Coenzyme q10 cyclodextrin corn starch inclusion compound and preparation method and application thereof

Abstract

The application relates to the technical field of inclusion compounds, in particular to a coenzyme Q10-cyclodextrin inclusion compound and a preparation method and application thereof, which comprises the following steps: dissolving coenzyme Q10 in an alcohol aqueous solution to obtain a first solution; performing ultrasonic treatment on the first solution at 40 DEG C-45 DEG C to obtain a second solution; performing cooling treatment on the second solution to obtain a third solution; adding a cyclodextrin derivative solution into the third solution to mix, and obtaining a fourth solution of the coenzyme Q10-cyclodextrin inclusion compound; adding corn starch into the fourth solution, stirring and reacting, removing a solvent, and obtaining a coenzyme Q10-cyclodextrin derivative corn starch inclusion compound. The preparation method has the advantages of simple operation and high encapsulation rate, 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 complexes, in particular to a cyclodextrin corn starch inclusion complex of coenzyme Q10 and a preparation method and application thereof. BACKGROUND

[0002] Coenzyme Q10 (CoQ10) is a naturally occurring quinone compound in the human body. Coenzyme Q10 is a key component of the mitochondrial electron transport chain and is involved in the generation of cellular energy (ATP). It is particularly important for high-energy 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 improve myocardial metabolic volume, and is used to treat heart failure, hypertension, and other cardiovascular diseases.

[0003] Coenzyme Q10 is composed of a benzoquinone (head) and a long-chain hydrocarbon (tail) and is a lipophilic compound. It is easily soluble in lipid solvents and almost insoluble in water, with low oral absorption. Cyclodextrin is a commonly used inclusion agent that is inexpensive and has good inclusion effects. Using cyclodextrin for inclusion can improve the water solubility of coenzyme Q10 and improve its bioavailability. However, when using cyclodextrin for inclusion, the size of the cyclodextrin cavity is limited, and usually only the head of coenzyme Q10 can be included. The tail, which is bulky and flexible, cannot be completely embedded in the cyclodextrin cavity, and the un-included tail may induce the head to precipitate, affecting the storage stability of the inclusion complex. Some methods propose using a double-layer coating method to solve the above problems, which first coats the head with cyclodextrin and then coats the tail with another inclusion agent. However, this method is complicated and costly.

[0004] Therefore, it is necessary to develop a simple cyclodextrin inclusion process with good long-term storage stability. SUMMARY

[0005] Therefore, it is necessary to develop a simple cyclodextrin inclusion process with good long-term storage stability.

[0006] The technical solution of the present application is as follows:

[0007] A preparation method of a cyclodextrin derivative corn inclusion complex of coenzyme Q10, comprising the following steps:

[0008] Dissolve coenzyme Q10 in an alcohol aqueous solution to obtain a first solution;

[0009] Ultrasonically treat the first solution at 40-45℃ to obtain a second solution;

[0010] cooling the first solution to obtain a third solution;

[0011] adding a cyclodextrin derivative solution to the third solution to obtain a fourth solution;

[0012] adding corn starch to the fourth solution, stirring and reacting, and then removing the solvent to obtain a coenzyme Q10 cyclodextrin derivative corn starch inclusion compound.

[0013] The preparation method of the coenzyme Q10 cyclodextrin inclusion compound of the embodiment of the application first dissolves coenzyme Q10 in an alcohol aqueous solution. The alcohol can dissolve the head of coenzyme Q10, forcing the hydrophobic long chain to fold inward. After dissolution, ultrasonic treatment is performed at 40-45°C. The thermal effect is used to reduce intermolecular aggregation, and the ultrasonic cavitation effect is used to destroy the stretched state of the long chain, inducing the tail to be preliminarily folded. Then, cooling treatment is performed. The low temperature drives the long alkyl chain of coenzyme Q10 to further fold and freeze the folded conformation, avoiding random aggregation of the tail. Then, a cyclodextrin derivative solution is added to the coenzyme Q10 solution after the above treatment. Because a large amount of organic solvent exists in the system, the high-concentration organic solvent reduces the solubility of cyclodextrin. It is accidentally found in the research process that, by adding corn starch and stirring and reacting, the hydrophobic cavity can actively capture the folded coenzyme Q10. The tail is embedded in the periphery of the cavity through hydrophobic interaction, forming a head-tail double inclusion structure. The inclusion compound is spontaneously precipitated due to low solubility after the formation of the inclusion compound, realizing high encapsulation efficiency and stable conformational locking, thereby significantly improving the storage stability and dissolution performance. The above preparation method can also coat the tail of coenzyme Q10 in cyclodextrin. The long-term storage stability is good, the operation is simple, special instruments are not required, the cost is low, and the method is suitable for industrial production.

[0014] Further, the step of ultrasonic treatment of the first solution at 40-45°C to obtain the second solution comprises:

[0015] After heating the first solution to 40-45°C, ultrasonic treatment is performed at a first power and a first frequency for a first time to obtain the second solution.

[0016] The first power is 150-250 W, the first frequency is 25-35 kHz, and the first time is 30-60 min.

[0017] In this embodiment, the first solution is ultrasonically treated at a suitable temperature to ensure that the ultrasonic cavitation effect is sufficient to destroy the intermolecular forces of coenzyme Q10, while avoiding excessive energy damage to the molecular structure. A suitable treatment time can balance the folding efficiency and energy consumption to ensure that the tail is fully folded inward.

[0018] Further, the step of cooling the second solution to obtain the third solution comprises:

[0019] cooling the first solution to a second temperature at a first rate, maintaining the second temperature for a second time, and then cooling the first solution to a third temperature at a second rate to obtain the third solution;

[0020] The first rate and the second rate are independently selected from 5℃ / min ~10℃ / min.

[0021] The second temperature is 30℃ ~35℃, the second time is 1min ~2min, and the third temperature is 20℃ ~25℃.

[0022] In this embodiment, the second solution is obtained by controlling the cooling rate (5℃ / min ~10℃ / min) and the intermediate holding (30℃ ~35℃ for 1min-2min), which avoids random aggregation caused by rapid cooling, and directs the "frozen" folding conformation, thereby improving the integrity of the tail inclusion.

[0023] Further, the step of adding an aqueous solution of cyclodextrin to the third solution to obtain a coenzyme Q10 cyclodextrin derivative inclusion compound includes:

[0024] The aqueous solution of cyclodextrin is added to the third solution at a third rate, and after stirring for a third time, a fourth solution of coenzyme Q10 cyclodextrin inclusion compound is obtained.

[0025] The third rate is 0.5mL / min ~1.5mL / min, and the third time is 1h ~3h.

[0026] In this embodiment, the aqueous solution of cyclodextrin is added to the third solution at a suitable rate, which can avoid local supersaturation and ensure uniform formation of the inclusion compound.

[0027] Further, the stirring speed is 500rpm ~700rpm.

[0028] In this embodiment, a suitable stirring speed can promote sufficient contact between cyclodextrin and coenzyme Q10, ensure uniform formation of the inclusion compound, and prevent coenzyme Q10 tail aggregation caused by excessive mechanical stirring.

[0029] In some embodiments, the volume fraction of alcohol in the aqueous alcohol solution is 60% ~80%.

[0030] In this embodiment, the aqueous solution of cyclodextrin is added to the third solution at a suitable rate, which can avoid local supersaturation and ensure uniform formation of the inclusion compound.

[0031] In this embodiment, the alcohol-water ratio of the alcohol solution is in a more suitable range, which not only dissolves the head of coenzyme Q10, but also forces the tail to fold through the driving force of the aqueous phase, avoiding the inhibition of cyclodextrin dissolution caused by too high alcohol concentration or insufficient folding caused by too low alcohol concentration.

[0032] Further, corn starch is added to the fourth solution, and after stirring and reaction, the solvent is removed to obtain a coenzyme Q10 cyclodextrin derivative corn starch inclusion compound. After stirring for a fourth time, the solvent is removed to obtain the coenzyme Q10 cyclodextrin starch inclusion compound;

[0033] The fourth time is 3h-7h, and the stirring speed is 500rpm-700rpm.

[0034] The method for removing the solvent includes oven drying, vacuum drying, spray drying, and freeze drying.

[0035] In some embodiments, the cyclodextrin derivative includes one or more of β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl cyclodextrin, sulfobutyl cyclodextrin, and γ-cyclodextrin.

[0036] In this embodiment, the cavity size of β-cyclodextrin, γ-cyclodextrin, or its derivative is more suitable for the folding conformation of coenzyme Q10, which helps to improve the adaptability of coenzyme Q10 and cyclodextrin inclusion.

[0037] In some embodiments, the weight ratio of coenzyme Q10 to cyclodextrin derivative and corn starch is (1-10):(3-10).

[0038] In this embodiment, the appropriate weight ratio of coenzyme Q10 and cyclodextrin ensures that the cyclodextrin is sufficient to include coenzyme Q10, while avoiding excessive multilayer coating or forming self-aggregates that hinder the dissolution of coenzyme Q10.

[0039] A coenzyme Q10 cyclodextrin derivative corn starch inclusion compound is prepared by the preparation method of any one of the above technical solutions.

[0040] Due to the use of the above preparation method, the coenzyme Q10 cyclodextrin derivative corn starch inclusion compound obtained has the advantages of high inclusion rate and good long-term storage stability.

[0041] The coenzyme Q10 cyclodextrin derivative corn starch inclusion compound of any one of the above technical solutions is used in the preparation of a medicine, health care product, or food containing coenzyme Q10.

[0042] Due to the use of the above coenzyme Q10 cyclodextrin derivative corn starch inclusion compound, the medicine, health care product, or food obtained has the advantages of high coenzyme Q10 content and good long-term storage stability.

[0043] Compared with the prior art, the present application has the following advantages and positive effects:

[0044] The present application researchers surprisingly found in the experiment that after the coenzyme Q10 solution is treated by ultrasonic, cooled, and then complexed with the cyclodextrin derivative solution, by adding corn starch, the complexing effect can be improved and the long-term storage stability is good. BRIEF DESCRIPTION OF DRAWINGS

[0045] In order to more clearly illustrate the technical solutions in the prior art or the specific embodiments of the present application, the drawings needed to be used in the description of the specific embodiments or the prior art will be briefly introduced. Obviously, the drawings in the following description are some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor.

[0046] Figure 1 The infrared spectrum of the raw material coenzyme Q10 of the embodiment of the present application.

[0047] Figure 2 The infrared spectrum of the raw material β-cyclodextrin of the embodiment of the present application.

[0048] Figure 3 The infrared spectrum of the raw material coenzyme Q10 and β-cyclodextrin, corn starch physical mixture of the embodiment of the present application.

[0049] Figure 4 The infrared spectrum of the cyclodextrin derivative complex of coenzyme Q10 of Example 1 of the present application.

[0050] Figure 5 The infrared spectrum of the cyclodextrin derivative corn starch complex of coenzyme Q10 of Example 1 of the present application. DETAILED DESCRIPTION

[0051] The present application will be further described below in conjunction 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 by the present application, those skilled in the art can make various modifications or changes to the present application, and these equivalent forms also fall within the protection scope of the claims attached to the present application.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. The terms used in the specification of the present application are only for the purpose of describing the specific embodiments and are not intended to limit the present application.

[0053] The term "and / or", as used in the applications herein, includes a selection from a group of two or more terms that are conjunctively expressed. The conjunctive expression includes any one of the conjunctively expressed terms, as well as any and all combinations of the conjunctively expressed terms.

[0054] The term "and / or", as used in the applications herein, includes a selection from a group of two or more terms that are conjunctively expressed. The conjunctive expression includes any one of the conjunctively expressed terms, as well as any and all combinations of the conjunctively expressed terms.

[0055] In the present application, "first", "second", "third", "fourth" and the like are merely used for descriptive purposes, and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the technical features indicated. Moreover, "first", "second", "third", "fourth" and the like merely serve the purpose of non-exhaustive enumeration, and should be understood as not constituting a closed limitation on the quantity.

[0056] In the present application, the technical features described in an open manner include both closed technical solutions consisting of the enumerated features and open technical solutions containing the enumerated features.

[0057] In the present application, with respect to a numerical interval (i.e. a numerical range), if no special instructions are given, the optional numerical distribution within the numerical interval is considered to be continuous, and includes both numerical end points (i.e. the minimum value and the maximum value) of the numerical range and every numerical value between the two numerical end points. If no special instructions are given, when the numerical interval only refers to integers within the numerical interval, it includes both end point integers of the numerical range and every integer between the two end points. In addition, when multiple ranges are provided to describe a feature or a characteristic, 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 encompassed therein.

[0058] In the present application, the temperature parameter, if not specifically limited, allows for constant temperature treatment and also allows for fluctuations within a certain temperature interval. It should be understood that the constant temperature treatment allows for fluctuations within the accuracy range controlled by the instrument.

[0059] In the present application, the weight can be μg, mg, g, kg, etc. mass units commonly known in the field of pharmaceuticals, health products or food.

[0060] Most of the existing preparation methods of coenzyme Q10 cyclodextrin inclusion complex can only include the head of coenzyme Q10, and the tail is difficult to be completely embedded in the cyclodextrin cavity due to its large volume and strong flexibility, and the un-included tail may induce the head to precipitate, affecting the storage stability of the inclusion complex.

[0061] To solve the above problems, the technical scheme of the embodiment of the present application provides a preparation method of coenzyme Q10 cyclodextrin derivative corn starch inclusion complex, which can also include the tail, and has good long-term storage stability.

[0062] The preparation method of coenzyme Q10 cyclodextrin inclusion complex of the embodiment of the present application comprises the following steps:

[0063] Dissolve coenzyme Q10 in an alcohol aqueous solution to obtain a first solution;

[0064] Ultrasonically treat the first solution at 40-45 DEG C to obtain a second solution;

[0065] Cool the second solution to obtain a third solution;

[0066] Add a cyclodextrin derivative solution to the third solution to obtain a fourth solution;

[0067] Add corn starch to the fourth solution, stir and react, remove the solvent, and obtain a coenzyme Q10 cyclodextrin derivative corn starch inclusion complex.

[0068] The preparation method of coenzyme Q10 cyclodextrin inclusion complex of the embodiment of the present application first dissolves coenzyme Q10 in an alcohol aqueous solution, the alcohol can dissolve the head of coenzyme Q10, force the hydrophobic long chain to fold inward, after dissolution, ultrasonically treat at 40-45 DEG C, use the thermal effect to reduce the intermolecular aggregation, and the ultrasonic cavitation effect destroys the stretched state of the long chain, induces the tail to preliminarily fold, then cool, drive the long alkyl chain of coenzyme Q10 to further fold and freeze the folded conformation by low temperature, avoid the random aggregation of the tail, then add a cyclodextrin aqueous solution to the coenzyme Q10 solution after the above treatment, because there is a large amount of organic solvent in the system, the high concentration of organic solvent reduces the solubility of cyclodextrin, it is accidentally found in the research process that after stirring and reaction, the starch can promote the hydrophobic cavity to actively capture the folded coenzyme Q10, the tail is embedded in the periphery of the cavity by hydrophobic interaction, a head-tail double inclusion structure is formed, the inclusion complex is precipitated spontaneously due to low solubility after formation, realizes high encapsulation efficiency and stable conformational locking, thereby significantly improves 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, and is simple to operate, does not need to use special instruments, has low cost, and is suitable for industrial production.

[0069] In the technical scheme of the embodiment of the application, the alcohol with a suitable proportion dissolves the quinone head of coenzyme Q10, and water increases the polarity of the system, forcing the hydrophobic long chain to fold inward.

[0070] In some embodiments, the volume proportion of alcohol in the aqueous alcohol solution is 60% to 80%.

[0071] In this embodiment, the alcohol-water proportion of the aqueous alcohol solution is in a more suitable range, which not only dissolves the head of coenzyme Q10, but also forces the tail to fold by 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.

[0072] In some embodiments, the concentration of coenzyme Q10 in the first solution is 0.1% to 0.5%, which can be fully dissolved and conducive to conformational folding.

[0073] Further, the step of subjecting the first solution to ultrasonic treatment at 40℃ to 45℃ to obtain a second solution comprises:

[0074] After heating the first solution to 40℃ to 45℃, ultrasonic treatment is performed at a first power and a first frequency for a first time to obtain a second solution.

[0075] The first power is 150W to 250W, the first frequency is 25Hz to 35Hz, and the first time is 30min to 60min.

[0076] In this embodiment, under the heating condition of 40℃ to 45℃, ultrasonic treatment is performed for 30min to 60min under suitable conditions. Moderate heating can reduce the intermolecular aggregation of coenzyme Q10, and the cavitation effect of ultrasonic waves can destroy the stretched state of the long chain, promoting intramolecular folding.

[0077] Further, the step of subjecting the second solution to cooling treatment to obtain a third solution comprises:

[0078] After cooling the second solution to a second temperature at a first rate for a second time, and then reducing to a third temperature at a second rate, a third solution is obtained.

[0079] The first rate and the second rate are independently selected from 5℃ / min to 10℃ / min.

[0080] The second temperature is 30℃ to 35℃, the second time is 1min to 2min, and the third temperature is 20℃ to 25℃.

[0081] In the technical scheme of the embodiment of the present application, the fully dispersed coenzyme Q10 is treated by rapid cooling to "freeze" the folded conformation, fixing the relative position of the long tail and the benzoquinone. However, if the cooling rate is too fast, the long chain of coenzyme Q10 may randomly aggregate through hydrophobic interaction, resulting in precipitation. In this embodiment, the coenzyme Q10 is cooled at a first rate to a second temperature, maintained for a second time, and then cooled at a second rate to a third temperature, which helps to orient the folded conformation of coenzyme Q10 and improve the integrity of the tail inclusion.

[0082] In this embodiment, the second solution is cooled at a rate of 5℃ / min~10℃ / min and maintained at an intermediate temperature of 30℃~35℃ for 1-2min to avoid random aggregation caused by rapid cooling, orient the "frozen" folded conformation, and improve the integrity of the tail inclusion.

[0083] Further, the step of adding an aqueous solution of cyclodextrin to the third solution to obtain a coenzyme Q10 cyclodextrin inclusion compound includes:

[0084] The aqueous solution of cyclodextrin is added to the third solution at a third rate, and after stirring for a third time, a coenzyme Q10 cyclodextrin derivative inclusion compound is obtained.

[0085] The third rate is 0.5mL / min~1.5mL / min; the third time is 1h~3h; the mass concentration of the aqueous solution of cyclodextrin is 5%~10%; and the mass concentration of the third solution is 0.5%~1%.

[0086] In this embodiment, adding the aqueous solution of cyclodextrin to the third solution at a suitable rate can avoid local supersaturation and ensure uniform formation of the inclusion compound. Further, the stirring speed is 500rpm~700rpm.

[0087] In this embodiment, a suitable stirring speed can promote sufficient contact between cyclodextrin and coenzyme Q10, ensure uniform formation of the inclusion compound, and prevent aggregation of the tail of coenzyme Q10 caused by excessive mechanical stirring.

[0088] Further, corn starch is added to the fourth solution, stirred and reacted, and then the solvent is removed to obtain a coenzyme Q10 cyclodextrin derivative corn starch inclusion compound. After stirring for a fourth time, the solvent is removed to obtain the coenzyme Q10 cyclodextrin starch inclusion compound.

[0089] The fourth time is 3h~7h; and the stirring speed is 500rpm~700rpm.

[0090] The method for removing the solvent includes oven drying, vacuum drying, spray drying, and freeze drying.

[0091] The cyclodextrin derivative includes one or more of β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl cyclodextrin, sulfobutyl cyclodextrin, and γ-cyclodextrin.

[0092] In this embodiment, the cavity size of β-cyclodextrin, γ-cyclodextrin or its derivative is more suitable for the folding conformation of coenzyme Q10, which helps to improve the adaptability of coenzyme Q10 and cyclodextrin inclusion.

[0093] In some embodiments, the weight ratio of coenzyme Q10 and cyclodextrin is 1: (1-10).

[0094] In this embodiment, the appropriate weight ratio of coenzyme Q10 and cyclodextrin ensures that coenzyme Q10 is sufficiently included in cyclodextrin, while avoiding excessive multilayer coating or forming self-aggregates to hinder the dissolution of coenzyme Q10.

[0095] The technical scheme of the embodiment of the present application also provides a cyclodextrin inclusion compound of coenzyme Q10 prepared by the preparation method of any of the above technical schemes.

[0096] In this embodiment, the cyclodextrin inclusion compound of coenzyme Q10 can fully include the tail of coenzyme Q10 due to the use of the above method, and the long-term storage stability is obviously improved.

[0097] The technical scheme of the embodiment of the present application also provides an application of the cyclodextrin inclusion compound of coenzyme Q10 of any of the above technical schemes in the preparation of a medicine, health care product or food containing coenzyme Q10.

[0098] In this embodiment, the medicine, health care product or food obtained by using the cyclodextrin inclusion compound of coenzyme Q10 has the advantages of high coenzyme Q10 content and good long-term storage stability.

[0099] In some embodiments, the cyclodextrin inclusion compound of coenzyme Q10 is a powder.

[0100] In some embodiments, the medicine, health care product or food is a capsule, and the core of the capsule is a powder obtained by the cyclodextrin inclusion compound of coenzyme Q10 and a co-ingredient. The above co-ingredient can be independently selected from the co-ingredients commonly used in the field of medicine, health care product or food.

[0101] The following are some specific embodiments

[0102] In the following specific embodiments, the experimental parameters not written are preferably referred to the guidance given in the present application file, and can also be referred to the experimental manual in the art or other experimental methods known in the art, or to the experimental conditions recommended by the manufacturer.

[0103] The raw materials and reagents involved in the following specific examples can be obtained commercially or prepared by those skilled in the art according to known means.

[0104] The infrared spectrum of coenzyme Q10 used in the following examples is Figure 1 , the infrared spectrum of β-cyclodextrin is Figure 2 , and the infrared spectrum of the physical mixture of coenzyme Q10 and β-cyclodextrin and corn starch is Figure 3 .

[0105] I. Preparation of coenzyme Q10 cyclodextrin derivative corn starch inclusion compound Example

[0106] This example provides a method for preparing the coenzyme Q10 cyclodextrin derivative corn starch inclusion compound of the present application, the steps of which are as follows:

[0107] (1) Dissolve 100 mg of coenzyme Q10 in 20 mL of a mixed solvent of ethanol:water = 7:3 (v / v) and stir until completely dissolved.

[0108] (2) Preheat the solution of step (1) to 40°C and maintain, and perform ultrasonic treatment (200W, 30kHz; 45min).

[0109] (3) Cool the solution of step (2) to 35°C at a rate of 5°C / min, maintain for 2 minutes, and then cool to 25°C at a rate of 10°C / min.

[0110] (4) Prepare a solution of 100 mg of hydroxypropyl-β-cyclodextrin (HP-β-CD) with a mass concentration of 10% for use. Stir the solution of step (3) at 500 rpm, and inject the HP-β-CD aqueous solution into the above stirring solution at a controllable speed and amount using a syringe, at a rate of 1 mL / min. After injecting 10 mL, stir for 2 h. Vacuum dry the solution of this step to obtain the coenzyme Q10 cyclodextrin derivative inclusion compound, and the infrared spectrum is shown in Figure 4 .

[0111] (5) Add 300 mg of corn starch to the solution obtained in step (4) and stir at a speed of 500 rpm for 3 h.

[0112] (6) Vacuum dry the solution obtained in step (5) to obtain the coenzyme Q10 cyclodextrin derivative corn starch inclusion compound.

[0113] Example 2

[0114] The embodiment provides a preparation method of the cyclodextrin derivative corn starch inclusion compound of coenzyme Q10.

[0115] Example 3

[0116] The embodiment provides a preparation method of the cyclodextrin derivative corn starch inclusion compound of coenzyme Q10.

[0117] Example 4

[0118] The embodiment provides a preparation method of the cyclodextrin derivative corn starch inclusion compound of coenzyme Q10.

[0119] Example 5

[0120] The embodiment provides a preparation method of the cyclodextrin derivative corn starch inclusion compound of coenzyme Q10.

[0121] Example 6

[0122] The embodiment provides a preparation method of the cyclodextrin derivative corn starch inclusion compound of coenzyme Q10.

[0123] (1) 100 mg of coenzyme Q10 is dissolved in 20 mL of a mixed solvent of ethanol: water = 7:3 (v / v) and stirred until completely dissolved.

[0124] (2) The solution in step (1) is preheated to 40 DEG C and subjected to ultrasonic treatment (200 W, 30 kHz; 45 min).

[0125] (3) The solution in step (2) is cooled to 35 DEG C at a rate of 5 DEG C / min and kept for 2 min; and then cooled to 25 DEG C at a rate of 10 DEG C / min.

[0126] (4) 200 mg of β-cyclodextrin (β-CD) is configured into a solution with a mass concentration of 5% for standby use. The solution in step (3) is stirred at 700 rpm, and the β-CD aqueous solution is injected into the above stirring solution by using a syringe with controllable speed and quantity, the injection rate is 1 mL / min, and after 10 mL of injection, the stirring is performed for 2 h.

[0127] (5) Add 1000 mg of corn starch, rotate at 700 rpm, and stir for 7 h.

[0128] (6) After oven drying the above solution, a cyclodextrin derivative corn starch inclusion compound of coenzyme Q10 is obtained.

[0129] Example 7

[0130] This example provides a preparation method of the cyclodextrin derivative corn starch inclusion compound of coenzyme Q10 of the present application, which is basically the same as that of Example 6, except that the cyclodextrin derivative used is γ-cyclodextrin, 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, the stirring time is 5 h, and freeze drying is used in step (6).

[0131] Example 8

[0132] This example provides a preparation method of the cyclodextrin derivative corn starch inclusion compound of coenzyme Q10 of the present application, which is basically the same as that of Example 6, except that the cyclodextrin derivative used is methyl cyclodextrin, 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, the stirring time is 6 h, and spray drying is used in step (6).

[0133] Example 9

[0134] This example provides a preparation method of the cyclodextrin derivative corn starch inclusion compound of coenzyme Q10 of the present application, which is basically the same as that of Example 6, except that the cyclodextrin derivative used is 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, the stirring time is 6 h, and oven drying is used in step (6).

[0135] Comparative Example 1

[0136] This comparative example provides another preparation method of a cyclodextrin derivative corn starch inclusion compound of coenzyme Q10, which is basically the same as that of Example 1, except that the solution of step (1) is preheated to 60°C in step (2).

[0137] Comparative Example 2

[0138] This comparative example provides another preparation method of a cyclodextrin derivative corn starch inclusion compound of coenzyme Q10, which is basically the same as that of Example 1, except that no ultrasonic treatment is performed in step (2).

[0139] Comparative Example 3

[0140] The comparative example provides another preparation method of the cyclodextrin derivative inclusion compound of coenzyme Q10, and the steps are basically the same as those of Example 1, except that in step (2), no heating is performed, only ultrasonic treatment is performed, and no cooling treatment of step (3) is performed.

[0141] Comparative Example 4

[0142] The comparative example provides another preparation method of the cyclodextrin derivative inclusion compound of coenzyme Q10, and the steps are basically the same as those of Example 6, except that in step (4), the inclusion compound of coenzyme Q10 and β-cyclodextrin is directly obtained by spray drying.

[0143] Comparative Example 5

[0144] The comparative example provides the infrared spectrum scanning situation of coenzyme Q10 raw material drug directly compressed with potassium bromide, see Figure 1 .

[0145] Comparative Example 6

[0146] The comparative example provides the infrared spectrum scanning situation of β-cyclodextrin directly compressed with potassium bromide, see Figure 2 .

[0147] Comparative Example 7

[0148] The comparative example provides the infrared spectrum scanning situation of coenzyme Q10 and β-cyclodextrin, corn starch physically mixed, see Figure 3 .

[0149] Comparative Example 8

[0150] The comparative example provides the infrared spectrum of the coenzyme Q10 and β-cyclodextrin inclusion compound of Comparative Example 4, see Figure 4 .

[0151] Comparative Example 9

[0152] The comparative example provides the infrared spectrum of the coenzyme Q10 and β-cyclodextrin corn starch inclusion compound of Example 6, see Figure 5 .

[0153] II. Performance test of the cyclodextrin inclusion compound of coenzyme Q10

[0154] 1. Particle size and dispersity

[0155] Table 1 Average particle size and polydispersity index (PDI) of each example and comparative example

[0156]

[0157] According to Table 1, the particle size distribution of the embodiments of the present application is in a suitable range, indicating complete inclusion and uniform dispersion. Comparative Example 1 has irreversible aggregates due to excessively high temperature, resulting in a large average particle size and uneven particle size distribution. Comparative Example 2 has a significantly larger average particle size and uneven particle size distribution due to insufficient folding of the long chain, causing aggregation after the tail is exposed. Comparative Example 3 has a larger micelle due to complete relaxation of the long chain, uneven particle size distribution, and an increased average particle size.

[0158] 2. Stability Test

[0159] Accelerated Test: 40°C / 75% RH for 30 days, and periodically check the precipitation.

[0160] Long-term Stability Test: 25°C / 60% RH for 6 months.

[0161] Table 2. Stability Test Results of Each Embodiment and Comparative Example

[0162]

[0163] According to Table 2, the precipitation degree of the embodiments 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. Comparative Example 1 has no obvious precipitation and is basically the same as the embodiments. Comparative Example 2 has insufficient folding of the long chain due to no ultrasonic treatment, and has poorer stability than the embodiments. Comparative Example 3 has poor stability due to almost no folding.

[0164] 3. Dissolution Test

[0165] Conditions: 900 mL pH 6.8 phosphate buffer, 37°C, 50 rpm (paddle method).

[0166] Sampling points: 5, 15, 60 minutes, and HPLC was used to determine the dissolution amount.

[0167] Table 3. Dissolution Test Results of Each Embodiment and Comparative Example

[0168]

[0169] According to Table 3, the embodiments of the present application can basically achieve rapid release, with a dissolution degree > 90% after 60 min.

[0170] All the documents mentioned in the present application are incorporated herein by reference. Unless and to the extent that the incorporated documents conflict with the description and / or technical solutions of the present application, the incorporated documents are incorporated herein by reference in their entireties. When the present application refers to the incorporated documents, the definitions of the relevant technical features, terms, names, phrases, etc. in the incorporated documents are also incorporated herein by reference. When the present application refers to the incorporated documents, the examples and preferred modes of the relevant technical features that are incorporated by reference can also be incorporated herein by reference, provided that the present application can be implemented. It should be understood that when the incorporated content conflicts with the description in the present application, the present application is the priority or is modified according to the description in the present application.

[0171] The technical features of the above-described embodiments and examples can be combined in any suitable manner. In order to make the description concise, not all possible combinations of the technical features in the above-described embodiments and examples are described, however, as long as the combinations of the technical features do not contradict each other, they should be considered to be within the scope of the present disclosure.

[0172] The above-described embodiments are merely representative of the present application, and should not be construed as limiting the scope of the patent application. It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present application, and these are within the scope of the present application. In addition, it should be understood that, after reading the above description of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms are also within the scope of the present application. It should also be understood that, based on the technical solutions provided in the present application, those skilled in the art can obtain technical solutions through logical analysis, reasoning or limited experiments, and these are within the scope of the claims of the present application. Therefore, the scope of the patent of the present application should be subject to the appended claims, and the description can be used to explain the content of the claims.

Claims

1. A method for preparing a cyclodextrin derivative of coenzyme Q10 corn starch inclusion complex, characterized by, The method comprises the following steps: coenzyme Q10 is made into a first solution with an alcohol solution; the alcohol solution is an aqueous solution of ethanol with a volume percentage of 60%-80% of ethanol; the first solution is subjected to ultrasonic treatment at 40-45 DEG C to obtain a second solution; the second solution is cooled to a second temperature at a first rate, maintained for a second time, and then cooled to a third temperature at a second rate to obtain a third solution; wherein the first rate and the second rate are independently selected from 5-10 DEG C / min; the second temperature is 30-35 DEG C, the second time is 1-2 min, and the third temperature is 20-25 DEG C; a cyclodextrin derivative solution is added to the third solution at a third rate, stirred for a third time to obtain a fourth solution; wherein the third rate is 0.5-1.5 mL / min; the third time is 1-3 h; and the stirring speed is 500-700 rpm; corn starch is added to the fourth solution, stirred for a reaction time, and then the solvent is removed to obtain a coenzyme Q10 cyclodextrin derivative corn starch inclusion compound.

2. The production method according to claim 1, characterized by, The step of subjecting the first solution to ultrasonic treatment at 40-45 DEG C to obtain a second solution comprises: the first solution is heated to 40-45 DEG C, then subjected to ultrasonic treatment at a first power and a first frequency for a first time to obtain the second solution; wherein the first power is 150-250 W, the first frequency is 25-35 Hz, and the first time is 30-60 min.

3. The production method according to claim 1, characterized by, The step of adding corn starch to the fourth solution, stirring for a reaction time, and then removing the solvent to obtain the product comprises: corn starch is added to the third solution, stirred for a fourth time, and then the solvent is removed to obtain the coenzyme Q10 cyclodextrin starch inclusion compound; wherein the fourth time is 3-7 h, and the stirring speed is 500-700 rpm.

4. The production method according to claim 3, characterized by, The method for removing the solvent comprises oven drying, vacuum drying, spray drying, and freeze drying.

5. The method of any one of claims 1 to 4, wherein the method further comprises the step of: The weight ratio of coenzyme Q10 to cyclodextrin derivative to corn starch is 1:(1-10):(3-10).

6. The preparation method according to any one of claims 1 to 4, characterized in that, The cyclodextrin derivative comprises one or more of beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, methyl cyclodextrin, sulfobutyl cyclodextrin, and gamma-cyclodextrin.

7. A cyclodextrin inclusion complex of coenzyme Q10, characterized by, The coenzyme Q10 cyclodextrin inclusion compound is prepared by the preparation method of any one of claims 1-6.

8. Use of the coenzyme Q10 cyclodextrin inclusion compound of claim 7 in the preparation of a medicine, health product, or food containing coenzyme Q10.

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