization of microcapsule preparation method

[0092] 2.2.1 Box-Behnken Experimental Design

[0093] The Box-Behnken design effect surface method is a second-order experimental design method based on three levels. It uses the Box-Behnke experimental design and experimental results, adopts multivariate quadratic equations to fit the functional relationship between each factor and the effect value, and seeks the optimal process parameters by analyzing the regression equation.

[0094] According to the results of the single factor test, the three factors of gelatin solution concentration (A), gum arabic solution concentration (B) and pH (C) were selected as independent variables, and the encapsulation rate (R) was used as the index to optimize the preparation process of Angelica volatile oil microcapsules using the Box-Behnken response surface methodology. The Box-Behnken test factor levels are shown in Table 10, and the Box-Behnken test arrangement and results are shown in Table 11.

[0095] Table 10 Box-Behnken test factor levels

[0096]

[0097] 2.2.2 Box-Behnken Experiment Results and Analysis

[0098] The experiment was carried out according to Table 11, with a total of 17 groups of experiments. Each group of experiments was repeated three times, and the average encapsulation rate of the three experiments was used as an indicator. The experimental design and results, and variance analysis are shown in Tables 11 and 12 respectively.

[0099] Table 11 Box-Behnken test arrangement and results

[0100]

[0101] Design Expert 8.0.6 software was used to establish a quadratic multiple regression model fitting of the angelica oil microcapsule encapsulation efficiency (R) to three factors (A, B, C). By performing regression fitting analysis on the data in Table 11, the quadratic multiple regression equation was obtained: R = 82.65 + 5.81A-6.15B-6.85C + 8.27AB + 1.06AC-11.16BC-4.62A 2 -8.25B 2 -2.74C 2 The model used in the regression equation has a P value of less than 0.05, indicating that the model is effective and reliable. The lack of fit term is used to indicate the degree of fit between the model and the experiment. The P value of the lack of fit term is 0.0979>0.05, indicating that there is no lack of fit factor in the model and the model can fit the actual value well. Model correlation coefficient r 2 =0.9504, indicating that the model can explain 95.04% of the response value changes; the adjusted determination coefficient Adj-r 2 =0.8865, indicating good credibility. This model can be used to predict and analyze the preparation process of angelica oil microcapsules. The results are shown in Table 12.

[0102] Table 12 Analysis of variance of regression model

[0103]

[0104] Note: P<0.05 was significant, P<0.01 was extremely significant.

[0105] Among them, A, B, C, AB, BC, B 2 The linear effect of the factors on the comprehensive score was extremely significant (P < 0.01). By comparing the F values, it can be seen that the order of the influence of various factors on the encapsulation efficiency of angelica oil microcapsules is: pH (C) > Arabic gum solution concentration (B) > gelatin solution concentration (A).

[0106] 2.2.3 Response surface analysis and prediction of optimal conditions

[0107] According to the fitting equation, Design-Expert software was used to optimize and predict the optimal conditions for the preparation process of angelica oil microcapsules, and a 3D response surface diagram was drawn between factors such as gelatin solution concentration, gum arabic solution concentration, and pH. The response surface diagram can intuitively reflect the impact of the interaction on the predicted value. The steeper the contour line and the greater the degree of curvature, the greater the impact of the interaction on its encapsulation efficiency, which is reflected in the three-dimensional stereogram as the steeper the surface, as shown in detail. Figure 1-Figure 3 . It can be seen that the curves of the AB and BC response surface 3D graphs are steeper, indicating that the interaction between the concentration of gum arabic solution and the concentration and pH of gelatin solution is more obvious, and the effect on the encapsulation efficiency is more significant; the curve of the AC response surface 3D graph is relatively gentle, indicating that the interaction between the concentration of gelatin solution and pH has little effect on the encapsulation efficiency, which is consistent with the results of variance analysis. The optimal preparation process parameters are gelatin solution concentration 3wt%, gum arabic solution concentration 1wt%, pH 4.2, and the predicted encapsulation efficiency is 86.87%.

[0108] Figure 1 The response surface diagram and contour diagram show the effect of the interaction between gelatin solution concentration and gum arabic solution concentration on the microcapsule encapsulation efficiency of Angelica volatile oil.

[0109] Figure 2 The response surface diagram and contour diagram show the effect of the interaction between gelatin solution concentration and pH on the encapsulation efficiency of Angelica volatile oil microcapsules.

[0110] Figure 3 The response surface diagram and contour diagram show the effect of the interaction between gum arabic solution concentration and pH on the encapsulation efficiency of Angelica volatile oil microcapsules.

[0111] 2.2.4 Optimal preparation method for angelica oil microcapsules

[0112] (1) Weigh 1.5 g of gelatin, soak it in a small amount of purified water, add 50 ml of purified water after it swells, stir and dissolve in a 60°C water bath to prepare a 3 wt% gelatin solution for later use. Dry the gum arabic in an oven at 80°C for 1 h to remove the oxidase therein, take 0.5 g of the dried gum arabic and add 50 ml of purified water to prepare a 1 wt% solution.

[0113] (2) Add 0.45 g of Angelica volatile oil to 50 ml of gelatin solution preheated to 40°C, and disperse at 13,000 rpm for 3 min to form an emulsion; add 50 ml of gum arabic solution preheated to the same temperature, stir evenly with magnetic stirring at 40°C, and stir at a speed of 600 r / min. Adjust the pH to 4.2 with 10% by volume acetic acid, and continue stirring at the constant temperature for 20 min.

[0114] (3) Add twice the volume of purified water at 30°C, stir and wait for it to cool naturally to room temperature, place in an ice water bath, stir and cool to below 10°C, add 10wt% NaOH solution to adjust the pH value of the system to 8-9, add 5ml 37% formaldehyde aqueous solution to solidify for 30min. Let it stand for sedimentation, pour off the supernatant, centrifuge, wash with purified water until there is no aldehyde smell, place in a freeze dryer and dry in vacuum at low temperature to obtain Angelica volatile oil microcapsules.

[0115] 2.2.5 Optimization process verification experiment

[0116] Five batches of angelica oil microcapsules were prepared according to the optimal preparation process conditions obtained in step 2.2.4, and their encapsulation efficiency was determined. The average encapsulation efficiency was 85.62%, which was 1.02% compared with the predicted value of 86.87%, as shown in Table 13. This shows that the mathematical model established by the Box-Behnken response surface methodology has good predictive power, and the optimized preparation conditions of angelica oil microcapsules are accurate and reliable.

[0117] Table 13 Results of the optimal extraction process verification test

[0118]

[0119]

[0120] 2.3 Microcapsule evaluation index

[0121] 2.3.1 Appearance

[0122] The appearance of the microcapsules was observed under an optical microscope. The microcapsules were preferably spherical, plump, uniform in size and of appropriate size.

[0123] 2.3.2 Yield

[0124] The microcapsule yield refers to the ratio of the weight of the microcapsules after freeze drying to the total mass of the wall material and the wall core. The higher the yield, the more microcapsules are prepared by this method. Yield (%) = (M microcapsules / M capsule material + M capsule core) × 100%, where M microcapsules refers to the mass of the microcapsules prepared after drying; M capsule material refers to the sum of the mass of gum arabic and gum arabic; M capsule core refers to the amount of angelica volatile oil added.

[0125] 2.3.3 Encapsulation efficiency

[0126] The encapsulation rate refers to the percentage of the actual drug content in the microcapsule to the dosage (calculated as ligustilide). The higher the encapsulation rate, the better the drug encapsulation degree and the better the quality. Encapsulation rate (100%) = (mass of Angelica volatile oil in microcapsule / total dosage) × 100%, calculated as ligustilide.

[0127] 2.3.4 Drug loading

[0128] Drug loading refers to the amount of drug loaded per unit weight or per unit volume of microspheres. Drug loading can be regarded as the drug content of microspheres. Drug loading (100%) = (mass of angelica oil contained in microcapsules / total mass of microcapsules) × 100%, calculated as ligustilide.

[0129] The following examples are given to specifically illustrate the method of the present invention:

[0130] Example 1

[0131] The steps of the preparation method of the Angelica volatile oil microcapsules of this embodiment are as follows:

[0132] (1) Weigh 1.5 g of gelatin, soak it in a small amount of purified water, add 50 ml of purified water after it swells, stir and dissolve in a 60°C water bath to prepare a 3 wt% gelatin solution for later use. Dry the gum arabic in an oven at 80°C for 1 h to remove the oxidase therein, take 0.5 g of the dried gum arabic and add 50 ml of purified water to prepare a 1 wt% solution.

[0133] (2) Add 0.45 g of Angelica volatile oil to 50 ml of gelatin solution preheated to 40°C, and disperse at 13,000 rpm for 3 min to form an emulsion; add 50 ml of gum arabic solution preheated to the same temperature, stir evenly with magnetic stirring at 40°C, and stir at a speed of 600 r / min. Adjust the pH to 4.2 with 10% by volume acetic acid, and continue stirring at the constant temperature for 20 min.

[0134] (3) Add two volumes of purified water at 30°C, stir and wait for it to cool naturally to room temperature, place in an ice water bath and stir to cool to below 10°C, add 10wt% NaOH solution to adjust the pH value of the system to 8-9, add 5ml 37% formaldehyde aqueous solution to solidify for 30min. Let it stand for sedimentation, pour off the supernatant, centrifuge, wash with purified water until there is no aldehyde smell, place in a freeze dryer and dry in vacuum at low temperature to obtain Angelica volatile oil microcapsules with a particle size range of 26.237μm on average.

[0135] In step (3), water is added to reduce the viscosity of the system and prevent microcapsules from sticking. 30°C water is used to slowly cool the system, and cooling the system in an ice bath to below 10°C is a condition for solidifying the microcapsules.

[0136] In step (3), adjusting the pH value of the system to 8-9 is conducive to the complete amine-aldehyde condensation reaction in the complex coagulation reaction. Too high or too low pH value is not conducive to the reaction.

[0137] In step (3), the formaldehyde aqueous solution is a curing agent, and the formaldehyde and gelatin produce an amine-aldehyde condensation reaction. Commonly used curing agents include formaldehyde aqueous solution and glutaraldehyde. In the present invention, formaldehyde has the best curing effect.

[0138] In step (3), the purpose of placing the mixture in a freeze dryer for low temperature vacuum drying is that the contents are volatile oils, which will be dispersed, decomposed and deteriorated at high temperatures. Low temperature vacuum drying can protect the volatile oils, and there is no special requirement for the temperature range, as long as freeze drying is possible.

[0139] Example 2

[0140] The steps of the preparation method of the Angelica volatile oil microcapsules of this embodiment are as follows:

[0141] (1) Weigh 0.5 g of gelatin, soak it in a small amount of purified water, add 50 ml of purified water after it swells, stir and dissolve in a 60°C water bath to prepare a gelatin solution with a concentration of 1 wt% for later use. Dry the gum arabic in an oven at 80°C for 1 h to remove the oxidase therein, take the dried 0.25 g of gum arabic and add 50 ml of purified water to prepare a solution with a concentration of 0.5 wt%.

[0142] (2) Add 0.3 g of Angelica volatile oil to 50 ml of gelatin solution preheated to 20°C, and disperse at 13,000 rpm for 3 min to form an emulsion; add 50 ml of gum arabic solution preheated to the same temperature, stir evenly with magnetic stirring at 20°C, and stir at a speed of 400 r / min. Adjust the pH to 4.8 with 10% by volume acetic acid, and continue stirring at the constant temperature for 20 min.

[0143] (3) Add two volumes of purified water at 30°C, stir and wait for the mixture to cool naturally to room temperature, place in an ice-water bath, stir and cool to below 10°C, drop 10wt% NaOH solution to adjust the pH value of the system to 8-9, add 2ml 37% formaldehyde aqueous solution to solidify for 40min. Allow to settle, decant the supernatant, centrifuge, wash with purified water until there is no aldehyde smell, place in a freeze dryer and dry under low temperature vacuum to obtain Angelica volatile oil microcapsules.

[0144] Example 3

[0145] The steps of the preparation method of the Angelica volatile oil microcapsules of this embodiment are as follows:

[0146] (1) Weigh 1.0 g of gelatin, soak it in a small amount of purified water, wait for it to swell, add 50 ml of purified water, stir and dissolve in a 60°C water bath to prepare a 2 wt% gelatin solution for later use. Dry the gum arabic in an oven at 80°C for 1 h to remove the oxidase therein, take 0.75 g of the dried gum arabic and add 50 ml of purified water to prepare a 1.5 wt% solution.

[0147] (2) Add 0.53 g of Angelica volatile oil to 50 ml of gelatin solution preheated to 60°C, and disperse at 13,000 rpm for 3 min to form an emulsion; add 50 ml of gum arabic solution preheated to the same temperature, stir evenly with magnetic stirring at 60°C, and stir at a speed of 500 r / min. Adjust the pH to 4.5 with 10% by volume acetic acid, and continue stirring at the constant temperature for 20 min.

[0148] (3) Add two volumes of purified water at 30°C, stir and wait for the mixture to cool naturally to room temperature, place in an ice-water bath, stir and cool to below 10°C, drop 10wt% NaOH solution to adjust the pH value of the system to 8-9, add 8ml 37% formaldehyde aqueous solution to solidify for 60min. Allow to settle, decant the supernatant, centrifuge, wash with purified water until there is no aldehyde smell, place in a freeze dryer and dry in vacuum at low temperature to obtain Angelica volatile oil microcapsules.

[0149] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing angelica volatile oil capsules, characterized in that: The following steps are involved: (1) preparing a gelatin solution and a gum arabic solution respectively; the concentration of the gelatin solution is 3wt%; the concentration of the gum arabic solution is 1wt%; (2) Complex coagulation and capsule formation: Angelica sinensis volatile oil and gelatin solution are mixed and dispersed into an emulsion, and the gum arabic solution is added thereto, stirred evenly and the pH value is adjusted to 4.2; the Angelica sinensis volatile oil is 30% of the total weight of the gelatin and gum arabic; the temperature during the capsule formation is 40° C.; the stirring speed during the capsule formation is 600 r / min; (3) adding a curing agent for curing; the curing agent is a 37% formaldehyde aqueous solution; the dosage ratio of the angelica volatile oil to the 37% formaldehyde aqueous solution is: 0.45 g: 5 ml; the curing time is 30 min.

2. The preparation method according to claim 1, characterized in that: In step (3), before solidification, the solution is cooled to below 10° C. and the pH value is adjusted to 8-9.

3. A drug, characterized in that: The medicine is made from angelica volatile oil capsules prepared by the method of claim 1 or 2.

4. A medicine according to claim 3, characterized in that: The dosage form of the drug is tablet, capsule, injection, patch or ophthalmic preparation.

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