KR102394648B1 - Composition for enhancing bioavailability of silymarin - Google Patents

Abstract

The present invention is an additive composition for improving the bioavailability of silymarin, containing at least one of lecithin and phosphatidylcholine as an active ingredient, and is added to a food composition comprising silymarin and vegetable oil, improving the bioavailability of silymarin Disclosed is an additive composition for Specifically, the additive composition for improving the bioavailability of silymarin according to the present invention can effectively improve the bioavailability of silymarin without including a synthetic surfactant. In addition, the food composition comprising the additive composition for improving the bioavailability of silymarin according to the present invention can exhibit excellent solubility and bioavailability of silymarin without using a synthetic surfactant and an organic solvent, and use a synthetic surfactant or organic solvent side effects can also be prevented.

Description

Additive composition for improving bioavailability of silymarin

The present invention relates to an additive composition for improving the bioavailability of silymarin and a food composition comprising the same.

Silymarin is a component extracted from Maria thistle with the scientific name of Carduus marianus Linne (Silybum mariannum), a medicinal plant belonging to the Asteraceae, and is a kind of flavonoid-based compound. This plant is native to southern Europe and North Africa, but later settled in the Americas and is now cultivated for ornamental or medicinal purposes.

It is known that silymarin stabilizes the hepatocyte membrane, inhibits the influx of harmful substances, and promotes the regeneration of hepatocytes by activating protein synthesis in hepatocytes. It is widely applied to the treatment of various liver diseases.

Formulations containing silymarin as an active ingredient have already been widely clinically applied to the treatment of liver disease, but the active ingredient, silymarin, is a poorly soluble substance that is hardly soluble in water. Only ~40%. Therefore, it can be said that improving the bioavailability by increasing the solubility and dissolution rate is important in the development of a silymarin-containing formulation.

Conventionally, in order to improve the low solubility and bioavailability of silymarin, a self-emulsifying drug delivery system consisting of a drug, oil, surfactant, co-surfactant, solvent, etc. was applied, but in this case, a large amount of synthetic interface By using a large amount of active agents (e.g., polysorbates) and non-food organic solvents (e.g., hexane, etc.), it further irritates users with gastrointestinal disorders such as gastritis or stomach ulcers, or reduces diarrhea and abdominal pain. In addition to causing side effects, such as causing, there was a disadvantage in that the volume of the preparation is large and it is inconvenient to take.

In addition, when silymarin is ingested as a tablet, there is a demand for soft capsules for the reason that consumer preference is low due to a characteristic odor, etc. is being demanded

Republic of Korea Patent Publication No. 10-2005-0075074

In order to solve the above problems, the present invention provides an additive composition for improving the bioavailability of silymarin that effectively improves solubility and bioavailability of silymarin without showing side effects because it does not contain a synthetic surfactant, and for improving the bioavailability of silymarin An object of the present invention is to provide a food composition that exhibits excellent bioavailability of silymarin, including an additive composition.

In order to achieve the above object, an embodiment of the present invention,

As an additive composition for improving the bioavailability of silymarin,

Contains at least one of lecithin and phosphatidylcholine as an active ingredient,

added to a food composition comprising silymarin and a vegetable oil,

It provides an additive composition for improving bioavailability of silymarin, which is added to the food composition so that the silymarin: at least one weight ratio of lecithin and phosphatidylcholine is 1:0.08 or more and 1:2.31.

In addition, another embodiment of the present invention,

As an additive composition for improving the bioavailability of silymarin,

Contains at least one of lecithin and phosphatidylcholine as an active ingredient,

added to a food composition comprising silymarin and a vegetable oil,

The food composition provides an additive composition for improving the bioavailability of silymarin, wherein the dissolution concentration of silymarin is 6 to 31 μg/mL within 240 minutes during a dissolution test in purified water according to the paddle method of the dissolution test method based on the Korean Pharmacopoeia. .

The additive composition for improving the bioavailability of silymarin according to the present invention can effectively improve the bioavailability of silymarin without including a synthetic surfactant.

In addition, the food composition comprising the additive composition for improving the bioavailability of silymarin according to the present invention can exhibit excellent solubility and bioavailability of silymarin without using a synthetic surfactant and an organic solvent, and use a synthetic surfactant or organic solvent side effects can also be prevented.

1 shows the dissolution rate test results according to Experimental Example 1.
Figure 2 shows the disintegration test results according to Experimental Example 2.
3 shows the bioavailability test results according to Experimental Example 3.

Hereinafter, the present invention will be described in detail.

In one aspect, the present invention may relate to an additive composition for improving the bioavailability of silymarin containing at least one of lecithin and phosphatidylcholine as an active ingredient.

The additive composition for improving the bioavailability of silymarin may be added to a food composition including silymarin and vegetable oil.

The silymarin (silymarin) is known to inhibit the influx of harmful substances into cells by stabilizing the hepatocyte membrane, and to promote the regeneration of hepatocytes by activating protein synthesis in hepatocytes. It is known to have the effect of preventing overaccumulation, reducing serum LDL, anti-inflammatory, anticancer, acute viral hepatitis, chronic hepatitis, and promoting recovery in patients with liver cirrhosis complications. It is widely applied in the treatment of diseases.

In addition, the silymarin is an aggregation of flavolignans in which the main component silybin, silicristin, which is an isomer of silybin, silidianin, and isosilybin, etc. are mixed. am.

In one embodiment, the silymarin may be obtained from milk thistle extract. In this case, "milk thistle" refers to a plant with a scientific name of Silybum marianum , and "milk thistle extract" refers to a material obtained by separating from milk thistle, specifically, a conventional extraction solvent known in the art. , for example, refers to a substance obtained from milk thistle by separation using water, a C1-C4 alcohol (eg, methanol, ethanol, butanol, etc.), or a mixed solvent of the alcohol and water.

In addition, the milk thistle extract may be obtained by using various known extraction methods, such as hot water extraction, organic solvent extraction, or supercritical extraction, and may be obtained by additional processes such as vacuum distillation and freeze drying or spray drying. It may be prepared in a powder state.

In one embodiment, the lecithin may be at least one of soybean lecithin and egg yolk lecithin.

The present invention does not use synthetic surfactants such as polysorbates, and contains natural surfactants such as lecithin and phosphatidylcholine, thereby avoiding side effects due to containing a large amount of synthetic surfactants.

In one embodiment, the vegetable oil is soybean oil, sunflower oil, rapeseed oil, avocado oil, corn oil (corn oil), palm oil, palm oil, brown rice oil, cottonseed oil (cottonseed oil), castor oil, sesame seed oil, flaxseed oil, It may be at least one selected from olive oil, canola oil, grape seed oil, almond oil, peanut oil, hazelnut oil, and walnut oil.

In one embodiment, the additive composition may be added to the food composition so that the weight ratio of silymarin: at least one of lecithin and phosphatidylcholine is 1:0.08 or more and 1:2.31.

In another embodiment, in the food composition, the silymarin: at least one weight ratio of lecithin and phosphatidylcholine is 1:0.08 or more, 1:0.15 or more, 1:0.23 or more, 1:0.35 or more, 1:0.40 or more, 1 It may be: 0.46 or more, 1:0.53 or more, 1:1 or more, 1:1.23 or more, or 1:1.53 or more, and the weight ratio of silymarin: at least one of lecithin and phosphatidylcholine is less than 1:2.31, 1:2.3 or less, 1:2 or less, 1:1.7 or less, 1:1.53 or less, 1:1.4 or less, 1:1.23 or less, 1:1 or less, 1:0.7 or less, 1:0.53 or less, or 1:0.46 or less. Preferably, the weight ratio of the silymarin: lecithin and phosphatidylcholine in the food composition may be 1:0.46 to 1:1.53, and the bioavailability of silymarin may be higher in the range.

In one embodiment, the food composition according to the present invention may be in the form of a soft capsule. In another embodiment, the food composition can be appropriately selected and formulated by those skilled in the art without difficulty in preparing the ingredients commonly used in the field in a soft capsule formulation in addition to the active ingredient.

In one embodiment, the food composition may have a viscosity of less than 1800 cps. Specifically, the viscosity of the food composition is less than 1800 cps, less than 1600 cps, less than 1400 cps, less than 1200 cps, less than 1000 cps, less than 800 cps, less than 600 cps, less than 400 cps or less than 200 cps, and may be less than 10 cps or more, 50 cps or more, 100 cps or more, 200 cps or more, 400 cps or more, 600 cps or more, 800 cps or more, 1000 cps or more, 1200 cps or more, 1400 cps or more, or 1600 cps or more.

In one embodiment, the food composition is tested for dissolution in purified water according to the paddle method of the dissolution test method based on the Korean Pharmacopoeia, specifically, when measured by rotating at 150 rpm at 37 ° C with 500 ml of purified water as the eluent, The elution concentration of silymarin within 240 minutes may be 6 to 31 μg/mL. In another embodiment, the elution concentration of the silymarin is 6 μg/mL or more, 6.5 μg/mL or more, 7 μg/mL or more, 8 μg/mL or more, 8.5 μg/mL or more, 9 μg/mL or more, 9.5 ≥ µg/mL, ≥ 15 µg/mL, ≥ 19 µg/mL, ≥ 19.6 µg/mL, ≥ 23 µg/mL, ≥ 24 µg/mL, ≥ 26 µg/mL, ≥ 28 µg/mL, or ≥ 30 µg/mL may be more than In addition, the elution concentration of the silymarin may be 31 μg/mL or less, 28.5 μg/mL or less, 25.5 μg/mL or less, or 22 μg/mL or less. Preferably, the elution concentration of the silymarin may be 19.6 to 31 μg/mL.

According to one embodiment, the food composition according to the present invention may be a health functional food composition, and may be used for improving liver function.

In this case, "improvement" refers to treatment, alleviation, and prevention of symptoms, and in the present invention, liver function, liver condition, liver disease, and liver disease are treated, alleviated or prevented.

In the present invention, "prevention" refers to any action that suppresses or delays the onset of liver disease by administration of the composition according to the present invention.

In the present invention, "liver disease" includes liver diseases that can be treated, alleviated or prevented by the composition of the present invention without limitation, but examples thereof include non-alcoholic fatty liver, alcoholic fatty liver, hepatitis, cirrhosis, liver cancer, etc. .

The health functional food composition of the present invention may include additives for nutrient supplementation effect and sensory improvement and formulation formation within a range that does not impair the effects of the present invention.

Hereinafter, the content of the present invention will be described in more detail through Examples and Test Examples. However, these Examples and Test Examples are only presented to understand the content of the present invention, and the scope of the present invention is not limited to these Examples and Test Examples, and modifications and substitutions commonly known in the art and insertion may be performed, and this is also included in the scope of the present invention.

[Examples and Comparative Examples]

Examples 1 to 21 and Comparative Examples 1 to 4, which are compositions having a total content of 600 mg, were prepared according to the composition of Table 1 (unit: mg).

Silymarin phosphatidyl
choline Soy Lecithin vegetable oil Silymarin
: At least one of phosphatidylcholine and soy lecithin
(weight ratio) soybean oil sunflower oil comparative example
One 130 - - remaining amount - - comparative example
2 130 300 - remaining amount - 1:2.31 comparative example
3 130 240 60 remaining amount - comparative example
4 130 - 300 remaining amount - Example
One 130 10 - remaining amount - 1:0.08 Example
2 130 8 2 remaining amount - Example
3 130 - 10 remaining amount - Example
4 130 30 - remaining amount - 1:0.23 Example
5 130 24 6 remaining amount - Example
6 130 - 30 remaining amount - Example
7 130 60 - remaining amount - 1:0.46 Example
8 130 48 12 remaining amount - Example
9 130 - 60 remaining amount - Example
10 130 70 - remaining amount - 1:0.53 Example
11 130 56 14 remaining amount - Example
12 130 - 70 remaining amount - Example
13 130 160 - remaining amount - 1:1.23 Example
14 130 128 32 remaining amount - Example
15 130 - 160 remaining amount - Example
16 130 200 - remaining amount - 1:1.53 Example
17 130 160 40 remaining amount - Example
18 130 - 200 remaining amount - Example
19 130 70 - - remaining amount 1:0.53 Example
20 130 56 14 - remaining amount Example
21 130 - 70 - remaining amount

[Experimental Example 1] Silymarin dissolution evaluation experiment

The dissolution rates of Examples 1 to 21, Comparative Examples 1 to 4, and milk thistle extract were comparatively evaluated. The milk thistle extract is a raw material prepared by filtration, concentration, and purification of milk thistle (white patterned milk thistle) after alcohol extraction. Milk thistle extract (HONSON INGREDIENTS, Canada) containing 50% silymarin was used.

In the dissolution evaluation test, in vitro dissolution was evaluated by the dissolution test method according to the Korean Pharmacopoeia, and the content of silybin, a representative component of silymarin, was quantified and evaluated by HPLC analysis. Specifically, according to the paddle method of the dissolution test item according to the Korean Pharmacopoeia, 3 ml of each of Examples 1 to 21, Comparative Examples 1 to 4, and milk thistle extract were taken, and 500 ml of purified water was used as the eluent, and the number of rotations at a temperature of 37 ° C. Measurement was carried out at 150 rpm. The results are shown in Table 2 (unit: μg/mL) and FIG. 1 below.

hours (minutes) 5 15 30 60 120 240 milk thistle
extract 5.93 13.76 16.28 17.97 18.51 19.55 comparative example
One 0.04 0.34 0.64 1.16 1.89 3.50 comparative example
2 0.06 3.04 9.70 17.27 25.59 33.24 comparative example
3 0.22 4.95 9.59 14.19 23.42 31.42 comparative example
4 0.10 2.50 8.12 12.57 22.82 27.84 Example
One 0.37 1.35 2.27 3.57 4.84 7.48 Example
2 0.17 1.21 2.37 3.53 5.49 7.85 Example
3 0.27 1.50 2.48 4.25 6.24 8.49 Example
4 0.14 0.89 1.75 2.43 3.91 6.87 Example
5 0.09 0.77 1.71 2.64 4.27 6.56 Example
6 0.09 0.77 2.50 3.01 6.53 9.38 Example
7 0.29 0.92 1.95 4.60 9.73 19.63 Example
8 0.92 4.38 6.94 11.32 16.68 21.29 Example
9 1.50 3.45 9.39 16.81 18.77 21.70 Example
10 0.23 2.69 5.30 9.03 21.64 25.13 Example
11 0.89 7.80 12.44 17.27 22.18 24.91 Example
12 0.72 6.40 13.33 18.84 22.77 24.02 Example
13 3.80 11.24 17.46 22.83 27.42 28.25 Example
14 2.98 10.58 14.29 19.92 23.74 26.25 Example
15 2.30 9.38 12.98 16.54 24.05 26.72 Example
16 0.99 9.46 18.51 22.97 27.92 30.90 Example
17 1.45 11.02 18.38 22.74 27.72 30.48 Example
18 1.20 8.50 12.59 18.71 25.02 28.52 Example
19 0.20 3.50 4.80 10.10 22.64 26.29 Example
20 0.18 2.50 15.23 18.94 22.65 25.44 Example
21 0.15 1.50 9.75 14.55 20.01 23.08

From the results of Table 2 and FIG. 1 , it was found that the elution concentration of silymarin was higher in Examples 1 to 21 containing silymarin, soybean oil, and at least one of lecithin and phosphatidylcholine, compared to Comparative Example 1 containing only silymarin and soybean oil. appeared, it was confirmed that the dissolution rate of silymarin is increased by including one or more of lecithin and phosphatidylcholine.

In addition, in the case of Examples 7 to 21 containing silymarin, lecithin, and one or more of phosphatidylcholine in a weight ratio of 1:0.46 to 1:1.53, it was found that the dissolution concentration of silymarin was significantly higher than that of the milk thistle extract when 240 minutes of the dissolution test elapsed. could check

That is, the additive composition for improving the bioavailability of silymarin according to the present invention and the health functional food composition containing silymarin according to the present invention can significantly improve the bioavailability due to the excellent dissolution rate of silymarin compared to the case of ingesting the milk thistle extract alone. was able to confirm

On the other hand, in Comparative Examples 2 to 4, as the content of one or more of lecithin and phosphatidylcholine increased, it was confirmed that the elution concentration of silymarin also increased. I could see the impossible.

[Experimental Example 2] Disintegration test of soft capsule formulation

A disintegration test was performed to evaluate whether the compositions of Example 11 and Comparative Example 2 were suitable for production into a soft capsule formulation. The disintegration test was conducted according to the disintegration test method of the Food Codex General Test Method. Specifically, water was used as a test solution, and it was carried out using a disintegration tester (J-DTC2, JISICO Co.). In the case of soft capsules, disintegration should be completed within 20 minutes, and after putting the auxiliary plate in and moving it up and down for 20 minutes, it was judged that disintegration was completed in the case of a film even if the residue of each composition was not in the glass tube.

The results are shown in FIG. 2 . From the results of FIG. 2 , in the case of the composition of Example 11 according to the present invention, it was confirmed that the composition was completely disintegrated within 20 minutes, so that it was suitable for production into a soft capsule. On the other hand, in the case of Comparative Example 2, the weight ratio of silymarin to at least one of lecithin and phosphatidylcholine was 1:2.31, and the content of lecithin and phosphatidylcholine was excessively high, so disintegration was not completed within 20 minutes due to increased viscosity. It was confirmed that the production was not suitable.

[Experimental Example 3] Bioavailability evaluation experiment

The bioavailability of silybin, the main component of silymarin, was evaluated by examining the pharmacokinetics of each of the milk thistle extract of Experimental Example 1 and the composition of Example 11. Specifically, the milk thistle extract and the composition of Example 11 were orally administered to 5 SD rats by 200 mg/kg based on the silybin concentration, respectively, and then a total of 11 times (0 min, 2 min, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes) blood was collected and the concentration of silybin in plasma was analyzed by high performance liquid chromatography (HPLC). .

HPLC analysis conditions are as follows.

-HPLC model: Shimadzu HPLC-UV system Prominence model

-Analytical column: Kientex C18 Column (250 × 4.6mm)

-Mobile phase: Isocratic mode, 10 mM Ammonium acetate buffer: Acetonitrile = 74: 26

-Flow rate: 1.0 mL/min

-UV Wavelength: 288 nm

-Sample injection volume: 20 μL

For HPLC analysis, specifically, 120 μL of plasma from SD rats was taken, 400 μL of acetonitrile containing an internal standard (Phenacetin 3 μg/mL) was added, and the protein was prepared by mixing for 5 minutes. After that, the protein sample was centrifuged at 15,000xg at 4°C for 10 minutes to take 400 μL of the supernatant, dried using a nitrogen concentrator, and then reconstructed into a 60 μL mobile phase. After that, 20 μL of the sample was injected into HPLC and analyzed.

The results are shown in Table 3 and FIG. 3 below.

AUC _last (μg min/mL) C _max (μg/mL) Milk Thistle Extract 76.5 ± 19.2 1.02 ± 0.24 Example 11 207 ± 28 3.13 ± 0.49

(AUC _last represents an index comparing the total blood absorption of the test drug, and C _max represents the index of the highest blood concentration of the test drug.)

From the results of Table 3 and FIG. 3, in the case of the composition of Example 11 according to the present invention, it was confirmed that both the total blood absorption amount and the highest blood concentration value of silybin, the main component of silymarin, were significantly increased compared to the milk thistle extract. . That is, in the case of Example 11 according to the present invention, it was confirmed that the bioavailability of silymarin was significantly higher than that of the milk thistle extract.

Claims (12)

As an additive composition for improving the bioavailability of silymarin,
phosphatidylcholine; Or lecithin (lecithin) and phosphatidylcholine; contains as an active ingredient,
added to a food composition comprising silymarin and a vegetable oil,
The silymarin: an additive composition for improving bioavailability of silymarin, which is added to the food composition so that the weight ratio of the active ingredient is greater than 1:0.46 and less than 1:2.31. According to claim 1,
The silymarin is an additive composition for improving bioavailability of silymarin, characterized in that it is obtained from a milk thistle extract. According to claim 1,
The lecithin is an additive composition for improving bioavailability of silymarin, characterized in that at least one of soybean lecithin and egg yolk lecithin. According to claim 1,
The vegetable oil is soybean oil, sunflower oil, rapeseed oil, avocado oil, corn oil, palm oil, palm oil, brown rice oil, cottonseed oil, castor oil, sesame seed oil, linseed oil, olive oil, canola oil, grape seed oil, almond oil, peanut oil , hazelnut oil and walnut oil, characterized in that at least one selected from, the additive composition for improving the bioavailability of silymarin. The method of claim 1,
The silymarin: an additive composition for improving bioavailability of silymarin, characterized in that the weight ratio of the active ingredient is greater than 1:0.46 and 1:1.53 or less. The method of claim 1,
The food composition is an additive composition for improving bioavailability of silymarin, characterized in that the viscosity is less than 1800 cps. As an additive composition for improving the bioavailability of silymarin,
phosphatidylcholine; Or lecithin (lecithin) and phosphatidylcholine; contains as an active ingredient,
added to a food composition comprising silymarin and a vegetable oil,
The food composition is an additive composition for improving the bioavailability of silymarin, wherein the dissolution concentration of silymarin is 24 to 31 μg/mL within 240 minutes when the dissolution test is performed in purified water according to the paddle method of the dissolution test method based on the Korean Pharmacopoeia. delete 8. The method of claim 7,
The silymarin: an additive composition for improving bioavailability of silymarin, characterized in that it is added to the food composition so that the weight ratio of the active ingredient is greater than 1:0.46 and less than 1:2.31. 10. The method according to any one of claims 1 to 7 and 9,
The food composition is an additive composition for improving bioavailability of silymarin, characterized in that it is a soft capsule formulation. 10. A food composition comprising the additive composition for improving the bioavailability of silymarin according to any one of claims 1 to 7 and 9, silymarin, and a vegetable oil. 12. The method of claim 11,
The food composition is characterized in that the soft capsule formulation, the food composition.

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