Preparation method of zedoary turmeric oil solubilizing compound

Abstract

The invention discloses a preparation method of a zedoary turmeric oil solubilizing compound, which comprises the following specific operation processes: weighing zedoary turmeric oil, a cyclodextrin compound, a water-soluble polymer auxiliary material, a flow aid and zirconium oxide beads, adding into a ball milling tank for ball milling, and sieving after ball milling to obtain the zedoary turmeric oil solubilizing compound, the cyclodextrin compound is any two of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and 2, 6-dimethyl-beta-cyclodextrin, and the cyclodextrin compound is any two of hydroxypropyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and 2, 6-dimethyl-beta-cyclodextrin. The zedoary turmeric oil solubilizing compound is prepared through a mechanochemical method, for highly volatile zedoary turmeric oil, use of an organic reagent is avoided, heating post-treatment such as solvent volatilization and drying is not needed, the raw material loss is low, and the inclusion efficiency is high.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of zedoary turmeric oil solubilizing complexes, and particularly relates to a preparation method of the zedoary turmeric oil solubilizing complex. Background Art

[0002] Curcuma oil is a volatile oil extracted from the Zingiberaceae plant, Curcuma zedoaria. Its main components include curcumol and curdion, among others. It has multiple biological activities, including anti-tumor, anti-inflammatory, and antibacterial activities, and shows great application potential in the medical field. Due to its high volatility, direct use of zecuma oil can easily lead to drug loss. In addition, zecuma oil has extremely low solubility in water and poor bioavailability, which greatly limits its clinical application. Currently, a variety of zecuma oil preparations have been developed, such as zecuma oil injection, which has been used clinically for antiviral treatments, but the injection has problems such as poor stability and the susceptibility to adverse reactions (Wang Dajin, Chen Liang, Lai Zhinong. A zecuma oil injection and its preparation method: CN202210608889.6). You et al. prepared a zedoary turmeric oil emulsion containing Aerosil 200 particles and hydroxypropylmethylcellulose acetate succinate (HPMCAS). Compared with the previous formulation, its dispersibility was improved to a certain extent and it showed stronger stability; however, the article did not explain the encapsulation effect of the new formulation (WANGX, GU Y, HE Y, et al. Preparation and optimization formulation of zedoary turmeric oil nanoemulsion based thermo-sensitive gel for improved application in ophthalmology [J]. Journal of Drug Delivery Science and Technology, 2021, 65: 102682.). Cyclodextrin inclusion compounds have the advantages of low industrial production costs and good solubilization and stabilization effects, and are a powerful means to address the limitations of the above-mentioned dosage forms. The formation of inclusion compounds can improve the stability of zedoary turmeric oil, reduce volatility losses, and significantly increase the solubility of zedoary turmeric oil in water, thereby improving bioavailability. Common methods for preparing zedoary turmeric oil solubilization complexes include saturated aqueous solution method, grinding method, ultrasonic method, etc. Among them, the saturated aqueous solution method is relatively simple to operate, but it is time-consuming and the inclusion rate needs to be improved (Xiao Xiaohe, Bai Zhaofang, Cui Herong, et al. Curcuma oil solubilized complex for preventing or treating acute liver failure and its preparation method. CN201611220461.5[2024-08-13].). Although the mortar grinding method can reduce the use of organic reagents, it requires manual grinding for 40 minutes and the inclusion rate can only reach 80%. The ultrasonic method can accelerate the inclusion rate, but the equipment requirements are high, and the ultrasonic process may cause local overheating and affect the quality of the volatile oil inclusion compound (Yi Jun, Li Xiaofang, Su Jianxiang, et al. Preparation of β-cyclodextrin inclusion compound of Acorus tatarinowii volatile oil by ultrasonic method [J]. Journal of Traditional Chinese Medicine, 2006, 17(3):3. DOI:10.3969 / j.issn.1008-0805.2006.03.038.).

[0003] Mechanochemistry is based on the application of mechanical energy to condensed matter such as solids and liquids by means of shearing, friction, impact, and extrusion, inducing changes in their structure and physicochemical properties, thereby inducing chemical reactions. Zhang et al. prepared an amorphous solid dispersion of curcumin and disodium glycyrrhizinate by mechanical ball milling. The dispersion can self-assemble into curcumin-loaded micelles when dissolved in water. The curcumin solid dispersion has higher cytotoxicity to glioblastoma cells, higher membrane permeability, and bioavailability is about 19 times higher than that of free curcumin (Zhang Q, Polyakov NE, Chistyachenko YS, et al. Preparation of curcumin self-micelle solid dispersion with enhanced bioavailability and cytotoxic activity by mechanochemistry [J]. Drug Delivery, 2018, 25 (1): 198-209.).

[0004] The preparation of cyclodextrin inclusion complexes based on mechanochemistry is usually limited to the use of a single cyclodextrin, which has multi-dimensional limitations when preparing inclusion complexes. From a structural perspective, the cavity size is fixed and lacks diversity. For example, the inner diameter of α-cyclodextrin is approximately 0.47-0.53nm, β-cyclodextrin is 0.75-0.83nm, and γ-cyclodextrin is 0.89-0.95nm. As a result, it can only adapt to guest molecules of a specific size. When the size of the guest molecule exceeds the adaptation range, incomplete inclusion or inability to be included is likely to occur. In terms of stability, the inclusion complex formed by a single cyclodextrin and a guest molecule mainly relies on weak interactions such as van der Waals forces and hydrogen bonds to maintain its stability, and lacks a synergistic stabilization mechanism of multiple types of forces. In the presence of high temperature, pH fluctuations or organic solvents, the inclusion complex is prone to dissociation, resulting in leakage of the active ingredients. In terms of solubility regulation, although β-cyclodextrin has a certain solubilizing effect, its own water solubility is low (the solubility is only 1.85g / 100mL water at 25°C), which not only limits its application in aqueous systems, but may also lead to a decrease in inclusion efficiency due to insufficient solubility. In addition, single cyclodextrin has poor selectivity for guest molecules, making it difficult to achieve specific inclusion for guest molecules with different properties (such as polarity and charge distribution differences). This leads to inclusion competition in complex systems, affecting the purity and yield of the final inclusion product. These inherent drawbacks have seriously restricted the expanded application of single cyclodextrin in the field of high-end inclusion compound preparation.

[0005] In summary, although zedoary turmeric oil has significant biological activity and potential for medical applications, its high volatility, multiple components, poor water solubility, and low bioavailability have severely restricted its clinical application. Existing zedoary turmeric oil preparations have problems such as poor stability and many adverse reactions. Although the new emulsion formula improves dispersibility, it does not fully demonstrate the encapsulation effect. Cyclodextrin inclusion compounds provide an effective way to solve the above problems and can improve the stability and solubility of zedoary turmeric oil. However, common preparation methods such as saturated aqueous solution method, grinding method, and ultrasonic method each have their own advantages and disadvantages. Although the mechanochemical method has performed well in solubilizing other drugs, the cyclodextrin inclusion compounds prepared based on this method mostly use a single cyclodextrin. Due to its structural limitations, there are limitations such as a narrow range of compatible guest molecules, insufficient stability, limited solubility control, and poor selectivity during the inclusion process. Therefore, considering the advantages of the compound cyclodextrin system and the characteristics of the new preparation technology, the performance of zedoary turmeric oil preparations is optimized to break through its clinical application bottleneck. Summary of the Invention

[0006] In view of the above problems, the object of the present invention is to provide a method for preparing a zedoary oil solubilized complex.

[0007] The specific technical solutions are as follows:

[0008] A method for preparing a zedoary turmeric oil solubilizing complex comprises the following steps: weighing zedoary turmeric oil, a cyclodextrin complex, a water-soluble polymer auxiliary material, a flow aid and zirconium oxide beads, adding the mixture into a ball milling jar for ball milling, and sieving the mixture after ball milling to obtain the zedoary turmeric oil solubilizing complex.

[0009] Furthermore, the mass ratio of zedoary turmeric oil, cyclodextrin complex, water-soluble polymer excipient and flow aid is 1:4-8:0.5-5:0.1-0.4, and the ball-to-material ratio is 10-30:1.

[0010] Furthermore, the cyclodextrin complex is any two of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and 2,6-dimethyl-β-cyclodextrin.

[0011] Furthermore, the water-soluble polymer excipient is one of hydroxypropyl methylcellulose E3, hydroxypropyl methylcellulose E5, polyvinyl pyrrolidone K30, polyvinyl pyrrolidone K60, polyvinyl pyrrolidone K90, polyethylene glycol-1000, polyethylene glycol-4000, polyethylene glycol-6000, poloxamer 188, poloxamer 407, poloxamer 338, polyvinyl alcohol 17-99, polyvinyl alcohol 20-99, polyvinyl alcohol 24-99, sodium lauryl sulfate, polysorbate 60, and polysorbate 80.

[0012] Furthermore, the glidant is any one or more of talc, silicon dioxide, magnesium oxide, magnesium stearate, calcium stearate, polyethylene glycol, microcrystalline cellulose 101, and microcrystalline cellulose 102.

[0013] Furthermore, the ball milling processing equipment is one of a drum ball mill, a vibrating ball mill, and a planetary ball mill.

[0014] Furthermore, when a drum ball mill is used, the ball milling speed is 100-300 rpm and the ball milling time is 1-6 h; when a planetary ball mill is used, the ball milling speed is 100-300 rpm and the ball milling time is 1-6 h; when a vibrating ball mill is used, the ball milling frequency is 15-35 Hz and the ball milling time is 15-35 min.

[0015] Furthermore, the cyclodextrin complex is β-cyclodextrin and hydroxypropyl-β-cyclodextrin, and the mass ratio of the two is 2-5:1.

[0016] The beneficial effects of the present invention are:

[0017] 1) The present invention promotes the synergistic effect of cyclodextrin and water-soluble polymer excipients through mechanical ball milling. The cavity size and chemical properties of the compounded cyclodextrin groups complement each other, adapting to a wider range of guest molecular structures. The cyclodextrin and water-soluble polymer excipients can interact with zedoary turmeric oil through hydrogen bonding and hydrophobic interactions, significantly improving the solubility of zedoary turmeric oil in water. This facilitates the development of various hydrophobic volatile oil solubilization preparations and broadens the application field of volatile oils.

[0018] 2) The present invention forms a protective layer around the zedoary oil through the effects of cyclodextrin cavity encapsulation and water-soluble polymer excipient agglomeration. The two together construct a stable microenvironment, effectively isolating the effects of factors such as light, oxygen, and temperature on the zedoary oil, thereby enhancing the chemical stability of the zedoary oil and extending its shelf life.

[0019] 3) The present invention prepares the zedoary oil solubilizing complex by a mechanochemical method. For the highly volatile zedoary oil, the use of organic reagents is avoided, and no post-treatment by heating such as solvent volatilization and drying is required. The raw material loss is low and the inclusion efficiency is high. This is a method for preparing the solubilizing complex with broad application prospects.

[0020] 4) The dry solid powder prepared by the present invention is suitable as an intermediate dosage form for subsequent development of multiple dosage forms. Due to its good solubility and stability, it can be quickly and evenly dispersed in matrices such as powders and gels, thereby being used to prepare multiple dosage forms such as tablets, gels, and suppositories. This provides a reliable intermediate for the development of efficient and diversified dosage forms of zedoary turmeric oil, which can greatly improve production efficiency and product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1The diagram shows the drug loading and encapsulation efficiency of zedoary turmeric oil in the zedoary turmeric oil solubilized complex prepared under different conditions;

[0022] Figure 2 The solubility diagram of zedoary turmeric oil in zedoary turmeric oil-solubilized complexes prepared under different conditions;

[0023] Figure 3 This is a graph showing the loss rate of zedoary turmeric oil in zedoary turmeric oil-solubilized complexes prepared under different conditions;

[0024] Figure 4 This is a graph showing the relative content change of zedoary turmeric oil in the zedoary turmeric oil solubilized complex prepared under different conditions from 0 to 14 days. DETAILED DESCRIPTION

[0025] The present invention will be further described below with reference to the accompanying drawings and embodiments, but the protection scope of the present invention is not limited thereto.

[0026] The experimental method for the drug loading capacity of zedoary oil is as follows: a certain mass (m1, in g) of zedoary oil inclusion complex is weighed, completely dissolved in anhydrous ethanol, transferred to a volumetric flask and fixed to a certain volume (V, in mL) to obtain an inclusion complex solution. The concentration of zedoary oil in the solution is determined by high performance liquid chromatography (c, in mg / mL). At the same time, a blank solvent is measured in parallel as a control to eliminate background interference. To ensure the accuracy of the experiment, each sample is measured three times and the average value is taken. The drug loading capacity is calculated as follows:

[0027]

[0028] The encapsulation efficiency test method of zedoary turmeric oil is as follows: a certain mass (m2, unit is g) of zedoary turmeric oil inclusion complex is weighed, washed with petroleum ether, and separated into zedoary turmeric oil in the inclusion complex and free zedoary turmeric oil. After dissolving in anhydrous ethanol, the mass of zedoary turmeric oil contained therein (m2, unit is g) is determined by high performance liquid chromatography. 内 , in g) and free zedoary oil content (m 外 , unit is g), each sample was measured three times, and the average value was taken. The encapsulation efficiency was calculated as follows:

[0029]

[0030] The experimental method for the solubility of zedoary turmeric oil inclusion complex is as follows: at a certain temperature, add an excess of zedoary turmeric oil inclusion complex to a certain volume (V0, in mL) of solvent. Stir thoroughly to form a saturated solution, let it stand for a certain time to allow the undissolved solid to completely settle, take the supernatant, and use high performance liquid chromatography to determine the concentration of zedoary turmeric oil inclusion complex in the supernatant (c 溶 , unit is mg / mL), three groups of samples were measured in parallel, and the average value was taken. The solubility was calculated as follows: solubility = c 溶 .

[0031] The experimental method of the loss rate of zedoary turmeric oil inclusion compound is as follows: weigh a certain mass (m 初始 , in g) of the zedoary oil inclusion compound sample, and record its theoretical zedoary oil content (which can be calculated by the drug loading amount measured in the early stage, assuming that the drug loading amount is D%, then After the ball milling, the sample was taken out and dissolved in anhydrous ethanol and fixed to a certain volume (V, unit: mL). The concentration of zedoary turmeric oil in the fixed solution was determined by high performance liquid chromatography (c, unit: mg / mL), and the mass of zedoary turmeric oil in the ball milled sample was calculated (c×V×10 -3 , unit is g), parallel determination was performed 3 times, and the average value was taken. The formula for calculating the loss rate of zedoary turmeric oil is:

[0032]

[0033] The experimental method for the relative content of zedoary turmeric oil inclusion complex from 0 to 14 days is as follows: an appropriate amount of zedoary turmeric oil inclusion complex sample was taken and divided into 7 equal parts, which were marked as 0-day, 2-day, 4-day, 6-day, 8-day, 10-day, and 14-day groups, respectively. The 0-day group sample was completely dissolved in anhydrous ethanol and transferred to a volumetric flask to a certain volume (V, in mL). The concentration of zedoary turmeric oil in the solution was determined by high-performance liquid chromatography quantitative analysis (c0, in mg / mL), and the mass of zedoary turmeric oil in the 0-day group sample was calculated (m0 = C0 × V × 10 -3 , unit is g), the remaining groups of samples were placed under set conditions, and the corresponding marked samples were taken out at 2 days, 4 days, 6 days, 8 days, 10 days, and 14 days, and the above dissolution, volume adjustment and determination steps were repeated to obtain the concentration of zedoary oil at different time points, and the corresponding mass was calculated. To ensure data reliability, the parallel determination was repeated 3 times and the average value was taken. The calculation formula for the relative content of zedoary oil is:

[0034]

[0035] Example 1

[0036] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (α-cyclodextrin: β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The prepared sample was passed through a 40 mesh sieve and sealed for storage.

[0037] Example 2

[0038] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (mass ratio of α-cyclodextrin and γ-cyclodextrin = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0039] Example 3

[0040] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (2,6-dimethyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0041] Example 4

[0042] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and sulfobutyl ether-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0043] Example 5

[0044] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0045] Effects of different cyclodextrin complexes on the drug loading capacity and encapsulation efficiency of zedoary turmeric oil Figure 1 As shown in (a), Example 5 has the best drug loading and encapsulation efficiency, which may be due to the suitable cavities of the two cyclodextrins, which can provide the best loading for zedoary oil. The effects of different cyclodextrin complexes on the solubility of zedoary oil are shown in FIG. Figure 2 As shown in (a), the inclusion compound prepared in Example 5 has the highest solubility, which may be due to the best water solubility of hydroxypropyl-β-cyclodextrin among several combinations; the effect of different cyclodextrin complexes on the loss rate of zedoary turmeric oil is shown in FIG. Figure 3As shown in (a), Example 5 performs best, which may be because the combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin has a better loading inclusion of zedoary turmeric oil, the least free zedoary turmeric oil, and the lowest loss rate; the effect of different cyclodextrin complexes on the relative content of zedoary turmeric oil is shown in FIG. Figure 4 As shown in (a), the combination of β-cyclodextrin and hydroxypropyl-β-cyclodextrin helps to improve the stability of zedoary turmeric oil. The possible reason is that these two combinations have the best binding force to each other and can effectively prevent the degradation of zedoary turmeric oil.

[0046] Example 6

[0047] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 1:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0048] Example 7

[0049] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 1:2), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0050] Example 8

[0051] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 2:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0052] Example 9

[0053] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 4:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0054] Effects of different cyclodextrin complex ratios on drug loading and encapsulation efficiency of zedoary turmeric oil Figure 1 As shown in (b), Example 5, wherein the mass ratio of β-cyclodextrin to hydroxypropyl-β-cyclodextrin is 3:1, performs best. The size of the β-cyclodextrin cavity is more suitable for zedoary turmeric oil. Although Example 9 also performs well, the differences between the parallel experimental groups are large. The effects of different cyclodextrin complex ratios on the solubility of zedoary turmeric oil are shown in FIG. Figure 2 As shown in (b), Example 5 performs best; the effect of different cyclodextrin complex ratios on the loss rate of zedoary turmeric oil is shown in Figure 3 As shown in (b), Example 5 has the lowest loss rate; the effect of different cyclodextrin complex ratios on the relative content of zedoary oil is shown in Figure 4 As shown in (b), the effects of Example 7 and Example 5 are similar. Taking all factors into consideration, the mass ratio of β-cyclodextrin to hydroxypropyl-β-cyclodextrin in Example 5 is 3:1, which is more preferable.

[0055] Example 10

[0056] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), hydroxypropyl methylcellulose E3, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0057] Example 11

[0058] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), polyethylene glycol-6000, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0059] Example 12

[0060] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), poloxamer 188, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0061] Example 13

[0062] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), polyvinyl alcohol 24-99, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar, set the speed at 100 rpm, and ball milling was performed for 3 h; the obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0063] Effects of different water-soluble polymer excipients on the drug loading and encapsulation efficiency of zedoary turmeric oil Figure 1 As shown in (c), Example 5 Sodium dodecyl sulfate is used as an anionic surfactant, and its hydrophobic long chain (dodecyl) can be combined with the hydrophobic group of zedoary turmeric oil (fat-soluble component) through hydrophobic interaction, and the hydrophilic sulfonic acid group is combined with the hydrophilic group (-OH) of β-cyclodextrin and hydroxypropyl-β-cyclodextrin inclusion material through hydrogen bonding or electrostatic interaction, thereby enhancing the compatibility of zedoary turmeric oil with the inclusion material and promoting the inclusion reaction. Silica is an inert carrier, and silica can prevent the inclusion material from agglomerating during the preparation process, promote the uniform mixing of the inclusion material and the drug, and avoid incomplete inclusion caused by excessive local drug concentration; magnesium stearate Magnesium stearate is used as a lubricant to reduce the friction between the inclusion material particles, making it easier to disperse evenly during the preparation process (such as spray drying, grinding, etc.), avoiding incomplete inclusion of the drug due to particle agglomeration, thereby improving the encapsulation efficiency; the effect of different water-soluble polymer excipients on the solubility of zedoary turmeric oil is shown in FIG. Figure 2 As shown in (c), the surfactant-carrier synergistic combination of sodium dodecyl sulfate, silicon dioxide and magnesium stearate can effectively improve the water solubility of the zedoary oil inclusion compound; the effect of different water-soluble polymer excipients on the loss rate of zedoary oil is shown in Figure 3 As shown in (c), Example 5 has the lowest loss rate; the influence of different water-soluble polymer excipients on the relative content of zedoary oil is shown in Figure 4 As shown in (c), the formula combination of Example 5 can effectively improve the inclusion effect, thereby improving the stability of Zedoaria oil.

[0064] Example 14

[0065] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 200 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0066] Example 15

[0067] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 300 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0068] Effects of different ball milling speeds on drug loading and encapsulation efficiency of zedoary turmeric oil Figure 1 As shown in (d), the drug loading and encapsulation efficiency of Example 5 are both optimal; the effect of different ball milling speeds on the solubility of zedoary oil is shown in Figure 2 As shown in (d), Example 5 is optimal at a speed of 100 rpm; the effect of different ball milling speeds on the loss rate of zedoary oil is shown in Figure 3 As shown in (d), the rotation speed of Example 5 has the least loss of zedoary turmeric oil, and too high a rotation speed will lead to more raw material loss; the effect of different ball milling speeds on the relative content of zedoary turmeric oil is shown in Figure 4 As shown in (d), Example 15 performs best. Taking all factors into consideration, the 100 rpm of Example 5 is selected.

[0069] Example 16

[0070] Using a drum ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 30 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 30 min. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0071] Example 17

[0072] Using a vibrating ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 30 mL ball mill jar. The vibration frequency was set to 30 Hz and the ball milling time was 30 min. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0073] Example 18

[0074] Using a vibrating ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 30 mL ball mill jar. The vibration frequency was set to 35 Hz and the ball milling time was 30 min. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0075] Effects of different grinding methods on drug loading and encapsulation efficiency of zedoary turmeric oil Figure 1 As shown in (e), the planetary ball mill in Example 5 has the best effect; the effect of different grinding methods on the solubility of zedoary oil is shown in Figure 2 As shown in (e), the oscillating ball mill at 35 Hz in Example 18 performs best; the effects of different grinding methods on the loss rate of zedoary turmeric oil are shown in Figure 3 As shown in (e), although the vibrating ball mill at 35 Hz in Example 18 performs best in terms of solubility, the loss rate is too high, and the loss in Example 5 is the least. The effect of different grinding methods on the relative content of zedoary turmeric oil is shown in FIG. Figure 4 As shown in (e), Example 5 uses a planetary ball mill to achieve the best effect.

[0076] Example 19

[0077] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 2 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0078] Example 20

[0079] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0080] Example 21

[0081] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 4 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0082] Example 22

[0083] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 5 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0084] Example 23

[0085] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 6 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0086] Effects of different grinding times on drug loading and encapsulation efficiency of zedoary turmeric oil Figure 1 As shown in (f), the ball milling time of Example 20 for 3 h is the best and the error is the smallest; the effect of different grinding times on the solubility of zedoary oil is shown in Figure 2 As shown in (f), the ball milling time of Example 20 for 3 h is the best; the effect of different grinding times on the loss rate of zedoary turmeric oil is shown in Figure 3 As shown in (f), the ball milling loss of Example 20 for 3h is the least; the effect of different grinding times on the relative content of zedoary oil is shown in Figure 4 As shown in (f), Example 20 was ball milled for 3 hours.

[0087] Example 24

[0088] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 10:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0089] Example 25

[0090] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15 mm zirconium oxide with a ball-to-material ratio of 15:1 was added into a 50 mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40 mesh sieve and sealed for storage.

[0091] Example 26

[0092] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15mm zirconium oxide with a ball-to-material ratio of 20:1 was added into a 50mL ball mill jar, set the speed at 100 rpm, and ball milling was performed for 3 hours; the obtained sample was passed through a 40-mesh sieve and sealed for storage.

[0093] Example 27

[0094] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15mm zirconium oxide with a ball-to-material ratio of 25:1 was added into a 50mL ball mill jar, set the speed at 100 rpm, and ball milling was performed for 3 hours; the obtained sample was passed through a 40-mesh sieve and sealed for storage.

[0095] Example 28

[0096] Using a planetary ball mill, zedoary turmeric oil, cyclodextrin complex (β-cyclodextrin and hydroxypropyl-β-cyclodextrin mass ratio = 3:1), sodium lauryl sulfate, silicon dioxide and magnesium stearate were weighed in a mass ratio of 1:4:0.5:0.2:0.2, and 15mm zirconium oxide with a ball-to-material ratio of 30:1 was added into a 50mL ball mill jar. The speed was set at 100 rpm and the ball milling time was 3 h. The obtained sample was passed through a 40-mesh sieve and sealed for storage.

[0097] Effects of different ball-to-material ratios on drug loading and encapsulation efficiency of zedoary turmeric oil Figure 1 As shown in (g), Example 25 performs best with the smallest error; the effect of different ball-to-material ratios on the solubility of zedoary oil is shown in Figure 2 As shown in (g), Example 25 has the highest solubility; the effect of different ball-to-material ratios on the loss rate of zedoary oil is shown in Figure 3 As shown in (g), Example 25 has the lowest loss rate; the effect of different ball-to-material ratios on the relative content of zedoary oil is shown in Figure 4 As shown in (g), Example 25 has the best stability.

Claims

1. A method for preparing a zedoary turmeric oil solubilized complex, characterized in that: The method comprises the following steps: weighing zedoary turmeric oil, cyclodextrin complex, water-soluble polymer auxiliary material, flow aid and zirconium oxide beads, adding them into a ball milling jar for ball milling, and sieving after ball milling to obtain zedoary turmeric oil solubilized complex.

2. The method for preparing a zedoary turmeric oil solubilized complex according to claim 1, wherein: The mass ratio of zedoary turmeric oil, cyclodextrin complex, water-soluble polymer excipient and flow aid is 1:4-8:0.5-5:0.1-0.4, and the ball-to-material ratio is 10-30:

1.

3. The method for preparing a zedoary turmeric oil solubilized complex according to claim 1, wherein: The cyclodextrin complex is any two of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and 2,6-dimethyl-β-cyclodextrin.

4. The method for preparing a zedoary turmeric oil solubilized complex according to claim 1, wherein: The water-soluble polymer excipient is one of hydroxypropyl methylcellulose E3, hydroxypropyl methylcellulose E5, polyvinyl pyrrolidone K30, polyvinyl pyrrolidone K60, polyvinyl pyrrolidone K90, polyethylene glycol-1000, polyethylene glycol-4000, polyethylene glycol-6000, poloxamer 188, poloxamer 407, poloxamer 338, polyvinyl alcohol 17-99, polyvinyl alcohol 20-99, polyvinyl alcohol 24-99, sodium lauryl sulfate, polysorbate 60, and polysorbate 80.

5. The method for preparing a zedoary turmeric oil solubilized complex according to claim 1, wherein: The glidant is any one or more of talc, silicon dioxide, magnesium oxide, magnesium stearate, calcium stearate, polyethylene glycol, microcrystalline cellulose 101, and microcrystalline cellulose 102.

6. The method for preparing a zedoary turmeric oil solubilized complex according to claim 1, wherein: The ball milling equipment is one of the following: drum ball mill, vibrating ball mill and planetary ball mill.

7. The method for preparing a zedoary turmeric oil-solubilized complex according to claim 6, wherein: When a drum ball mill is used, the ball milling speed is 100-300 rpm and the ball milling time is 1-6 hours. When a planetary ball mill is used, the ball milling speed is 100-300 rpm and the ball milling time is 1-6 hours. When a vibrating ball mill is used, the ball milling frequency is 15-35 Hz and the ball milling time is 15-35 minutes.

8. The method for preparing a zedoary turmeric oil solubilized complex according to claim 3, wherein: The cyclodextrin complex comprises beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin, and the mass ratio of the two is 2-5:1.

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