Cyclodextrin corn starch inclusion compound of coenzyme Q10 as well as preparation method and application of cyclodextrin corn starch inclusion compound

Abstract

The invention relates to the technical field of clathrates, in particular to a coenzyme Q10-cyclodextrin clathrate and a preparation method and application thereof.The preparation method comprises the steps that coenzyme Q10 is dissolved in an aqueous solution of alcohol, and a first solution is obtained; performing ultrasonic treatment on the first solution at 40-45 DEG C to obtain a second solution; cooling the second solution to obtain a third solution, adding a cyclodextrin derivative solution into the third solution, and mixing to obtain a cyclodextrin inclusion compound fourth solution of the coenzyme Q10; and adding corn starch into the fourth solution, stirring for reaction, and removing the solvent to obtain the coenzyme Q10 cyclodextrin derivative corn starch inclusion compound. The preparation method provided by the invention has the advantages of simple operation and high encapsulation efficiency, and the coenzyme Q10-cyclodextrin derivative corn starch inclusion compound has good long-term storage stability.

Description

Technical Field

[0001] The present application relates to the technical field of inclusion compounds, and particularly relates to a cyclodextrin corn starch inclusion compound of coenzyme Q10, a preparation method thereof, and an application thereof. Background Art

[0002] Coenzyme Q10 (CoQ10) is a quinone compound naturally present in the human body. CoQ10 is a key component of the mitochondrial electron transport chain, participates in the generation of cellular energy (ATP), and is particularly important for highly energy-consuming organs such as the heart and liver. It can also neutralize free radicals, protect cell membranes, proteins, and DNA from oxidative damage, delay aging, and can also improve myocardial energy metabolism, and is used for the adjuvant treatment of cardiovascular diseases such as heart failure and hypertension.

[0003] CoQ10 consists of two parts: benzoquinone (head) and long-chain hydrocarbon (tail), and is a lipophilic compound. It is easily soluble in lipid solvents and almost insoluble in water, with a low oral absorption rate. Cyclodextrin is a commonly used complexing agent, which is cheap and has a good complexing effect. Using cyclodextrin for complexing can improve the water solubility of CoQ10 and increase its bioavailability. However, when using cyclodextrin for complexing, due to the limited cavity size of cyclodextrin, usually only the head of CoQ10 can be complexed, and the tail is difficult to completely embed into the cyclodextrin cavity due to its large volume and strong flexibility. The uncomplexed tail may induce the precipitation of the head, affecting the storage stability of the inclusion compound. There is a method proposed to solve the above problems by using a double-layer coating method, first coating the head with cyclodextrin for the first time, and then using other complexing agents to perform a secondary coating on the tail. However, this method has cumbersome steps and high costs.

[0004] Therefore, it is necessary to develop a cyclodextrin complexing process with good long-term storage stability and simplicity. Summary of the Invention

[0005] Based on this, the objectives of the present application include providing a cyclodextrin corn starch inclusion compound of coenzyme Q10, a preparation method thereof, and an application thereof. The preparation method of the present application has the advantages of simple operation and high encapsulation efficiency, and the cyclodextrin corn starch inclusion compound of coenzyme Q10 has good long-term storage stability.

[0006] The technical solution of the present application is as follows: A preparation method of a cyclodextrin derivative corn inclusion compound of coenzyme Q10, comprising the following steps: Dissolve coenzyme Q10 in an aqueous solution of alcohol to obtain a first solution; Perform ultrasonic treatment on the first solution at 40°C to 45°C to obtain a second solution; Perform a temperature reduction treatment on the first solution to obtain a third solution; Add the cyclodextrin derivative solution to the third solution to obtain a fourth solution; Add corn starch to the fourth solution, stir and react, and then remove the solvent to obtain a coenzyme Q10 cyclodextrin derivative corn starch inclusion complex.

[0007] In the preparation method of the cyclodextrin inclusion complex of coenzyme Q10 according to the embodiment of the present application, coenzyme Q10 is first dissolved in an aqueous solution of alcohol. Alcohol can dissolve the head of coenzyme Q10, forcing the hydrophobic long chain to fold inward. After dissolution, ultrasonic treatment is carried out at 40-45 °C. The thermal effect is used to reduce intermolecular aggregation, and at the same time, the ultrasonic cavitation effect destroys the extended state of the long chain, inducing the initial folding of the tail. Then, cooling treatment is carried out. Through low-temperature driving, the long alkane chain of coenzyme Q10 is further folded and the folded conformation is frozen to avoid random aggregation of the tail. Then, the cyclodextrin derivative solution is added to the coenzyme Q10 solution treated above. Due to the presence of a large amount of organic solvents in the system, the high concentration of organic solvents reduces the solubility of cyclodextrin. It was unexpectedly found during the research of the present application that by adding corn starch and stirring and reacting, it can promote its hydrophobic cavity to actively capture the folded coenzyme Q10, and the tail is embedded in the periphery of the cavity through hydrophobic interaction to form a head-tail double inclusion structure. After the inclusion complex is formed, it will spontaneously precipitate due to low solubility, realizing high encapsulation efficiency and stable conformation locking, thereby significantly improving the storage stability and dissolution performance. The above preparation method can also coat the tail of coenzyme Q10 in cyclodextrin, has good long-term storage stability, is simple to operate, does not require special instruments, has low cost, and is suitable for industrial production.

[0008] Further, the step of subjecting the first solution to ultrasonic treatment at 40 °C to 45 °C to obtain a second solution includes: Heat the first solution to 40 °C to 45 °C, and then perform ultrasonic treatment at the first power and the first frequency for the first time to obtain the second solution; Wherein, the first power is 150W to 250W, the first frequency is 25kHz to 35kHz, and the first time is 30min to 60min.

[0009] In this embodiment, the first solution is subjected to ultrasonic treatment at a suitable temperature to ensure that the ultrasonic cavitation effect is sufficient to destroy the intermolecular force of coenzyme Q10 molecules, while avoiding excessive energy damage to the molecular structure. The appropriate treatment time can balance the folding efficiency and energy consumption to ensure that the tail is fully folded inward.

[0010] Further, the step of subjecting the second solution to cooling treatment to obtain a third solution includes: Cool the first solution to the second temperature at the first rate, maintain for the second time, and then reduce to the third temperature at the second rate to obtain the third solution; Among them, the first rate and the second rate are independently selected from 5°C / min to 10°C / min respectively; The second temperature is 30°C to 35°C, the second time is 1 min to 2 min, and the third temperature is 20°C to 25°C.

[0011] In this embodiment, by controlling the cooling rate (5°C / min to 10°C / min) and intermediate heat preservation (maintaining at 30°C to 35°C for 1 min - 2 min) of the second solution, random aggregation caused by sudden cooling is avoided, and the folding conformation is directionally "frozen" to improve the integrity of the tail inclusion.

[0012] Further, the step of adding an aqueous solution of cyclodextrin to the third solution and mixing to obtain a cyclodextrin derivative inclusion complex of coenzyme Q10 includes: Adding the aqueous solution of cyclodextrin to the third solution at a third rate, and after stirring for a third time, a fourth solution of a cyclodextrin inclusion complex of coenzyme Q10 is obtained; Among them, the third rate is 0.5 mL / min to 1.5 mL / min; the third time is 1 h to 3 h.

[0013] In this embodiment, adding the aqueous solution of cyclodextrin to the third solution at an appropriate rate can avoid local supersaturation and ensure the uniform formation of the inclusion complex.

[0014] Further, the rotation speed of the stirring is 500 rpm to 700 rpm.

[0015] In this embodiment, an appropriate stirring rotation speed can promote the full contact between cyclodextrin and coenzyme Q10, ensure the uniform formation of the inclusion complex, and prevent the polymerization of the tail of coenzyme Q10 caused by too fast mechanical stirring.

[0016] In some embodiments, the volume ratio of alcohol in the aqueous solution of alcohol is 60% to 80%.

[0017] In this embodiment, adding the aqueous solution of cyclodextrin to the third solution at an appropriate rate can avoid local supersaturation and ensure the uniform formation of the inclusion complex.

[0018] In this embodiment, the alcohol-water ratio of the aqueous solution of alcohol is in a more appropriate range, which can not only dissolve the head of coenzyme Q10, but also force the tail to fold through the driving force of the water phase, avoiding the inhibition of cyclodextrin dissolution caused by too high alcohol concentration or insufficient folding caused by too low alcohol concentration.

[0019] Further, adding corn starch to the fourth solution, after stirring and reacting, removing the solvent to obtain a coenzyme Q10 cyclodextrin derivative corn starch inclusion complex. After stirring for a fourth time, removing the solvent to obtain the cyclodextrin starch inclusion complex of coenzyme Q10; Among them, the fourth time is 3h to 7h; the rotation speed of the stirring is 500rpm to 700rpm.

[0020] Among them, the methods for removing the solvent include oven drying, vacuum drying, spray drying, and freeze drying.

[0021] In some embodiments, the cyclodextrin derivatives include one or more of β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl cyclodextrin, sulfobutyl cyclodextrin, and γ-cyclodextrin.

[0022] In this embodiment, the cavity size and hydrophobicity of β-cyclodextrin, γ-cyclodextrin or their derivatives are more suitable for the folded conformation of coenzyme Q10, which helps to improve the compatibility of the inclusion of coenzyme Q10 and cyclodextrin.

[0023] In some embodiments, the weight ratio of coenzyme Q10, the cyclodextrin derivative, and corn starch is (1 to 10):(3 to 10).

[0024] In this embodiment, the appropriate weight ratio of coenzyme Q10 and cyclodextrin ensures that cyclodextrin sufficiently includes coenzyme Q10, while avoiding excessive multi-layer coating or forming self-aggregates, which hinders the dissolution of coenzyme Q10.

[0025] A cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 is prepared by using the preparation method described in any of the above technical solutions.

[0026] Due to the adoption of the above preparation method in this embodiment, the obtained cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 has the advantages of high inclusion rate and good long-term storage stability.

[0027] An application of the cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 described in any of the above technical solutions in the preparation of drugs, health products, or foods containing coenzyme Q10.

[0028] Due to the adoption of the above cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 in this embodiment, the obtained drugs, health products, or foods have the advantages of high coenzyme Q10 content and good long-term storage stability.

[0029] This application has the following advantages and positive effects compared with the prior art: The researchers of this application unexpectedly found in the experiment that after the coenzyme Q10 solution is ultrasonically treated, cooled, and included with the cyclodextrin derivative solution, by adding corn starch, it has the advantages of improving the inclusion effect and good long-term storage stability. Description of the Drawings

[0030] To more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the following will briefly introduce the accompanying drawings required for the description of the specific embodiments or the prior art. Obviously, the accompanying drawings in the following description are some embodiments of the present application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0031] Figure 1 It is the infrared spectrum diagram of the raw material coenzyme Q10 of the embodiment of the present application.

[0032] Figure 2 It is the infrared spectrum diagram of the raw material β-cyclodextrin of the embodiment of the present application.

[0033] Figure 3 It is the infrared spectrum diagram of the physical mixture of the raw material coenzyme Q10 and β-cyclodextrin and corn starch of the embodiment of the present application.

[0034] Figure 4 It is the infrared spectrum diagram of the cyclodextrin derivative inclusion complex of coenzyme Q10 of Example 1 of the present application.

[0035] Figure 5 It is the infrared spectrum diagram of the cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 of Example 1 of the present application. Specific Embodiments

[0036] The following further elaborates the present application in combination with the embodiments and examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. In addition, it should be understood that after reading the content taught in the present application, those skilled in the art can make various changes or modifications to the present application, and these equivalent forms also fall within the protection scope of the appended claims of the present application.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present application belongs. The terms used in the specification of the present application herein are only for the purpose of describing specific embodiments and are not intended to limit the present application.

[0038] The selection range of the term "and / or" used herein includes any one of two or more related listed items, and also includes any and all combinations of the related listed items. The said any and all combinations include any two related listed items, any more related listed items, or the combination of all related listed items.

[0039] As used herein, the term "and / or" includes any one of two or more related listed items, as well as any and all combinations of the related listed items. The any and all combinations include combinations of any two related listed items, any more related listed items, or all related listed items.

[0040] In this application, "first", "second", "third", "fourth", etc. are only for descriptive purposes and cannot be construed as indicating or implying relative importance or quantity, nor can they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumerative description and should be understood not to constitute a closed limitation on quantity.

[0041] In this application, among the technically characterized features described in an open-ended manner, it includes a closed technical solution composed of the listed features, as well as an open technical solution containing the listed features.

[0042] In this application, regarding numerical intervals (i.e., numerical ranges), unless otherwise specified, the selectable numerical values are considered continuous within the above numerical intervals, and include the two numerical endpoints of the numerical range (i.e., the minimum value and the maximum value), as well as each numerical value between these two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers within the numerical interval, it includes the two endpoint integers of the numerical range, as well as each integer between the two endpoints. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0043] For the temperature parameter in this application, unless otherwise specified, it allows both constant temperature treatment and fluctuations within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument.

[0044] In this application, the weight can be μg, mg, g, kg, etc., which are well-known mass units in the fields of pharmaceuticals, health products, or foods.

[0045] Most of the existing preparation methods of coenzyme Q10 cyclodextrin inclusion complexes can only include the head of coenzyme Q10. However, due to the large volume and strong flexibility of the tail, it is difficult to completely embed it into the cyclodextrin cavity. The unincluded tail may induce the precipitation of the head, affecting the storage stability of the inclusion complex.

[0046] To solve the above problems, the technical solution of the embodiment of this application provides a preparation method of a coenzyme Q10 cyclodextrin derivative corn starch inclusion complex. This preparation method can also include the tail, and has good long-term storage stability.

[0047] The preparation method of the cyclodextrin inclusion complex of coenzyme Q10 according to the embodiment of the present application comprises the following steps: Dissolve coenzyme Q10 in an aqueous solution of alcohol to obtain a first solution; Perform ultrasonic treatment on the first solution at 40°C to 45°C to obtain a second solution; Perform a cooling treatment on the second solution to obtain a third solution; Add a cyclodextrin derivative solution to the third solution and mix to obtain a fourth solution; Add corn starch to the fourth solution, stir and react, and then remove the solvent to obtain a coenzyme Q10 cyclodextrin derivative corn starch inclusion complex.

[0048] In the preparation method of the cyclodextrin inclusion complex of coenzyme Q10 according to the embodiment of the present application, first dissolve coenzyme Q10 in an aqueous solution of alcohol. Alcohol can dissolve the head of coenzyme Q10, forcing the hydrophobic long chain to fold inward. After dissolution, perform ultrasonic treatment at 40 - 45°C. The thermal effect is used to reduce intermolecular aggregation, and at the same time, the ultrasonic cavitation effect destroys the extended state of the long chain and induces the initial folding of the tail. Then perform a cooling treatment. Through low-temperature driving, the long alkane chain of coenzyme Q10 is further folded and the folded conformation is frozen to avoid random aggregation of the tail. Then add an aqueous solution of cyclodextrin to the coenzyme Q10 solution treated above. Due to the presence of a large amount of organic solvent in the system, the high concentration of organic solvent reduces the solubility of cyclodextrin. It was unexpectedly found in the research process of the present application that by adding starch and stirring and reacting, it can prompt its hydrophobic cavity to actively capture the folded coenzyme Q10, and the tail is embedded in the periphery of the cavity through hydrophobic interaction to form a head-tail double inclusion structure. After the inclusion complex is formed, it will spontaneously precipitate due to low solubility, achieving a high encapsulation rate and stable conformation locking, thereby significantly improving the storage stability and dissolution performance. The above preparation method can also coat the tail of coenzyme Q10 in cyclodextrin, with good long-term storage stability, simple operation, no need to use special instruments, low cost, and is suitable for industrial production.

[0049] In the technical solution of the embodiment of the present application, an appropriate proportion of alcohol dissolves the benzoquinone head of coenzyme Q10, and water increases the polarity of the system, forcing the hydrophobic long chain to fold inward.

[0050] In some embodiments, the volume proportion of alcohol in the aqueous solution of alcohol is 60% - 80%.

[0051] In this embodiment, the alcohol-water proportion of the aqueous solution of alcohol is in a more appropriate range, which can not only dissolve the head of coenzyme Q10, but also force the tail to fold through the driving force of the water phase, avoiding the inhibition of cyclodextrin dissolution caused by too high alcohol concentration or insufficient folding caused by too low alcohol concentration.

[0052] In some embodiments, the concentration of coenzyme Q10 in the first solution is 0.1% - 0.5%, which can be fully dissolved and is beneficial to conformation folding.

[0053] Further, the step of subjecting the first solution to ultrasonic treatment at 40°C to 45°C to obtain a second solution includes: Heating the first solution to 40°C to 45°C and then ultrasonically treating it at a first power and a first frequency for a first time to obtain a second solution; wherein the first power is 150 W to 250 W, the first frequency is 25 Hz to 35 Hz, and the first time is 30 min to 60 min.

[0054] In this embodiment, under the heating condition of 40°C to 45°C, ultrasonic treatment is carried out for 30 min to 60 min under suitable conditions. Moderate heating can reduce the intermolecular aggregation of coenzyme Q10, and at the same time, the cavitation effect of ultrasonic waves is used to destroy the extended state of the long chain and promote intramolecular folding.

[0055] Further, the step of cooling the second solution to obtain a third solution includes: Cooling the second solution to a second temperature at a first rate, maintaining it for a second time, and then reducing it to a third temperature at a second rate to obtain a third solution; wherein the first rate and the second rate are each independently selected from 5°C / min to 10°C / min; the second temperature is 30°C to 35°C, the second time is 1 min to 2 min, and the third temperature is 20°C to 25°C.

[0056] In the technical solution of the embodiment of the present application, the well-dispersed coenzyme Q10 is subjected to a cooling treatment, and the folded conformation is "frozen" by rapid cooling to fix the relative positions of the long tail chain and benzoquinone. However, if the cooling is too fast, the long chain of coenzyme Q10 may randomly aggregate through hydrophobic interactions, resulting in precipitation. In this embodiment, after cooling to the second temperature at the first rate, maintaining it for the second time, and then reducing it to the third temperature at the second rate, it helps the directional folding of the long chain of coenzyme Q10.

[0057] In this embodiment, the second solution avoids random aggregation caused by rapid cooling and directionally "freezes" the folded conformation by controlling the cooling rate (5°C / min to 10°C / min) and intermediate heat preservation (maintaining at 30°C to 35°C for 1 - 2 min), thereby improving the integrity of the tail inclusion.

[0058] Further, the step of adding an aqueous solution of cyclodextrin to the third solution and mixing to obtain a cyclodextrin inclusion complex of coenzyme Q10 includes: Adding the aqueous solution of cyclodextrin to the third solution at a third rate, and stirring for a third time to obtain a cyclodextrin derivative inclusion complex of coenzyme Q10; Among them, the third rate is 0.5 mL / min to 1.5 mL / min; the third time is 1 h to 3 h; the mass concentration of the aqueous solution of cyclodextrin is 5% to 10%; the mass concentration of the third solution is 0.5% to 1%.

[0059] In this embodiment, adding the aqueous solution of cyclodextrin to the third solution at an appropriate rate can avoid local supersaturation and ensure the uniform formation of the inclusion complex. Further, the rotation speed of stirring is 500 rpm to 700 rpm.

[0060] In this embodiment, an appropriate stirring rotation speed can promote the full contact between cyclodextrin and coenzyme Q10, ensure the uniform formation of the inclusion complex, and prevent the polymerization of the tail of coenzyme Q10 caused by too fast mechanical stirring.

[0061] Further, corn starch is added to the fourth solution, and after stirring and reacting, the solvent is removed to obtain a coenzyme Q10 cyclodextrin derivative corn starch inclusion complex. After stirring for the fourth time, the solvent is removed to obtain the cyclodextrin starch inclusion complex of coenzyme Q10; Among them, the fourth time is 3 h to 7 h; the rotation speed of the stirring is 500 rpm to 700 rpm.

[0062] Among them, the methods for removing the solvent include oven drying, vacuum drying, spray drying, and freeze drying.

[0063] The cyclodextrin derivative includes one or several of β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl cyclodextrin, sulfobutyl cyclodextrin, and γ-cyclodextrin.

[0064] In this embodiment, the cavity size and hydrophobicity of β-cyclodextrin, γ-cyclodextrin or their derivatives are more suitable for the folded conformation of coenzyme Q10, which helps to improve the compatibility of the inclusion of coenzyme Q10 and cyclodextrin.

[0065] In some embodiments, the weight ratio of coenzyme Q10 to cyclodextrin is 1:(1 to 10).

[0066] In this embodiment, an appropriate weight ratio of coenzyme Q10 to cyclodextrin ensures that cyclodextrin sufficiently includes coenzyme Q10, while avoiding excessive multi-layer coating or the formation of self-aggregates, which hinders the dissolution of coenzyme Q10.

[0067] The technical solution of the embodiment of the present application also provides a cyclodextrin inclusion complex of coenzyme Q10, which is prepared by using the preparation method of any of the above technical solutions.

[0068] In this embodiment, the cyclodextrin inclusion complex of coenzyme Q10 prepared in the above manner can fully include the tail of coenzyme Q10, and the long-term storage stability is significantly improved.

[0069] The technical solution of the embodiment of the present application also provides an application of the cyclodextrin inclusion complex of coenzyme Q10 in any of the above technical solutions in the preparation of drugs, health products or foods containing coenzyme Q10.

[0070] Since the above cyclodextrin inclusion complex of coenzyme Q10 is adopted in this embodiment, the obtained drugs, health products or foods have the advantages of high coenzyme Q10 content and good long-term storage stability.

[0071] In some embodiments, the cyclodextrin inclusion complex of coenzyme Q10 is in powder form.

[0072] In some embodiments, the drug, health product or food is a capsule, and the core of the capsule is a powder obtained by formulating the cyclodextrin inclusion complex of coenzyme Q10 and its excipients. The above excipients can be independently selected from the excipients commonly used in the fields of drugs, health products or foods.

[0073] The following are some specific examples For the experimental parameters not specified in the following specific examples, preferably refer to the guidance given in the present application document, and can also refer to the experimental manuals in the art or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturers.

[0074] The raw materials and reagents involved in the following specific examples can be obtained commercially, or those skilled in the art can prepare them according to known means.

[0075] Among the raw materials used in the following examples, the infrared spectrum of coenzyme Q10 is Figure 1 , and the infrared spectrum of β-cyclodextrin is Figure 2 , and the infrared spectrum of the physical mixture of coenzyme Q10, β-cyclodextrin and corn starch is as Figure 3 .

[0076] I. Preparation of coenzyme Q10 cyclodextrin derivative corn starch inclusion complex Example

[0077] This example provides a preparation method of the coenzyme Q10 cyclodextrin derivative corn starch inclusion complex of the present application, and the steps are as follows: (1) Take 100 mg of coenzyme Q10 and dissolve it in 20 mL of a mixed solvent of ethanol:water = 7:3 (v / v), and stir until completely dissolved.

[0078] (2) Preheat the solution in step (1) to 40 °C and keep it, and perform ultrasonic treatment (200 W, 30 kHz; 45 min).

[0079] (3) Cool the solution in step (2) to 35 °C at a rate of 5 °C / min, keep it warm for 2 minutes; then cool it to 25 °C at a rate of 10 °C / min.

[0080] (4) Prepare a solution of 100 mg of hydroxypropyl-β-cyclodextrin (HP-β-CD) with a mass concentration of 10% for standby. Maintain the solution in step (3) at 500 rpm for stirring, and inject the HP-β-CD aqueous solution into the above-mentioned stirred solution with a syringe at a controlled rate and amount. The injection rate is 1 mL / min. After the injection amount reaches 10 mL, stir for 2 h. After vacuum drying the solution in this step, a cyclodextrin derivative inclusion complex of coenzyme Q10 is obtained. The infrared spectrum is shown in Figure 4 .

[0081] (5) Add 300 mg of corn starch to the solution obtained in step (4), rotate at 500 rpm, and stir for 3 h.

[0082] (6) After vacuum drying the solution obtained in step (5), a cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 is obtained.

[0083] Example 2 This example provides a method for preparing a cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 of the present application. The steps are basically the same as those in Example 1, except that in step (1), ethanol:water = 5:5 (v / v).

[0084] Example 3 This example provides a method for preparing a cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 of the present application. The steps are basically the same as those in Example 1, except that in step (2), the power of ultrasonic wave is 300 W, the frequency is 50 kHz, and the time is shortened to 20 min.

[0085] Example 4 This example provides a method for preparing a cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 of the present application. The steps are basically the same as those in Example 1, except that in step (3), the temperature is directly decreased from 40 °C to 25 °C at 10 °C / min.

[0086] Example 5 This example provides a method for preparing a cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 of the present application. The steps are basically the same as those in Example 1, except that in step (4), the injection rate is 0.1 mL / min.

[0087] Example 6 This example provides a method for preparing a cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 of the present application. The steps are as follows: (1) Take 100 mg of coenzyme Q10 and dissolve it in 20 mL of a mixed solvent of ethanol:water = 7:3 (v / v), and stir until completely dissolved.

[0088] (2) Preheat the solution in step (1) to 40 °C and maintain it, then perform ultrasonic treatment (200 W, 30 kHz; 45 min).

[0089] (3) Cool the solution in step (2) to 35 °C at a rate of 5 °C / min, keep it warm for 2 minutes; then cool it to 25 °C at a rate of 10 °C / min.

[0090] (4) Prepare a 5% (mass concentration) solution of 200 mg of β-cyclodextrin (β-CD) for standby. Maintain the solution in step (3) at 700 rpm for stirring, and inject the β-CD aqueous solution into the above-mentioned stirred solution with a syringe at a controllable speed and amount. The injection rate is 1 mL / min. After injecting 10 mL, stir for 2 h.

[0091] (5) Add 1000 mg of corn starch, rotate at 700 rpm, and stir for 7 h.

[0092] (6) After drying the above solution in an oven, obtain the cyclodextrin derivative corn starch inclusion complex of coenzyme Q10.

[0093] Example 7 This example provides a preparation method of the cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 of the present application. The steps are basically the same as those in Example 6, except that: the cyclodextrin derivative used is γ-cyclodextrin, and 300 mg of γ-cyclodextrin is used in step (4); 500 mg of corn starch is added in step (5), the rotation speed is 600 rpm, and stir for 5 h; freeze-drying is adopted in step (6).

[0094] Example 8 This example provides a preparation method of the cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 of the present application. The steps are basically the same as those in Example 6, except that: the cyclodextrin derivative used is methyl cyclodextrin, and 400 mg of γ-cyclodextrin is used in step (4); 400 mg of corn starch is added in step (5), the rotation speed is 500 rpm, and stir for 6 h; spray drying is adopted in step (6).

[0095] Example 9 This example provides a preparation method of the cyclodextrin derivative corn starch inclusion complex of coenzyme Q10 of the present application. The steps are basically the same as those in Example 6, except that: the cyclodextrin derivatives used are sulfobutyl cyclodextrin and γ-cyclodextrin, 900 mg of sulfobutyl cyclodextrin and 100 mg of γ-cyclodextrin are used in step (4); 500 mg of corn starch is added in step (5), the rotation speed is 500 rpm, and stir for 6 h; oven drying is adopted in step (6).

[0096] Comparative Example 1 This comparative example provides another preparation method of a cyclodextrin derivative corn starch inclusion complex of coenzyme Q10. The steps are basically the same as those in Example 1, except that: in step (2), the solution in step (1) is preheated to 60 °C.

[0097] Comparative Example 2 This comparative example provides another preparation method of a cyclodextrin derivative corn starch inclusion complex of coenzyme Q10. The steps are basically the same as those in Example 1, except that: in step (2), ultrasonic treatment is not carried out.

[0098] Comparative Example 3 This comparative example provides another preparation method of a cyclodextrin derivative corn starch inclusion complex of coenzyme Q10. The steps are basically the same as those in Example 1, except that: in step (2), there is no heating, only ultrasonic treatment is carried out, and the cooling treatment in step (3) is not carried out.

[0099] Comparative Example 4 This comparative example provides another preparation method of a cyclodextrin derivative inclusion complex of coenzyme Q10. The steps are basically the same as those in Example 6, except that: in step (4), the inclusion complex of coenzyme Q10 and β-cyclodextrin is directly obtained by spray drying.

[0100] Comparative Example 5 This comparative example provides the infrared spectrum scanning situation of a coenzyme Q10 raw material drug directly pressed into tablets with potassium bromide, as shown in Figure 1 .

[0101] Comparative Example 6 This comparative example provides the infrared spectrum scanning situation of β-cyclodextrin directly pressed into tablets with potassium bromide, as shown in Figure 2 .

[0102] Comparative Example 7 This comparative example provides the infrared spectrum scanning situation of the physical mixture of coenzyme Q10, β-cyclodextrin and corn starch, as shown in Figure 3 .

[0103] Comparative Example 8 This comparative example provides the infrared spectrum of the coenzyme Q10 and β-cyclodextrin inclusion complex in Comparative Example 4, as shown in Figure 4 .

[0104] Comparative Example 9 This comparative example provides the infrared spectrum of the coenzyme Q10 and β-cyclodextrin corn starch inclusion complex in Example 6, as shown in Figure 5 .

[0105] II. Performance Test of Cyclodextrin Inclusion Complex of Coenzyme Q10 1. Particle Size and Dispersibility Table 1 Average particle size and polydispersity index (PDI) of each embodiment and comparative example

[0106] According to Table 1, the particle size distribution of the embodiment of the present application is in a suitable range, indicating that the inclusion is complete and the dispersion is uniform. Due to the high temperature, irreversible aggregates appear in Comparative Example 1, the average particle size becomes larger, and the particle size distribution is uneven. Due to the insufficient folding degree of the long chain in Comparative Example 2, the tail is exposed and aggregation occurs, the average particle size becomes significantly larger, and the particle size distribution is uneven. The long chain of Comparative Example 3 is completely relaxed, forming larger micelles, the particle size distribution is uneven, and the average particle size increases.

[0107] 2. Stability test Accelerated test: Store at 40℃ / 75% RH for 30 days and check the precipitation regularly.

[0108] Long-term stability test: 6 months storage at 25℃ / 60% RH.

[0109] Table 2 Stability test results of various embodiments and comparative examples

[0110] According to Table 2, the precipitation degree of the examples of the present application in the accelerated test and the long-term stability test is consistent, indicating that the tail is completely included and will not precipitate due to long-term storage. The precipitation of Comparative Example 1 is not obvious, which is basically the same as the example. Comparative Example 2 is not ultrasonically treated, the long chain folding degree is not enough, and the stability is not as good as the example. Comparative Example 3 is almost not folded, and the stability is poor.

[0111] 3. Dissolution test Conditions: 900 mL pH 6.8 phosphate buffer, 37°C, 50 rpm (paddle method).

[0112] Sampling points: 5, 15, 60 minutes, dissolution was determined by HPLC.

[0113] Table 3 Dissolution test results of various embodiments and comparative examples

[0114] According to Table 3, the embodiments of the present application can basically achieve rapid release, and the dissolution rate is greater than 90% after 60 minutes.

[0115] All documents mentioned in this application are incorporated herein by reference as if each document was individually incorporated by reference. Unless it conflicts with the purpose and / or technical solution of this application, the cited documents involved in this application are incorporated by reference in their entirety and for all purposes. When referring to cited documents in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also incorporated by reference. When referring to cited documents in this application, the examples and preferred ways of the relevant technical features cited can also be incorporated as references into this application, but only to the extent that this application can be implemented. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or be amended adaptively according to the description in this application.

[0116] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity of description, not all possible combinations of the various technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered to be within the scope described in this specification.

[0117] The above-described examples only represent several embodiments of this application, but should not be construed as limiting the scope of the patent application. It should be noted that for those of ordinary skill in the art, without departing from the concept of this application, several modifications and improvements can still be made, and these all fall within the protection scope of this application. In addition, it should be understood that after reading the above teachings of this application, those skilled in the art can make various changes or modifications to this application, and the equivalent forms obtained also fall within the protection scope of this application. It should also be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments based on the technical solutions provided in this application are all within the protection scope of the appended claims of this application. Therefore, the protection scope of this patent application shall be subject to the appended claims, and the specification can be used to explain the content of the claims.

Claims

1. A preparation method of a cyclodextrin derivative corn starch inclusion complex of coenzyme Q10, characterized in that, It includes the following steps: Prepare a first solution by mixing coenzyme Q10 with an alcohol solution; Ultrasonically treat the first solution at 40°C to 45°C; Cool the second solution to obtain a third solution; Add a cyclodextrin derivative solution to the third solution to obtain a fourth solution; Add corn starch to the fourth solution, stir and react, then remove the solvent to obtain a coenzyme Q10 cyclodextrin derivative corn starch inclusion complex.

2. The preparation method according to claim 1, wherein The step of ultrasonically treating the first solution at 40°C to 45°C to obtain a second solution includes: Heat the first solution to 40°C to 45°C, and then ultrasonically treat it at a first power and a first frequency for a first time to obtain the second solution; Wherein, the first power is 150W to 250W, the first frequency is 25kHz to 35kHz, and the first time is 30min to 60min.

3. The preparation method according to claim 1, characterized in that, The step of cooling the second solution to obtain a third solution includes: Cool the second solution to a second temperature at a first rate, maintain it for a second time, and then reduce it to a third temperature at a second rate to obtain the third solution; Wherein, the first rate and the second rate are each independently selected from 5°C / min to 10°C / min; The second temperature is 30°C to 35°C, the second time is 1min to 2min, and the third temperature is 20°C to 25°C.

4. The preparation method according to claim 1, characterized in that, The step of adding a cyclodextrin derivative solution to the third solution to obtain a fourth solution includes: Add the cyclodextrin derivative solution to the third solution at a third rate, stir for a third time, and then obtain the fourth solution; Wherein, the third rate is 0.5mL / min to 1.5mL / min; the third time is 1h to 3h; the rotation speed of the stirring is 500rpm to 700rpm.

5. The preparation method according to claim 1, wherein The step of adding corn starch to the fourth solution, stirring and reacting, and then removing the solvent to obtain the product includes: Add corn starch to the third solution, stir for a fourth time, and then remove the solvent to obtain the coenzyme Q10 cyclodextrin starch inclusion complex; Wherein, the fourth time is 3h to 7h; the rotation speed of the stirring is 500rpm to 700rpm.

6. The preparation method according to claim 5, characterized in that, The methods for removing the solvent include oven drying, vacuum drying, spray drying, and freeze drying.

7. The preparation method according to any one of claims 1 to 5, characterized in that, The weight ratio of coenzyme Q10 to cyclodextrin derivative and corn starch is 1:(1 - 10):(3 - 10).

8. The preparation method according to any one of claims 1 to 5, characterized in that, The cyclodextrin derivative includes one or more of β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl cyclodextrin, sulfobutyl cyclodextrin, and γ-cyclodextrin.

9. A cyclodextrin inclusion compound of coenzyme Q10, characterized in that, It is prepared by using the preparation method described in any one of claims 1 to 8.

10. Use of the coenzyme Q10 cyclodextrin inclusion complex described in claim 9 in the preparation of a medicament, health product, or food containing coenzyme Q10.

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