KR102262740B1 - Tablet composition comprising milk thistle and preparation method thereof - Google Patents

Abstract

The present invention relates to a tablet, a composition, and a method for manufacturing the same, in which a dissolution rate and stability of milk thistle are improved by maximizing the dissolution rate of milk thistle by adsorbing poorly soluble milk thistle with a mixture containing a surfactant and a dissolution enhancer. Milk thistle tablets can be manufactured without separate injection equipment through the manufacturing method of the present invention.

Description

Tablet composition comprising milk thistle and preparation method thereof

The present invention relates to a tablet composition containing milk thistle and a method for preparing the same.

In order to deliver drugs by penetrating the lipid mucosa of the gastrointestinal tract, most of the drugs recently developed have lipophilic properties and are often poorly soluble in aqueous solution. However, absorption occurs in the intestinal mucosa only after dissolution in the release stage of the drug, so the dissolution rate is slow, so absorption in the digestive tract is delayed, and thus the expression of drug effect and bioavailability are also low in many cases. Therefore, it is important to design a formulation with excellent dissolution rate of poorly soluble drugs to increase bioavailability.

Milk Thistle (Milk Thistle) is a 1 or 2 year plant in the Asteraceae family, and is known as a medicinal plant that grows wild in the Mediterranean region, North America, Central Asia, and the like. Milk thistle seeds contain 2-3% of silymarin, a type of flavonoid.

The solubility of silymarins contained in milk thistle extract is known to be poorly soluble in aqueous solution. In Korean Patent Nos. 0342942 and 0818091, it was solubilized using a lipid-based drug delivery system, and in Korean Patent No. 1269665, a surfactant is used as a solubilizer and a disintegrant and other pharmaceutically acceptable excipients are used to solubilize. method was used.

The lipid-based solubilization method using surfactants, oils, and auxiliary surfactants dissolves the main component of the solid in the lipid in the liquid state. The solubility can be increased by forming micelles in the aqueous solution, but when taken using a relatively large amount of surfactant, oil, etc., the weight increases and inconvenient, and since it is in a liquid state, formulations such as soft capsules are limited. In the case of silymarins of milk thistle, stability is secured in weak acidity and neutrality, so this should be considered. In addition, when adsorbed to a porous agent to solidify a liquid lipid using a lipid-based drug delivery system, the dissolution of the drug may be hindered by curing over time, so it is difficult to formulate.

In some cases, a solid dispersion method is used in which poorly soluble components are dissolved in organic solvents and organic solvents and then spray-dried to form an amorphous form and solubilize. Therefore, there is a disadvantage that the solubility is rapidly lowered because it changes to a crystalline form with the lapse of time. Therefore, in order to secure the solubilization method for improving the dissolution rate and bioavailability of milk thistle and the convenience of administration, a solid formulation is required.

Registered Patent No. 0342942 Registered Patent No. 0818091 Registered Patent No. 1269665

It is an object of the present invention to provide a tablet with improved milk thistle dissolution and a composition thereof.

It is an object of the present invention to provide a method for preparing a tablet having an improved milk thistle dissolution rate.

It is an object of the present invention to provide a pharmaceutical composition and a health functional food comprising a tablet having an improved milk thistle dissolution rate.

1. A core part containing milk thistle and an adsorbent; and a shell part coating the core part, including a surfactant and a dissolution enhancer. A tablet comprising particles comprising a.

2. The tablet according to 1 above, wherein the milk thistle has a particle diameter of 0.1 to 50 μm, and the adsorbent has a particle diameter of 50 to 150 μm.

3. The tablet of the above 1, wherein the adsorbent is at least one selected from the group consisting of magnesium metasilicate aluminate and calcium silicate.

4. The tablet according to 1 above, wherein the adsorbent is included in an amount of 0.1 to 3.0 parts by weight based on 1 part by weight of milk thistle.

5. The tablet of the above 1, wherein the surfactant is at least one selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid esters, and polyoxyglycerides.

6. The tablet according to 1 above, wherein the surfactant is included in an amount of 0.1 to 3.0 parts by weight based on 1 part by weight of milk thistle.

7. The tablet of 1 above, wherein the dissolution enhancer is at least one selected from the group consisting of povidone and hypromellose.

8. The tablet of the above 1, wherein the dissolution enhancer is included in an amount of 0.1 to 2.0 parts by weight based on 1 part by weight of milk thistle.

9. The tablet of the above 1, wherein the tablet further comprises a pharmaceutically acceptable excipient, and the particles and the excipient are in a mixed state.

10. The tablet according to 9 above, wherein the excipient is at least one selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate.

11. The tablet according to 9 above, wherein the excipient is included in an amount of 1.0 to 5.0 parts by weight based on 1 part by weight of milk thistle.

12. A pharmaceutical composition for preventing or treating liver disease comprising the tablet of any one of items 1 to 11 above.

13. A health functional food for improving liver function, comprising the tablet of any one of items 1 to 11 above.

14. adsorbing the surfactant and dissolution enhancer solution to the mixture of milk thistle and adsorbent; and drying the adsorbed solution.

15. The method of manufacturing a tablet according to the above 14, further comprising mixing and tableting a pharmaceutically acceptable excipient after the drying step.

Through the present invention, it is possible to provide a tablet having an improved dissolution rate of milk thistle and a composition thereof.

Milk thistle tablets can be manufactured without separate injection equipment through the manufacturing method of the present invention.

1 is a graph showing the dissolution rates of Examples 1, 3, 5 and Comparative Examples 1 and 2 in water eluate (●: Example 1, ○: Example 3, ■: Example 5, ▲: Comparative Example 1 , △: Comparative Example 2).
2 shows the milk thistle HPLC chromatogram results in the water eluate.

Hereinafter, the present invention will be described in detail. Unless otherwise defined, all terms in this specification have the same general meaning as understood by those of ordinary skill in the art to which the present invention belongs, and in case of conflict with the meaning of the terms used in this specification, the The meaning used in the specification is followed.

The present invention provides a core comprising milk thistle and an adsorbent; and a surfactant and a dissolution enhancer, and a shell part coating the core part. It relates to a tablet containing particles comprising a.

Milk thistle seeds contain 2-3% of silymarin, a type of flavonoid. The medical effects of milk thistle by silymarin include liver function improvement, hangover improvement effect, hyperlipidemia improvement, antioxidant, neuroprotective effect, and the like. However, the present invention is not limited thereto.

In addition to silymarin, milk thistle also contains ingredients such as tocopherol, which is known to have an antioxidant effect that inhibits the generation of lipid peroxide, which is often related to aging in vivo. It is known that seed oil contains 40-50% of linoleic acid, 21.3% of oleic acid, 9.4% of palmitic acid, and 6.6% of stearic acid. These fatty acids are mainly present in combination in the form of triacyl glycerol rather than in the form of a single compound. In particular, unsaturated fatty acids such as linoleic acid are considered as inhibitors of atherosclerosis by lowering plasma cholesterol and triglyceride concentrations. In addition, it contains β-sitosterol, which is reported to be an effective substance for the treatment and prevention of adult diseases, immunomodulation, and treatment of rheumatoid arthritis, and stigmasterol, which is used as a synthetic raw material for sex hormones. Also, it contains Apigenin and Apigenin 7 from the leaves and stems of milk thistle. -O-β-D-glucuronide and Kaempferol contain a large amount of flavonoid compounds, and in flowers, Apigenin 7-O-β-D-(2''-O-α-L-rhamnosyl) galacturonide, Kaempferol 3- O-α-L-rhamnoside 7-O-β-D-galacturonide, Apigenin 7-O-β-D-glucuronide 6''-ethyl ester, Apigenin 7-O-β-D-glucuronide have.

The tablet of the present invention includes particles including a core part containing milk thistle and an adsorbent, and a shell part containing a surfactant and a dissolution enhancer coating the same. Due to these structures and components, the dissolution rate of milk thistle in the tablet is increased. This increase in the dissolution rate of milk thistle can speed up absorption in the body, thereby enhancing the effect of silymarin, an active ingredient of milk thistle, and the like.

In the present invention, the milk thistle particle size may be, for example, 0.1 to 50 μm, specifically 1 to 50 μm, 1 to 40 μm, 1 to 30 μm, 1 to 20 μm, or 5 to 20 μm, and more specifically 10 to 20 μm. can be However, the present invention is not limited thereto.

_{Silybin A (C 25} H ₂₂ O ₁₀ : molecular weight 482.40, refer to Chemical Formula 1) and silybin B (C ₂₅ H ₂₂ O ₁₀ : molecular weight 482.40, refer to Chemical Formula 2), which are the main components of milk thistle, the active ingredient of the present invention. It is a brown powder.

[Formula 1]

[Formula 2]

The saturation solubility in the buffer solution of silybin A and B was measured by experimentation. After adding an excess of silybin A and B to each buffer, the mixture was saturated by stirring for 24 hours at a solution temperature of 37° C. and atmospheric pressure, and then centrifuged at 15,000 rpm for 20 minutes using a centrifuge. The supernatant was diluted with methanol and analyzed by HPLC ( See Example 2.3 and Table 4).

As a result of the experiment on the saturated solubility, the saturated solubility in water and buffer was very low (see Table 1).

menstruum Solubility (μg/ml) pH 1.2 buffer ¹⁾ 2.9 pH 4.0 buffer ²⁾ 1.2 pH 6.8 buffer ³⁾ 2.8 water 2.4 pH 7.5 buffer ⁴⁾ 1.4 1) Prepare 1,000 ml by adding 7.0 ml of hydrochloric acid and water to 2.0 g of sodium chloride
2) pH 4.0 acetate buffer
3) pH 6.8 Phosphate Buffer : Water Mixture (1:1)
4) Dissolve 27.20 g of potassium dihydrogen phosphate and 6.08 g of sodium hydroxide in water to make 4,000 ml, and a mixture of 1 moL/L sodium hydroxide to pH 7.5.

In general, in the process of manufacturing compressed tablets for pharmaceuticals, mixing the main and auxiliary materials, compression tableting, and wet granulation when the fluidity of the powder is poor, drying, compression tableting, and, if necessary, coating process to manufacture pharmaceuticals. do. Solubilization methods such as micellarization method using surfactant, solid dispersion method, etc., which are methods used to increase the dissolution rate of milk thistle having low solubility, were carried out through comparative example experiments.

In the present invention, the adsorbent is used to increase the solubility of milk thistle, a poorly soluble drug, and serves to adsorb and solidify a liquid surfactant. For example, colloidal silica, calcium silicate, and magnesium metasilicate are included, and specifically, magnesium metasilicate and calcium silicate are preferable. However, the present invention is not limited thereto.

The adsorbent is preferably 0.01 to 10.0 parts by weight, more preferably 0.05 to 5.0 parts by weight, and most preferably 0.1 to 2.5 parts by weight, based on 1 part by weight of milk thistle. If its content is less than 0.01 parts by weight, the adsorption of surfactants and the like may not be sufficient, and if it is 10.0 parts by weight or more, it may be excessively adsorbed and the formulation may not be formed.

The particle size of the adsorbent in the present invention may be, for example, 10-200 μm, specifically 10-180 μm, 20-180 μm, 30-170 μm, 40-160 μm, 50-150 μm, 60-140 μm, 70-130 μm, 80 to 120 μm, 90 to 110 μm or 95 to 105 μm. However, the present invention is not limited thereto.

The surfactant used in the present invention serves to solubilize poorly soluble drugs, and any surfactant that is pharmaceutically acceptable in the art can be used. For example, polyoxyethylene alkyl ethers, polyoxyethylene castor oils (eg, ^{Cremophor ⓡ} RH40, etc.), polyoxyethylene sorbitan fatty acid esters (eg, polysorbate 80, etc.), Polyoxyglycerides (eg, ^{Jeluther ⓡ} 44/14, etc.), polyoxyethylene stearate, macrochol 15 hydroxystearate, poloxamer, etc. may be used. Specifically, it is preferable to use polysorbate 80, Cremophor ⓡ RH40, and Jeluther ⓡ 44/14. However, the present invention is not limited thereto.

In the present invention, the content of the surfactant is preferably 0.01 to 10.0 parts by weight, more preferably 0.05 to 5.0 parts by weight, and most preferably 0.1 to 2.5 parts by weight, based on 1 part by weight of milk thistle. If its content is less than 0.01 parts by weight, the solubilization of the active ingredient is not sufficient, and if it is 10.0 parts by weight or more, it is excessively solubilized and the formulation may collapse due to moisture during storage.

In the present invention, the dissolution enhancer serves to enhance the dissolution and absorption of milk thistle, a poorly soluble drug, in the body after ingestion of the tablet. Examples include polyvinylpyrrolidone and hypromellose. However, the present invention is not limited thereto.

The dissolution enhancer is preferably 0.01 to 5.0 parts by weight, more preferably 0.05 to 2.5 parts by weight, and most preferably 0.1 to 1.0 parts by weight, based on 1 part by weight of milk thistle. If its content is less than 0.01 parts by weight, the solubilization of the active ingredient is not sufficient, and if it is 5.0 parts by weight or more, it is excessively solubilized and the formulation may collapse due to moisture during storage.

In the present specification, a tablet refers to a product made easy to take by compressing a powdered medicine into a small disk shape. The tablet may contain particles and excipients.

As used herein, the particle has a structure including a core part containing milk thistle and an adsorbent, and a shell part containing a surfactant and a dissolution enhancer. The particles may be included in a single or plural number in the tablet, and may exist in a mixed state with other components such as excipients in the tablet. However, the present invention is not limited thereto.

In the present specification, the core portion refers to the central portion of the particles included in the tablet. Specifically, the core part is a part containing milk thistle and an adsorbent, and is coated by the following shell part to form particles.

In the present specification, the shell portion refers to the surface portion of the particles included in the tablet. Specifically, the shell portion includes a surfactant and a dissolution enhancer, and the core portion is coated to form particles.

The composition of the present invention may include a pharmaceutically acceptable excipient. The excipient may be used when formulating a solid for oral administration, and may include, for example, a diluent, a binder, a disintegrant, and a lubricant. However, the present invention is not limited thereto.

The content of the excipient is preferably 0.1 to 10.0 parts by weight, more preferably 1.0 to 10.0 parts by weight, and most preferably 1.0 to 5.0 parts by weight, based on 1 part by weight of milk thistle. However, the present invention is not limited thereto.

As the diluent, at least one selected from starch, microcrystalline cellulose, lactose, lactose hydrate, glucose, di-mannitol, and dextrin may be physically mixed or a mixture dried after dissolving and dispersing may be used.

Examples of the binder include cellulose derivatives such as low-substituted hydroxypropyl cellulose; natural gums such as xanthan gum, alginate, gum arabic, and the like; Sugars such as starch, pregelatinized starch and the like can be used.

As the disintegrant, starch or modified starch such as sodium starch glycolate, corn starch, potato starch, pregelatinized starch; celluloses such as microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose; alginic acids such as sodium alginate or alginic acid; crosslinked celluloses such as croscarmellose sodium; Cross-linked polymers, such as crospovidone, etc. can be mixed and used.

The lubricants include silicic anhydride, talc, stearic acid, magnesium stearate, alkaline earth metal calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, glycerin fatty acid derivatives such as glyceryl monostearate, glyceryl behenate and glyceryl palmitate stearate. Late, polyethylene glycol 6000, and the like, and in addition to those commonly used as lubricants in the art, all are possible. In addition, pharmaceutically acceptable additives may be selectively used as various selected additives such as colorants and fragrances.

In the composition of the present invention, an effective amount of an effective drug means an amount required to achieve treatment of a disease. In general, the effective amount of the effective drug is determined by the type of disease, the severity of the disease, the type and content of excipients other than the active drug contained in the composition, the dosage form, the patient's age, weight, general health status, sex, diet, administration time, route of administration, It can be adjusted depending on various factors including the duration of treatment and the drugs used at the same time. In the case of milk thistle, which is the effective drug of the present invention, it is preferable to administer 175 mg to 700 mg in total, once or several times a day, based on an adult (60 kg/person). When used in excess, allergic reactions may occur due to side effects.

In addition, the composition of the present invention is formulated into oral dosage forms such as tablets, capsules, powders, and granules, and tablets are particularly preferred.

The present invention provides a pharmaceutical composition for preventing or treating liver disease, comprising a tablet comprising a core part comprising milk thistle and an adsorbent, a surfactant, and a dissolution enhancer, and a tablet comprising particles comprising a shell part coating the core part do.

As used herein, liver disease refers to a disease in which the function of the liver is impaired due to bacteria or the like. For example, it may include hepatitis, liver cirrhosis, hepatotoxicity, fatty liver, alcoholic liver disease, liver abscess, and liver atrophy. However, the present invention is not limited thereto.

Silymarin, one of the active ingredients of milk thistle in the present invention, is one of the therapeutic agents for liver disease. For example, it can be used to treat liver diseases such as hepatitis and liver cirrhosis. However, the present invention is not limited thereto.

The present invention provides a health functional food for improving liver function, comprising a tablet comprising a core part containing milk thistle and an adsorbent, a surfactant, and a dissolution enhancer, and a tablet containing particles including a shell part coating the core part.

In the present specification, liver function improvement means that the antioxidant function of milk thistle component enhances liver detoxification, fatigue recovery, and the like. However, it is not limited to these effects.

The present invention provides a method for preparing a tablet, comprising the steps of adsorbing a solution of a surfactant and a dissolution enhancer to a mixture of milk thistle and an adsorbent, and drying the adsorbed solution.

Surfactants, dissolution enhancers, milk thistle, adsorbents, and excipients in the preparation method are those exemplified in the previous part of this specification.

In the present invention, the mixture of milk thistle and the adsorbent may be mixed by putting the milk thistle powder and the adsorbent powder together in a mixer, a mixing board, or a mixing container, and then mixing them evenly. However, it is not limited to this method.

The surfactant and dissolution enhancer solution of the present invention can be prepared by putting the surfactant and the dissolution enhancer in a container in which purified water is placed and then dissolving by heating. However, it is not limited to this method.

In the present invention, the adsorption step is to pour the surfactant and dissolution enhancer solution into the adsorption container coated with the mixture of milk thistle and the adsorbent to the extent that the mixture is submerged to adsorb the components of the solution on the surface of the mixture. can be performed. However, it is not limited to this method.

In the present invention, the drying step may be performed after the adsorption step. Drying may be performed using any drying method used in the art without limitation.

Through the adsorption and drying steps, it is possible to prepare particles including a core part containing milk thistle and an adsorbent, and a shell part containing a surfactant and a dissolution enhancer.

In addition, the manufacturing method of the present invention may be performed after the drying step, further comprising mixing and tableting a pharmaceutically acceptable excipient.

In the present invention, the tableting may be performed using a tableting technique known in the art without limitation.

Hereinafter, examples will be given to describe the present invention in detail.

Example

1. Preparation of Milk Thistle Tablets

1) Surfactant, dissolution enhancer and purified water were placed in a container and dissolved by heating at 60°C

2) After mixing milk thistle, adsorbent and diluent, the lysate of 1) was added and adsorbed.

3) The adsorbate of 2) was put in a dryer and dried.

4) After sieving the dried particles of 3), the sieved particles, a diluent, a disintegrant and a lubricant were added and mixed, followed by tableting using a tableting machine.

Milk thistle-containing products were prepared by varying the content ratio of each component (see Tables 2 and 3).

purpose of mixing Raw material name Example 1.1 Example 1.2 Example 1.3 Example 1.4 Example 1.5 Example 1.6 active ingredient milk thistle 175.0 175.0 175.0 175.0 175.0 175.0 Surfactants Polysorbate 80 105.0 105.0 - - - - Cremophor®RH40 - - 105.0 105.0 - - Jeluther® 44/14 - - - - 105.0 105.0 dissolution enhancer Povidone K30 105.0 105.0 105.0 105.0 105.0 105.0 hypromellose - - - - - - absorbent Magnesium metasilicate aluminate 150.0 - 150.0 - 150.0 - calcium silicate - 150.0 - 150.0 - 150.0 diluent Microcrystalline Cellulose 300.0 300.0 300.0 300.0 300.0 300.0 disintegrant Croscarmellose Sodium 30.0 30.0 30.0 30.0 30.0 30.0 Sodium Lauryl Sulfate 20.0 20.0 20.0 20.0 20.0 20.0 lubricant magnesium stearate 10.0 10.0 10.0 10.0 10.0 10.0 solvent Purified water 300.0 300.0 300.0 300.0 300.0 300.0

(Unit: mg)

purpose of mixing Raw material name Example 1.7 Example 1.8 Example 1.9 Example 1.10 Example 1.11 Example 1.12 active ingredient milk thistle 175.0 175.0 175.0 175.0 175.0 175.0 Surfactants Polysorbate 80 105.0 105.0 - - - - Cremophor®RH40 - - 105.0 105.0 - - Jeluther® 44/14 - - - - 105.0 105.0 dissolution enhancer Povidone K30 - - - - - - hypromellose 105.0 105.0 105.0 105.0 105.0 105.0 absorbent Magnesium metasilicate aluminate 150.0 - 150.0 - 150.0 - calcium silicate - 150.0 - 150.0 - 150.0 diluent Microcrystalline Cellulose 300.0 300.0 300.0 300.0 300.0 300.0 disintegrant Croscarmellose Sodium 30.0 30.0 30.0 30.0 30.0 30.0 Sodium Lauryl Sulfate 20.0 20.0 20.0 20.0 20.0 20.0 lubricant magnesium stearate 10.0 10.0 10.0 10.0 10.0 10.0 solvent Purified water 300.0 300.0 300.0 300.0 300.0 300.0

(Unit: mg)

2. Check the dissolution rate

2.1. Preparation of sample solution

The composition prepared in Example 1 was placed in 900 mL of purified water at 37° C. and tested at 50 rotations per minute by the second dissolution test method among the general test methods of the Korean Pharmacopoeia. At 15, 30, 45 and 60 minutes from the start of the dissolution test, 5 ml of the eluate was taken and filtered through a 0.45 µm membrane filter to obtain a sample solution.

2.2. Preparation of standard solution

10 mg of silybin standard was precisely weighed, placed in methanol, and 100 ml was used as a standard solution.

2.3. HPLC condition setting

- Column: Capcellpak C18, 5㎛, 4.6 × 150㎜

- Detection wavelength: UV 288nm

- Mobile phase: mobile phase A and mobile phase B gradient concentration control

Mobile Phase A - Water, Methanol and 85% Phosphoric Acid Solution (130:70:1)

Mobile phase B - water, methanol, 85% phosphoric acid solution (100:100:1)

hours (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 28 0 100 35 0 100 36 100 0

(Flow rate: 1.0 mL/min, injection amount: 10 μL, oven temperature: 40°C)

2.4. Calculation of dissolution rate

Test according to the HPLC method, measure the peak areas of the sample solution and the standard solution through the peaks of silycristine, silydianin, silybin A, silybin B, isosilybin A, and isosilybin B, and then calculate the dissolution rate by the following formula Calculated. The average values of the dissolution rates of Examples 1.1 to 1.12 are shown in Table 5.

[Formula 1]

Amount of silymarin [as silybin (C25H22O10)]

[Formula 2]

Amount of silycricristine (C25H22O10) and silydianin (C25H22O10)

[Formula 3]

Amount of silybin A (C25H22O10) and silybin B (C25H22O10)

[Formula 4]

Amount of isosilybin A (C25H22O10) and isosilybin B (C25H22O10)

(F1 = silycristine peak area of the sample solution, F2 = silydianine peak area of the sample solution, F3 = silybin A peak area of the sample solution, F4 = silybin B peak area of the sample solution, F5 = isosilybin A peak area of the sample solution , F6 = isosilybin B peak area of the sample solution, F7 = silybin A peak area of the standard solution, F8 = silybin B peak area of the standard solution, m1 = silybin standard weight)

division(%) 15 minutes 30 minutes 45 minutes 60 minutes Example 1.1 75.2 85.6 88.3 91.5 Example 1.2 69.4 75.5 82.1 86.0 Example 1.3 76.1 83.3 85.4 89.2 Example 1.4 68.3 77.9 79.5 81.1 Example 1.5 73.1 84.4 87.0 89.6 Example 1.6 64.3 79.5 86.8 87.2 Example 1.7 55.3 74.4 78.9 79.1 Example 1.8 48.1 55.4 63.0 72.8 Example 1.9 57.3 66.7 71.5 75.8 Example 1.10 45.4 58.2 65.4 71.3 Example 1.11 56.3 72.8 78.5 79.8 Example 1.12 41.7 52.1 66.4 72.2

Among the compositions of Examples 1.1 to 1.12, Examples 1.1, 1.3, in which polysorbate 80, Cremophor RH40, Geluser 44/14, and Povidone K30 as a dissolution enhancer were used as surfactants and magnesium metasilicate was used as an adsorbent. 1.5 showed the best dissolution rate results.

3. Stability Experiment

In order to confirm the stability of Milk Thistle, Examples 1.1, 1.3, and 1.5 with excellent dissolution rates were stored at a temperature of 40 ° C. and a relative humidity of 75% R/H. Stability was evaluated. As for HPLC analysis conditions, the milk thistle content was measured under the same conditions as those of the dissolution test (see Table 6).

division(%) Early 1 month 2 months 3 months Example 1.1 103.3 101.7 100.3 99.5 Example 1.3 101.8 99.8 100.1 99.7 Example 1.5 102.5 102.8 101.0 99.4

In the case of Examples 1.1, 1.3 and 1.5, the content decreased within about 5% after 3 months, and it was found that the stability of the content was excellent.

Comparative Example 1

175.0 mg of milk thistle, 5.0 mg of polyoxy40 hydrogenated castor oil, and 120.0 mg of povidone were dissolved in 500.0 mg of ethanol to obtain a binding solution. After mixing 24.4 mg of colloidal silicon dioxide and 10.0 mg of croscarmellose sodium, the binding solution was added and kneaded and granulated. The granulated material was put in a dryer, dried, and sieved using a sieve, and then 10.0 mg of croscarmellose sodium and 2.0 mg of magnesium stearate were added and finally mixed, and then the contents per capsule were filled with 346.4 mg using a capsule filling machine.

Comparative Example 2

175.0 mg of milk thistle, 365.0 mg of polyethylene glycol 400, 120.0 mg of polyoxyl 40 hydrogenated castor oil, 480.0 mg of polysorbate 80, and 60.0 mg of propylene glycol were mixed and dissolved by heating and stirring at 80°C to prepare the contents. . Using a soft capsule molding filling machine, 1,200 mg of contents per soft capsule were filled.

Comparative Example 3

Milk thistle 175.0 mg, polysorbate 80 350.0 mg, poloxamer 407 200.0 mg, propylene carbonate 200.0 mg, polyethylene glycol 400 380.0 mg, and propylene glycol 20.0 mg were mixed and dissolved by stirring at 80 ° C., heating and stirring manufacture the contents. Using a soft capsule molding filling machine, 1,325 mg of the contents per soft capsule was filled.

Comparative Example 4

700 mg of magnesium metasilicate aluminate was added to 1,200 mg of the contents prepared in Comparative Example 2, mixed, and adsorbed. After sieving the adsorbate, 70 mg of sodium lauryl sulfate, 45 mg of crospovidone, 70 mg of low-substituted hydroxypropyl cellulose, and 20 mg of magnesium stearate were added and mixed, followed by tableting using a tableting machine.

Comparative Example 5

700 mg of magnesium metasilicate aluminate was added to 1,325 mg of the contents prepared in Comparative Example 3, mixed, and adsorbed. After sieving the adsorbate, 70 mg of sodium lauryl sulfate, 45 mg of crospovidone, 70 mg of low-substituted hydroxypropyl cellulose, and 20 mg of magnesium stearate were added and mixed, followed by tableting using a tableting machine.

Dissolution rate calculation result of comparative example

The average values of the dissolution rates of Comparative Examples 1 to 5 are shown in Table 7. In the case of Comparative Example, Comparative Example 2 showed the best dissolution rate.

division(%) 15 minutes 30 minutes 45 minutes 60 minutes Comparative Example 1 20.4 20.9 21.4 21.2 Comparative Example 2 70.5 84.9 85.3 89.7 Comparative Example 3 68.4 72.8 80.7 86.3 Comparative Example 4 65.2 72.7 82.4 85.0 Comparative Example 5 62.5 70.3 82.1 83.6

Stability test result of comparative example

In order to confirm the stability of Milk Thistle, Comparative Examples 2, 3, 4 and 5, which had excellent dissolution rates, were stored at a temperature of 40°C and a relative humidity of 75% R/H. In the process, stability was evaluated. For HPLC analysis, the milk thistle content was measured under the same conditions as the dissolution test (see Table 8).

division(%) Early 1 month 2 months 3 months Comparative Example 2 104.5 101.3 95.4 89.3 Comparative Example 3 103.4 99.4 96.3 91.6 Comparative Example 4 101.0 96.1 95.8 90.8 Comparative Example 5 102.7 97.7 94.3 90.4

As a result of the stability test, Comparative Examples 2, 3, 4 and 5 showed a content decrease of about 10% or more after 3 months, showing a relatively large content decrease rate compared to Examples.

Claims (15)

a core part including milk thistle and an adsorbent; and
Containing a surfactant and a dissolution enhancer, the shell portion coating the core portion; including particles comprising a,
The adsorbent is magnesium metasilicate aluminate,
The surfactant is at least one selected from the group consisting of polyoxyethylene castor oils, polyoxyethylene sorbitan fatty acid esters and polyoxyglycerides,
The dissolution enhancer is povidone,
A tablet comprising 0.1 to 3.0 parts by weight of the adsorbent, 0.1 to 3.0 parts by weight of the surfactant, and 0.1 to 2.0 parts by weight of the dissolution enhancer, based on 1 part by weight of the milk thistle.
The tablet of claim 1, wherein the milk thistle has a particle diameter of 0.1 to 50 μm, and the adsorbent has a particle diameter of 50 to 150 μm.
delete delete delete delete delete delete The tablet of claim 1, wherein the tablet further comprises a pharmaceutically acceptable excipient, and the particles and the excipient are in a mixed state.
The tablet according to claim 9, wherein the excipient is at least one selected from the group consisting of microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate.
The tablet according to claim 9, wherein the excipient is included in an amount of 1.0 to 5.0 parts by weight based on 1 part by weight of milk thistle.
A pharmaceutical composition for preventing or treating liver disease, comprising the tablet of any one of claims 1, 2 and 9 to 11.
A health functional food for improving liver function, comprising the tablet of any one of claims 1, 2 and 9 to 11.
adsorbing a solution of a surfactant and a dissolution enhancer to a mixture of milk thistle and an adsorbent; and
Including; drying the adsorbed solution;
The adsorbent is magnesium metasilicate aluminate,
The surfactant is at least one selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid esters, and polyoxyglycerides,
The dissolution enhancer is povidone,
The method for manufacturing a tablet, wherein the adsorbent is included in an amount of 0.1 to 3.0 parts by weight, the surfactant is 0.1 to 3.0 parts by weight, and the dissolution enhancer is 0.1 to 2.0 parts by weight based on 1 part by weight of the milk thistle.
The method of claim 14, further comprising mixing and tableting a pharmaceutically acceptable excipient after the drying step.

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