Coenzyme Q10 enteric capsule as well as preparation method and application thereof

Abstract

The invention provides a coenzyme Q10 enteric capsule as well as a preparation method and application thereof, and belongs to the technical field of preparation of pharmaceutical preparations. The coenzyme Q10 enteric capsule provided by the invention is prepared from coenzyme Q10, olive oil, carnauba wax, vitamin E and an enteric coating material. The coenzyme Q10 enteric capsule provided by the invention can effectively protect the coenzyme Q10 from being damaged by gastric acid and can be quickly released in intestinal tracts, so that the bioavailability of the medicine is remarkably improved. In-vitro dissolution experiments show that the release rate of the coenzyme Q10 enteric capsule in simulated gastric juice within 2 hours is lower than 10%, and the release rate of the coenzyme Q10 enteric capsule in simulated intestinal juice within 30 minutes is higher than 80%. Cell experiments prove that the coenzyme Q10 enteric capsule provided by the invention is good in biocompatibility and free of remarkable cytotoxicity. Animal pharmacokinetic experiments show that the plasma peak concentration and bioavailability of the coenzyme Q10 enteric capsule provided by the invention are obviously higher than those of commercially available soft capsules and tablets.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparation, and particularly relates to a coenzyme Q10 enteric capsule and a preparation method and application thereof. BACKGROUND

[0002] Coenzyme Q10 is a liposoluble quinone compound widely existing in human cells, is an important hydrogen carrier in the respiratory chain of cells, and has important physiological functions such as antioxidant, immunity improvement, and heart function improvement. However, coenzyme Q10 has poor water solubility, low oral absorption rate (only 2-3%), and is easily destroyed by gastric acid, resulting in that the bioavailability is not ideal.

[0003] At present, commercially available coenzyme Q10 oral preparations mainly include ordinary tablets and soft capsules. The ordinary tablets have the problems of poor solubility and low absorption efficiency; the soft capsules can be improved to a certain extent, but cannot avoid the degradation of the active ingredient by gastric acid, and may be released too early in the stomach to cause gastrointestinal discomfort.

[0004] An enteric preparation can ensure that the drug is released in the alkaline environment of the intestinal tract, avoid destruction by gastric acid, and target the absorption site. However, directly filling coenzyme Q10 powder into an enteric capsule shell still has limited dissolution and absorption in the intestinal tract due to poor solubility. Therefore, it is of important practical significance to develop a new type of coenzyme Q10 enteric preparation that can overcome the problems of degradation by gastric acid and low dissolution. SUMMARY

[0005] Therefore, the purpose of the present application is to provide a coenzyme Q10 enteric capsule which can effectively protect coenzyme Q10 from being destroyed by gastric acid and can be quickly released in the intestinal tract to significantly improve the bioavailability of the drug.

[0006] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical solutions. The present application provides a coenzyme Q10 enteric capsule which is made of coenzyme Q10, olive oil, carnauba wax, vitamin E, and an enteric coating material.

[0007] Preferably, the weight parts of each raw material are as follows: coenzyme Q10 2.5-12.5 parts, olive oil 85-97 parts, carnauba wax 0.1-2 parts, vitamin E 0.01-0.1 parts, and enteric coating material 5-10 parts.

[0008] Preferably, the enteric coating material comprises hydroxypropyl methyl cellulose.

[0009] The application further provides a preparation method of the coenzyme Q10 enteric capsule, comprising the following steps: mixing and heating the carnauba wax and the olive oil, then adding the coenzyme Q10 and vitamin E to obtain a mixture; homogenizing the mixture by high-speed shearing, and then homogenizing the mixture by high pressure to obtain a suspension; filling the suspension into a capsule shell, and coating the capsule shell by using an enteric coating material to obtain the coenzyme Q10 enteric capsule.

[0010] Preferably, the temperature of the mixing and heating is 70-75 DEG C.

[0011] Preferably, the rotating speed of the high-speed shearing homogenization is 4000-6000 rpm, and the time of the high-speed shearing homogenization is 5-15 min.

[0012] Preferably, the pressure of the high-pressure homogenization is 500-700 bar, and the cycle number of the high-pressure homogenization is 2-5 times.

[0013] The application further provides application of the coenzyme Q10 enteric capsule in preparation of any one of the following products: (1) an antioxidant product; (2) an immunity improving product; (3) a cardiovascular disease preventing and treating product.

[0014] The application further provides a composition with antioxidant, immunity improving and / or cardiovascular disease preventing and treating effects, comprising the coenzyme Q10 enteric capsule.

[0015] The application has the following beneficial effects: The coenzyme Q10 enteric capsule can effectively protect the coenzyme Q10 from being destroyed by gastric acid, and can be quickly released in the intestinal tract, thereby significantly improving the bioavailability of the drug. In vitro dissolution experiments show that the coenzyme Q10 enteric capsule has a release rate of less than 10% in simulated gastric juice within 2 hours, and a release rate of more than 80% in simulated intestinal juice within 30 minutes. Cell experiments show that the coenzyme Q10 enteric capsule has good biocompatibility and no significant cytotoxicity. Animal pharmacokinetic experiments show that the peak blood concentration and bioavailability of the coenzyme Q10 enteric capsule are significantly higher than those of commercially available soft capsules and tablets.

[0016] The preparation method of the coenzyme Q10 enteric capsule is stable in process, suitable for industrial production, and has a good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 is a coenzyme Q10 standard curve; Figure 2 is a dissolution curve of the medicaments in different groups in simulated gastric juice; Figure 3 is a dissolution curve of the medicaments in different groups in simulated intestinal juice; Figure 4The results are from the cell safety test of the coenzyme Q10-treated group alone. Figure 5 The results are from a cell safety test of coenzyme Q10 enteric-coated capsules after drug loading; Figure 6 The blood drug concentration-time curves in rats from different groups are shown. Detailed Implementation

[0018] This invention provides a coenzyme Q10 enteric-coated capsule, which is made of coenzyme Q10, olive oil, carnauba wax, vitamin E and enteric coating material.

[0019] This invention does not specifically limit the source of the above-mentioned raw materials; commercially available raw materials commonly used in the field can be used. In this invention, the amount of coenzyme Q10 added is preferably 2.5-12.5 parts, more preferably 5-10 parts, and even more preferably 6.3-8.3 parts; the amount of olive oil added is preferably 85-97 parts, more preferably 88-94 parts, and even more preferably 90-92 parts; the amount of carnauba wax added is preferably 0.1-2 parts, more preferably 0.5-1.5 parts; the amount of vitamin E added is preferably 0.01-0.1 parts, more preferably 0.02-0.08 parts, and even more preferably 0.04-0.06 parts; and the amount of enteric coating material added is preferably 5-10 parts, more preferably 6-9 parts, and even more preferably 7-8 parts.

[0020] In this invention, olive oil, which has the highest solubility for coenzyme Q10, is selected as the oil phase carrier, which significantly increases the drug content per unit dose; carnauba wax is added as a stabilizer to effectively prevent sedimentation and stratification of the contents; vitamin E is added as an antioxidant to protect the chemical stability of coenzyme Q10; the above raw materials ensure that the coenzyme Q10 enteric-coated capsules provided by this invention have high drug loading and stability.

[0021] In this invention, the enteric coating material preferably includes hydroxypropyl methylcellulose. The use of hydroxypropyl methylcellulose for enteric coating ensures that the drug release rate of the capsule is extremely low (<10%) within 2 hours in an acidic gastric environment (such as simulated gastric fluid at pH 1.2), while in an intestinal environment (such as simulated intestinal fluid at pH 6.8), the drug release rate exceeds 80% within 30 minutes.

[0022] This invention highly disperses the drug Coenzyme Q10 in the oil phase and combines it with enteric-coated targeted release technology, so that the drug Coenzyme Q10 is released in the small intestine in an easily absorbed form, thereby overcoming the bottleneck of gastric acid degradation and low dissolution, and theoretically can significantly improve oral bioavailability.

[0023] This invention compares the solubility of coenzyme Q10 in the oil phase when sunflower oil, olive oil, corn oil, soybean oil, glycerol, and medium-chain triglycerides (MCT) are used as the oil phase. The specific determination method is as follows: Excess coenzyme Q10 is weighed into a vial, and the oil phase (sunflower oil, olive oil, corn oil, soybean oil, glycerol, or MCT) is added separately, followed by vortex dispersion. The vial is placed in a water bath shaker at 37°C and shaken at 80 rpm for 72 hours (protected from light). An appropriate amount of sample is taken into a centrifuge tube and centrifuged at 10,000 rpm for 10 minutes. An appropriate amount of supernatant is taken and diluted with anhydrous ethanol to a suitable concentration, and the coenzyme Q10 concentration is determined by chromatography. Olive oil was ultimately determined to be the optimal carrier, combining good solubility with cost advantages.

[0024] To determine the optimal ratio of each raw material, the present invention designed a single-factor experiment as follows: 1. Stabilizer Ratio: With other components fixed, the effect of stabilizers on the oil seepage rate and consistency of the contents was investigated, and the optimal ratio for physical stability was selected. 2. Oil Phase Loading: The amount of oil was varied while other components were fixed, and the flowability and drug loading uniformity of the contents were evaluated. 3. Antioxidant Addition: The protective effect of different vitamin E contents on the retention rate of coenzyme Q10 in accelerated tests was tested. 4. Coating Weight Gain: The weight gain of the enteric coating material was adjusted to verify its tolerance and disintegration time in different pH media. Only a single variable was changed in each experiment, and key performance indicators were used as the evaluation basis to preliminarily determine the reasonable range of each factor. The results of the above single-factor experiments showed that the optimal ratio of coenzyme Q10 (2.5-12.5 parts), olive oil (oil phase) (85-97 parts), carnauba wax (stabilizer) (0.1-2 parts), vitamin E (antioxidant) (0.01-0.1 parts), and enteric coating material (5-10 parts) was the best ratio for each raw material.

[0025] The present invention also provides a method for preparing the above-mentioned coenzyme Q10 enteric-coated capsules, comprising the following steps: mixing and heating carnauba wax and olive oil, then adding coenzyme Q10 and vitamin E to obtain a mixture; subjecting the mixture to high-speed shear homogenization, and then subjecting it to high-pressure homogenization to obtain a suspension; filling the suspension into capsule shells, and coating the capsule shells with an enteric coating material to obtain coenzyme Q10 enteric-coated capsules.

[0026] In this invention, the mixing and heating temperature is preferably 70-75℃, more preferably 72-73℃. In this invention, the mixture (contents) composed of carnauba wax, olive oil, coenzyme Q10, and vitamin E, through high-speed shear homogenization and high-pressure homogenization, can form a suspension system with fine particle size, uniform distribution, and high stability, resulting in stable product quality and ease of industrial-scale production. In this invention, the high-speed shear homogenization preferably uses a colloid mill, the high-speed shear homogenization speed is preferably 4000-6000 rpm, more preferably 4500-5500 rpm, and the high-speed shear homogenization time is preferably 5-15 min, more preferably 8-12 min. In this invention, the high-pressure homogenization pressure is preferably 500-700 bar, more preferably 550-650 bar, and the high-pressure homogenization cycle number is preferably 2-5 times, more preferably 3-4 times.

[0027] This invention also provides the application of the above-mentioned coenzyme Q10 enteric-coated capsules in the preparation of any of the following products: (1) antioxidant products; (2) products for improving immunity; (3) products for preventing and treating cardiovascular diseases. In this invention, the products preferably include pharmaceuticals or health products.

[0028] This invention also provides a composition having antioxidant, immune-enhancing, and / or cardiovascular disease-preventing effects, comprising the above-mentioned coenzyme Q10 enteric-coated capsules. Preferably, the composition of this invention also includes pharmaceutically acceptable excipients. This invention does not specifically limit the type of pharmaceutically acceptable excipients; any excipient that does not affect the biological activity of coenzyme Q10 can be used.

[0029] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0030] Unless otherwise specified, the following embodiments are all conventional methods.

[0031] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0032] Example 1 A coenzyme Q10 enteric-coated capsule is made from 5.0g coenzyme Q10, 93.48g olive oil, 1.5g carnauba wax, 0.02g vitamin E and 8g hydroxypropyl methylcellulose.

[0033] The preparation method is as follows: Carnauba wax was melted in olive oil at 70°C, then coenzyme Q10 and vitamin E were added. The mixture was mechanically stirred for 30 minutes until initially dispersed, yielding a mixture. The mixture was then homogenized using a high-speed homogenizer at 5000 rpm for 10 minutes to obtain a preliminary suspension. This preliminary suspension was then transferred to a high-pressure homogenizer and homogenized three times at 600 bar to obtain a final suspension. The suspension was filled into transparent capsule shells using a fully automated capsule filling machine, producing approximately 1000 capsules (each containing 5 mg of coenzyme Q10). Fluidized bed coating technology was used with hydroxypropyl methylcellulose as the coating material to perform enteric coating, resulting in coenzyme Q10 enteric capsules.

[0034] Example 2 A coenzyme Q10 enteric-coated capsule is made from 2.5g coenzyme Q10, 85g olive oil, 0.1g carnauba wax, 0.01g vitamin E and 5g hydroxypropyl methylcellulose.

[0035] The preparation method is as follows: Carnauba wax was melted in olive oil at 75°C, then coenzyme Q10 and vitamin E were added and mechanically stirred until initially dispersed to obtain a mixture. The mixture was then homogenized using a high-speed homogenizer at 4000 rpm for 15 minutes to obtain a preliminary suspension. This preliminary suspension was then transferred to a high-pressure homogenizer and homogenized five times at 500 bar to obtain a final suspension. The suspension was then filled into transparent capsule shells using a fully automated capsule filling machine. Fluidized bed coating technology was employed, using hydroxypropyl methylcellulose as the coating material, to perform enteric coating on the capsules, resulting in coenzyme Q10 enteric capsules.

[0036] Example 3 A coenzyme Q10 enteric-coated capsule is made from 12.5g coenzyme Q10, 97g olive oil, 2g carnauba wax, 0.1g vitamin E and 10g hydroxypropyl methylcellulose.

[0037] The preparation method is as follows: Carnauba wax was melted in olive oil at 73°C in a water bath, then coenzyme Q10 and vitamin E were added, and the mixture was mechanically stirred until initially dispersed to obtain a mixture. The mixture was first homogenized using a high-speed homogenizer at 6000 rpm for 5 minutes to obtain a preliminary suspension. The preliminary suspension was then transferred to a high-pressure homogenizer and homogenized twice at 700 bar to obtain a final suspension. The suspension was filled into transparent capsule shells using a fully automated capsule filling machine. Fluidized bed coating technology was used with hydroxypropyl methylcellulose as the coating material to perform enteric coating on the capsules, resulting in coenzyme Q10 enteric capsules.

[0038] Experimental Example 1 Dissolution test The dissolution rate of the coenzyme Q10 enteric-coated capsules prepared in Example 1 was determined according to the dissolution test method (Method I, basket method) in the Chinese Pharmacopoeia. Commercially available coenzyme Q10 soft capsules, commercially available ordinary coenzyme Q10 tablets, and coenzyme Q10 single active pharmaceutical ingredient were used as control groups, and comparative dissolution experiments were conducted simultaneously (the commercially available coenzyme Q10 soft capsules were Xinhuyuan brand coenzyme Q10 soft capsules, containing 18g / 100g of drug; the commercially available tablets were Nengqilang coenzyme Q10 tablets, 10mg / tablet).

[0039] Simulated gastric fluid: using a 0.1 mol / L hydrochloric acid solution containing 1.0% Tween 80 as the medium, rotating at 100 rpm, and at a temperature of 37℃.

[0040] Simulated intestinal fluid: using a pH 6.8 phosphate buffer solution containing 1.0% Tween 80 as the medium, rotating at 100 rpm, and at a temperature of 37°C.

[0041] The standard curve for coenzyme Q10 is as follows: Figure 1 As shown, the test results are as follows Figure 2 and Figure 3 As shown. By Figure 2 It can be seen that the coenzyme Q10 enteric-coated capsules provided by this invention exhibit a cumulative drug release rate of less than 5% after 2 hours in simulated gastric juice, indicating that they have good resistance to gastric acid. Figure 3 It can be seen that after being transferred to simulated intestinal fluid, the drug was released more rapidly within 45 minutes than the other three groups, and the drug release rate was higher than that in gastric fluid, indicating that it can dissolve more quickly in the intestine, which is conducive to absorption. In simulated gastric fluid ( Figure 2 The commercially available product released less drug within 2 hours than the enteric-coated capsule group, indicating that it was less effective at protecting the drug from gastric acid degradation than the enteric-coated capsule group. In simulated intestinal fluid ( Figure 3 The release rate of commercially available products is also lower than that of the product of this invention.

[0042] The above results indicate that the coenzyme Q10 enteric-coated capsules prepared in this invention, through optimized formulation and advanced preparation process, achieve the design goal of not releasing in the stomach but rapidly releasing in the intestine, providing a novel, efficient, and stable formulation for solving the problem of oral absorption of coenzyme Q10.

[0043] Experimental Example 2 Cell safety testing GES-1 cell viability was determined using the MTT assay. To simulate the effects of enteric-coated capsules in the human intestinal environment, this study aimed to assess whether the material components of enteric-coated capsules would release substances toxic to GES-1 cells into the body fluids, thus providing a preliminary in vitro evaluation of their biocompatibility. The extraction medium was DMEM cell culture medium. The coenzyme Q10 enteric-coated capsules prepared in Example 1 were placed in DMEM cell culture medium and extracted at 37°C for 24 hours to obtain the coenzyme Q10 enteric-coated capsule extract.

[0044] MTT experiment: Day 1: Plate preparation: Each well contains 5k cells, with the outermost ring of PBS in each well. Four plates were prepared: single Coenzyme Q10 group, enteric-coated Coenzyme Q10 capsule group, culture medium control group, and cell-cultured medium control group. Incubate at 37°C for 24 hours.

[0045] Day 2: Drug administration: Dilute the drug with culture medium / PBS, carefully remove the waste culture medium, add the drug, and continue culturing for 24 hours. There are 6 replicates for each concentration.

[0046] Day 3: Remove the old culture medium, add 100µL of MTT stock solution to each well, and place in an incubator for 4 hours. After 4 hours, remove the culture medium, add 100µL of dmso to each well, and shake on a shaker for 10-15 minutes until the formazan crystals are completely dissolved.

[0047] Calculate cell viability by measuring absorbance.

[0048] The results are as follows Figure 4 and Figure 5 As shown, the cell viability of the coenzyme Q10 enteric-coated capsule extract at a concentration of 100 μg / mL was >90%, indicating good biocompatibility.

[0049] Experimental Example 3 Pharmacokinetic studies Using rats as a rat model, the pharmacokinetic parameters of the coenzyme Q10 enteric-coated capsules obtained in Example 1 were compared with those of commercially available coenzyme Q10 soft capsules (the commercially available coenzyme Q10 soft capsules are Xinhuyuan brand coenzyme Q10 soft capsules with a drug content of 18g / 100g), coenzyme Q10 tablets (the commercially available tablets are Nengqilang coenzyme Q10 tablets, 10mg / tablet) and the active pharmaceutical ingredient coenzyme Q10.

[0050] The results are as follows Figure 6As shown, the coenzyme Q10 enteric-coated capsules of the present invention reached a peak blood concentration of 2.11 μg / mL at 2 hours. The peak elution time of the enteric-coated capsules was slightly earlier and its blood concentration was much higher than that of the original coenzyme Q10 drug. The pharmacokinetic data of rats were fitted using Origin software to obtain the area under the curve (AUG). The AUG of the coenzyme Q10 enteric-coated capsule group of the present invention was 25.525±0.981 mg / (L·h), the AUG of the commercially available capsule group was 17.453±0.701 mg / (L·h), the AUG of the commercially available tablet group was 10.915±0.121 mg / (L·h), and the AUG of the original drug group was 8.395±0.581 mg / (L·h). This indicates that the bioavailability of the coenzyme Q10 enteric-coated capsule group of the present invention is 3.04 times that of the original drug, the bioavailability of the commercially available capsule group is 2.08 times that of the original drug, and the bioavailability of the commercially available tablet group is 1.3 times that of the original drug. The bioavailability of the coenzyme Q10 enteric-coated capsule group of the present invention is significantly improved.

[0051] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A coenzyme Q10 enteric-coated capsule, characterized in that, Made from coenzyme Q10, olive oil, carnauba wax, vitamin E, and enteric coating materials.

2. The coenzyme Q10 enteric-coated capsule according to claim 1, characterized in that, The weight parts of each raw material are as follows: Coenzyme Q10 2.5~12.5 parts, olive oil 85~97 parts, carnauba wax 0.1~2 parts, vitamin E 0.01~0.1 parts, and enteric coating material 5~10 parts.

3. The coenzyme Q10 enteric-coated capsule according to claim 1, characterized in that, The enteric coating material includes hydroxypropyl methylcellulose.

4. The method for preparing the coenzyme Q10 enteric-coated capsules according to any one of claims 1 to 3, characterized in that, The process includes the following steps: mixing and heating carnauba wax and olive oil, then adding coenzyme Q10 and vitamin E to obtain a mixture; first, homogenizing the mixture by high-speed shearing, then homogenizing by high pressure to obtain a suspension; filling the suspension into capsule shells, and coating the capsule shells with enteric coating material to obtain coenzyme Q10 enteric capsules.

5. The preparation method according to claim 4, characterized in that, The temperature of the mixed heating is 70~75℃.

6. The preparation method according to claim 4, characterized in that, The high-speed shear homogenization speed is 4000~6000 rpm, and the high-speed shear homogenization time is 5~15 min.

7. The preparation method according to claim 4, characterized in that, The pressure of the high-pressure homogenization is 500~700 bar, and the number of cycles of the high-pressure homogenization is 2~5.

8. The use of the coenzyme Q10 enteric-coated capsules according to any one of claims 1 to 3 in the preparation of any one of the following products, characterized in that: (1) Antioxidant products; (2) Immunity-boosting products; (3) Products for the prevention and treatment of cardiovascular diseases.

9. A composition having antioxidant, immune-enhancing, and / or cardiovascular disease-preventing effects, characterized in that, Includes the coenzyme Q10 enteric-coated capsules according to any one of claims 1 to 3.

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