KR102528183B1 - Wet granule formulation containing Centipeda minima extract and ion exchange resin, and method for preparing the same - Google Patents

Abstract

The present invention relates to a wet granulation formulation containing an extract of P. chinensis and an ion exchange resin and a method for producing the same. This ease has the effect. In addition, the wet granulation formulation containing the extract of chinensis parsley and the ion exchange resin has an excellent dissolution rate of the main component and is suitable for use as an oral formulation because it does not have a bitter taste and has good dosage compliance.

Description

Wet granule formulation containing Centipeda minima extract and ion exchange resin, and method for preparing the same}

It relates to a wet granulation formulation containing an extract of P. chinensis and an ion exchange resin and a method for preparing the same.

Brevilin A, known as the main component of centipeda minima extract, exhibits excellent kinase inhibitory and anti-inflammatory effects on the JAE-STAT signaling mechanism, which is the inventive mechanism of autoimmune diseases such as psoriasis and rheumatoid arthritis, and has high development potential. It is a natural product extract.

Brevilin A inhibits and inhibits JAK-STAT signaling, and is effective in autoimmune diseases such as rheumatoid arthritis. , rhinitis, ulcerative colitis, asthma, empyema, dermatitis, ailment, seawater, paracetamol, and whooping cough (childhood disease), as well as autoimmune diseases including rheumatoid arthritis, cancer or tumor, and premature alopecia, patchy alopecia, alopecia areata, and neurogenic alopecia , pityroid alopecia, trichotillomania, malignant hair loss, female pattern hair loss, male pattern hair loss, androgenic hair loss, telogen effluvium, tinea capitis, alopecia totalis, hypotrichosis, hereditary alopecia or generalized alopecia, etc. can

Labrafac lipophile, one of the extraction liquids used for the extract of P. chinensis, is a very hydrophobic and poorly water-soluble substance with an HLB (Hydrophilic lipophilic balance) value of 1. proceed On the other hand, Labrafac shows a high affinity with the active ingredient in the extract and shows the advantage of easy extraction, but due to poor water solubility, it has low bioavailability and severe stimulation in the body, so it is difficult to use because it has a strong bitter taste for oral use.

As a follow-up study of Korean Patent Publication No. 10-2020-0085024 'Selective Extraction Method of Natural Substances', the present inventors combined an O/W microemulsified liquid material with low bioavailability with an ion exchange resin to solidify the composite. It was intended to secure the physical and chemical safety of the extract and to secure the advantages of easy storage and handling of the preparation prepared using it, as well as reducing the bitter taste of the extract through the reaction of the ion exchange resin, and then producing the extract through granulation. After research to improve the dissolution rate of Brevilin A, which is my main ingredient, the present invention was completed.

One object of the present invention is,

It is to provide a solidified composite comprising an ion exchange resin and an extract of chinensis chinensis containing a lipophilic solubilizing agent.

Another object of the present invention is,

It is to provide a wet granulation formulation containing an extract of P. chinensis formed by mixing a P. chinensis extract containing a lipophilic solubilizing agent, an ion exchange resin, and an organic solvent.

Another object of the present invention is,

It is to provide a method for preparing a wet granulation formulation containing the above-mentioned chinensis extract.

Another object of the present invention is,

It is to provide a wet granulation formulation formed by mixing an organic solvent and a common parsnip extract containing a lipophilic solubilizing agent.

In order to achieve the above purpose,

One aspect of the present invention is a medulla grass containing a lipophilic solubilizing agent ( Centipeda minima ) Extract; And it provides a solid composite comprising an ion exchange resin.

The chinensis extract may contain Brevilin A or a derivative thereof.

Brevilin A, known as the main component of Centipeda minima extract, is known to exhibit excellent kinase inhibitory effects and anti-inflammatory effects on the JAE-STAT signaling mechanism, which is the inventive mechanism of autoimmune diseases such as psoriasis and rheumatoid arthritis.

Brevilin A inhibits or inhibits the JAK-STAT signal transduction process, thereby preventing colds, open mouths, diabetes, tinnitus, leukemia, coloriosis, rhinitis, ulcers, asthma, empyema, dermatitis, ailments, seawater, paracetamol, and whooping cough (a pediatric disease) as well as rheumatism. Arthritis and autoimmune diseases including cancer or tumors, and premature alopecia, patchy alopecia, alopecia areata, neurogenic alopecia, pityroid alopecia, trichotillomania, malignant alopecia, female pattern baldness, androgenetic alopecia, androgenetic alopecia, telogen effluvium It can be effective in treating autoimmune diseases such as tinea capitis, alopecia totalis, hypotrichosis, hereditary hair loss or generalized hair loss.

Another aspect of the present invention is wet granules containing Centipeda minima extract containing a lipophilic solubilizing agent and a solid composite containing an ion exchange resin, and an organic solvent containing a Centipeda minima extract. provide a formulation.

Another aspect of the present invention is to prepare a solid composite by mixing an ion exchange resin with a centipeda minima extract containing a lipophilic solubilizing agent; And mixing the solid complex with an organic solvent; provides a method for preparing a wet granulation formulation containing a burdock extract.

Another aspect of the present invention is,

Preparing a solid composite by mixing an ion exchange resin and an extract of Centipeda minima containing the lipophilic solubilizing agent; and mixing the solid composite with an organic solvent.

Another aspect of the present invention is,

To provide a wet granulation formulation formed by mixing an organic solvent with a centipeda minima extract containing a lipophilic solubilizer.

The present invention relates to a wet granulation formulation containing an extract of P. chinensis and an ion exchange resin and a method for producing the same. This ease has the effect. In addition, the wet granulation formulation containing the extract of chinensis parsley and the ion exchange resin has an excellent dissolution rate of the main component and is suitable for use as an oral formulation because it does not have a bitter taste and has good dosage compliance.

1 is a view showing a manufacturing process diagram of the ion-exchange resin solid composites according to Examples 1 to 6.
Figure 2 is a view showing a manufacturing process diagram of the extract-organic solvent wet granulation formulation according to Example 7.
Figure 3 is a view showing a manufacturing process diagram of the solid composite-organic solvent wet granulation formulation according to Examples 8 and 9 (Acid extract - ion exchange resin).
Figure 4 is a view showing the results of evaluating the dissolution rate of Comparative Example 1, Example 4, and Examples 6 to 9 under pH 1.2 conditions.
Referring to FIG. 4 , the wet granulation formulation prepared through the method for preparing a wet granulation formulation containing an organic solvent of the present invention using an organic solvent is an extract prepared through the conventional manufacturing method of a parsley extract according to Comparative Example 1 It can be seen that the dissolution rate is excellently improved compared to
5 is a view showing the results of evaluating the dissolution rate of Comparative Example 1, Example 4, and Examples 6 to 9 under pH 6.8 conditions.
Referring to FIG. 5 , the wet granulation formulation prepared through the method for preparing a wet granulation formulation containing an extract of P. It can be seen that the dissolution rate is excellently improved compared to

Hereinafter, the present invention will be described in detail.

On the other hand, the embodiments of the present invention can be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. Furthermore, "include" a certain component throughout the specification means that other components may be further included without excluding other components unless otherwise stated.

Terms used in this specification are only used to describe exemplary embodiments, and are not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as "comprise", "comprise" or "having" are intended to indicate that there is an embodied feature, number, step, component, or combination thereof, but one or more other features or It should be understood that the presence or addition of numbers, steps, components, or combinations thereof is not precluded.

Since the present invention can have various changes and various forms, specific embodiments will be exemplified and described in detail below. However, it should be understood that this is not intended to limit the present invention to the specific disclosed form, and includes all modifications, equivalents, and substitutes included in the spirit and scope of the present invention.

Technical terms used herein are only for referring to specific embodiments and are not intended to limit the present invention. And, as used herein, the singular forms also include the plural forms unless the phrases clearly indicate the opposite. In addition, the meaning of 'including' or 'including' as used herein specifies a specific characteristic, region, integer, step, operation, element, or component, and other specific characteristics, regions, integers, steps, operations, elements, or The addition of ingredients is not excluded.

One aspect of the present invention is a medulla grass containing a lipophilic solubilizing agent ( Centipeda minima ) Extract; And it provides a solid composite comprising an ion exchange resin.

The ion exchange resin may have, for example, a gel type or macroporous matrix. The ion exchange resin may be an anion exchange resin or a cation exchange resin. Anion exchange resins have covalently bound cationic groups. Cation exchange resins have covalently bound anionic groups. The ion exchange resin used in the present invention may preferably have an anionic group as a cation exchange resin.

The cation exchange resin may be used without limitation as long as it does not negatively affect the pharmacological activity of the extract of chinensis chinensis or the active ingredient contained in the chinensis chinensis extract, and for example, a crosslinked polymer of methacrylic acid and divinylbenzene ( The carboxylic acid functional group of methacrylic acid and potassium form weakly acidic salts (eg C100HMR®, C108DR®, C115HMR®, C115KMR®, IRP64®, IRP88®, INDION204®, INDION214®, INDION234®, INDION234S®, INDION264 ®, INDION414®, INDION464® or INDION294® (polacrylin potassium)), cross-linked polymers of styrenesulfonic acid and divinylbenzene (sulfonic acid groups of styrenesulfonic acid and sodium form strongly acidic salts) (eg IRP69®, INDION224®, INDION254 ®, INDION404®, INDION284®), or cross-linked polymers of styrene and divinylbenzene (eg AP143/1083®, INDION244®).

The chinensis extract may contain Brevilin A or a derivative thereof.

The non-polar natural substance, which is an active ingredient extracted from the Chinese parsley, can inhibit or inhibit the JAK-STAT signal transduction process.

Brevilin A is a natural substance, and it is widely known that it inhibits JAK (janus kinase activity) and STAT3 signal transduction in cancer cells.

That is, Brevilin A inhibits and inhibits JAK-STAT signaling, and is effective in autoimmune diseases such as rheumatoid arthritis.

Brevilin A inhibits or inhibits the JAK-STAT signal transduction process, thereby preventing colds, open mouths, diabetes, tinnitus, leukemia, coloriosis, rhinitis, ulcers, asthma, empyema, dermatitis, ailments, seawater, paracetamol, and whooping cough (a pediatric disease) as well as rheumatism. Arthritis and autoimmune diseases including cancer or tumors, and premature alopecia, patchy alopecia, alopecia areata, neurogenic alopecia, pityroid alopecia, trichotillomania, malignant alopecia, female pattern baldness, androgenetic alopecia, androgenetic alopecia, telogen effluvium It can be effective in treating autoimmune diseases such as tinea capitis, alopecia totalis, hypotrichosis, hereditary hair loss or generalized hair loss.

The medulla extract is preferably,

Preparing a primary extract by extracting the extract of medulla chinensis;

Secondary extraction by mixing a phase separation composition containing a lipophilic solubilizer and water in the first extraction solution; and

It may be extracted by an extraction method comprising the step of obtaining a non-polar natural material by separating the upper layer of the phase-separated solution,

Korean Patent Laid-open Publication No. 10-2020-0085024 'Selective Extraction Method of Natural Substances' Manufactured by the method described in the examples, or prepared by a method applied to the extent that a person skilled in the art can appropriately modify it according to the experimental environment. Not limited.

Specifically, as in the method described in the examples of Korean Patent Laid-open Publication No. 10-2020-0085024, the natural raw material, jungmeori grass (middle head chinensis), was obtained from Goesan Medicinal Herb Organic Agricultural Products Cooperative Association (https://natural-herbcokr). Vinegar (Middle Headgrass, Yeongcheon) was purchased, washed and dried, and 10 g of Middle Head Head hay was hot water extracted with 400 mL of 80% ethanol to obtain a primary extract. Thereafter, the primary extract was concentrated under reduced pressure to remove ethanol, and the primary extract concentrated under reduced pressure and the phase separation composition (nonionic surfactant, lipophilic solubilizer) were mixed, stirred for 10 minutes, and then allowed to stand for 60 minutes. The phase-separated supernatant was prepared by separating.

The extraction method disclosed in Korean Patent Publication No. 10-2020-0085024 is disclosed as providing a method for relatively easily extracting non-polar natural substances with high efficiency using a Dissolution-Emulsion Extract (DEE) method. , Steps such as drying can be omitted because the liquid-liquid extraction method using toxic solvents is not used, and since the solvent is harmless to the human body, the extract containing natural substances is separated and immediately used as a product without any other steps. This is possible, and it is disclosed that the absorption rate of the product can be increased due to microemulsion or limiting micelle concentration.

Another aspect of the present invention is,

Provided is a wet granulation formulation containing Centipeda minima extract containing a lipophilic solubilizer and a solid composite containing an ion exchange resin, and an organic solvent.

At this time, the organic solvent may be used without particular limitation as long as it is a C _1-5 alcohol, and for example, methanol, ethanol, isopropyl alcohol or butanol may be used. In the present invention, wet granules containing the extract of P. chinensis were prepared using ethanol as an organic solvent through Examples.

In the present invention, the dissolution rate of the wet granulation formulation was improved by using the organic solvent.

As used herein, the term "granule" is also referred to as "granule" and may include wet granules immediately before tableting.

The above-mentioned hair extract, likewise

Preparing a primary extract by extracting the extract of medulla chinensis;

Secondary extraction by mixing a phase separation composition containing a lipophilic solubilizer and water in the first extraction solution; and

It can be prepared by extraction by an extraction method comprising separating the upper layer of the phase-separated solution to obtain a non-polar natural material,

Korean Patent Laid-open Publication No. 10-2020-0085024 'Selective Extraction Method of Natural Substances' Manufactured by the method described in the examples, or prepared by a method applied to the extent that a person skilled in the art can appropriately modify it according to the experimental environment. Not limited.

The wet granulation formulation may further include at least one pharmaceutically acceptable excipient. At this time, the excipient is not particularly limited as long as it can be appropriately selected and used by those skilled in the art or is a commonly used excipient, for example, lactose, microcrystalline cellulose, cellulose, pregelatinized starch, mannitol, dicalcium phosphate, calcium sulfate or sodium chloride.

In the present invention, wet granules containing the extract of P. chinensis were prepared using lactose through the examples.

The wet granulation composition may further include at least one pharmaceutically acceptable additive selected from adsorbents, stabilizers, sustained-release agents, sweeteners, and lubricants.

The adsorbent may be, for example, colloidal silicon dioxide, hydrous silicon dioxide, light anhydrous silicic acid or magnesium metasilicate aluminate,

The stabilizer is beta-carotene, riboflavin, riboflavin butyrate, locotriboflavin, sodium riboflavin phosphate, ascorbic acid, ascorbyl palmitate, calcium ascorbate, ascorbic acid nicotinamide, sodium ascorbate, dihydroascorbic acid, glutathione, Glutathione disulfide, selenium, selenium sulfide, sodium selenium, sodium selenite, silymarin, resveratrol, pyridoxamine hydrochloride, pyridoxine hydrochloride, pyridoxal phosphate, agaro oligosaccharide, melatonin, ubidecarenone, ornithine, ornithine aspartate , ornithine hydrochloride, arginine, arginine hydrochloride, arginine sodium, arginine glutamate, protoporphyrin disodium, haematoporphyrin, cyclosilic acid, cyiolon, urazamide, azintamide or hymechromone,

The sustained-release agent is a cellulose derivative such as hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, or sodium carboxylmethylcellulose, polyethylene oxide, polyvinylpyrrolidone, guar gum, locust bean gum , It may be polyvinyl acetate, polyvinyl acetate phthalate, polymethacrylate, polyacrylic acid, glycerol monostearate or poloxamer,

The sweetener may be glucose, sucrose, saccharin, sorbitol, aspartame, acesulfame salt or neotime,

The lubricant may be magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide, talc, sodium stearyl fumarate, aluminum magnesium silicate, stearic acid or sucrose fatty acid ester.

The weight ratio of the solid composite and the excipient may be 1:1 to 1:15, but is not necessarily limited thereto, and may be 1:1 to 1:12, 1:2 to 1:10, 1:1 to 1:5, 1 :5 to 1:12, 1:6 to 1:10, 1:8 to 1:10, 1:3, or 1:9.

The wet granulation formulation may include Brevilin A or a derivative thereof.

The wet granulation preparation can be used for oral use, and is particularly suitable for oral use because it has excellent masking effect and has little bitter taste.

One aspect of the present invention,

Preparing a solid complex by mixing an ion exchange resin with an extract of Centipeda minima containing a lipophilic solubilizing agent; and

It provides a method for preparing a wet granulation formulation containing the extract of chinensis chinensis, comprising the step of mixing the solid composite with an organic solvent.

In this case, before mixing the solid composite with the organic solvent, mixing with a pharmaceutically acceptable excipient may be further included.

In addition, before the step of mixing the parsley extract and the ion exchange resin, a pretreatment step of mixing the parsley parsley extract with purified water and stirring for 5 to 50 hours may be further included.

At this time, the weight ratio of the extract of the parsley versicolor and the ion exchange resin may be 1:2 to 1:20, but is not necessarily limited thereto, 1:2 to 1:18, 1:2 to 1:16, 1: 2 to 1:15, 1:2 to 1:12, 1:5 to 1:15, 1:6 to 1:12, 1:8 to 1:12, 1:9 to 1:11, 1:2 to It may be 1:5, 1:3 or 1:10.

The weight ratio of the solid composite and the excipient may be 1:1 to 1:15, but is not necessarily limited thereto, and may be 1:1 to 1:12, 1:2 to 1:10, 1:1 to 1:5, 1 :5 to 1:12, 1:6 to 1:10, 1:8 to 1:10, 1:3, or 1:9.

Another aspect of the present invention is,

Preparing a solid composite by mixing an ion exchange resin and an extract of Centipeda minima containing the lipophilic solubilizing agent; and

Mixing the solid composite with an organic solvent; provides a wet granulation formulation containing a Centipeda minima extract prepared by a method for preparing a wet granulation formulation containing an extract of Centipeda minima .

Another aspect of the present invention is,

Provided is a wet granulation formulation formed by mixing an organic solvent and a Centipeda minima extract containing a lipophilic solubilizer.

Hereinafter, examples and experimental examples of the present invention will be specifically illustrated and described. However, the Examples and Experimental Examples to be described below are merely illustrative of a part of the present invention, and the present invention is not limited thereto.

< Example 1 to Example 6> middle hair Preparation of extract-ion exchange resin solid composites

In order to prepare a solid composite containing a Chinese parsley extract containing a lipophilic solubilizing agent and an ion exchange resin, first, the method disclosed in the Examples of Korean Patent Publication No. 10-2020-0085024, or a person skilled in the art constructed therefrom and a lipophilic solubilizing agent was prepared by a method within a range that can be appropriately applied at a level that does not change the effect.

Then, after adding 300 mL of purified water and the extract of chinensis in the amount shown in Table 1 to a 1,000 mL glass container, the pretreatment was stirred for 12 to 24 hours at 100 rpm under a temperature of about 50 ° C. Subsequently, the ion exchange resin was added in the type and capacity according to Table 1, and then stirred under the same conditions for 24 hours. Then, the whole amount was taken and centrifuged, and the ionic compound of the lower layer was taken, filtered under reduced pressure with a 200 nm filter, and dried in a tray dryer to prepare a polyps extract-ion exchange resin solid composite according to Examples 1 to 6. .

The manufacturing process of the extract-ion exchange resin solid composites of Examples 1 to 6 is shown in FIG. 1 .

ion exchange resin
type chinensis extract
(g) ion exchange resin
(g) Pretreatment Stirring Time
(hour) Example 1 Dowex 1x2 One 3 12 Example 2 Dowex 1x2 0.3 3 12 Example 3 Dowex 1x8 One 3 12 Example 4 Dowex 1x8 0.3 3 12 Example 5 Dowex 1x2 One 3 24 Example 6 Dowex 1x2 One 10 24

< Example 7> middle hair Extract - organic solvent wet granulation formulation

Centella asiatica extract - To prepare an organic solvent wet granulation formulation, 1 g of diorama chinensis extract containing a lipophilic solubilizing agent prepared in the same manner as in Examples 1 to 6 and 3.945 g of ethanol was weighed and mixed for 5 minutes using a vortex mixer, and used as a combined solution of chinensis extract and ethanol. Then, 9 g of lactose (Glanulac ^® 140) was weighed and mixed with the combined solution of the above-mentioned parsley extract and ethanol. Mixing was carried out using a plastic bag, and mixing was performed by adding 1 mL of the binding solution using a pipette. After mixing, the mixture was sieved through a #35 sieve and then tray dried at a temperature of about 50° C. for 12 hours to prepare an extract-organic solvent wet granulation formulation according to Example 7.

The manufacturing process of the extract-organic solvent wet granulation formulation of Example 7 is shown in FIG. 2.

< Example 8 and Example 9> ( middle hair extract - ion exchange resin) solid compound - organic solvent wet granulation formulation

In order to prepare the solid composite-organic solvent wet granulation formulation, first, the extract-ion exchange resin solid composite prepared in Example 6 was prepared in the amount shown in Table 2 below, and 9 g of lactose (Glanulac ^® 140) was added. or 3 g was weighed and then mixed. Mixing was carried out using a plastic bag. Then, 3.945 g of ethanol was added by 1 mL each using a pipette and mixed using a plastic bag. After mixing, the mixture was sieved through a #35 sieve and then tray dried at about 50° C. for 12 hours to prepare solid composite-organic solvent wet granulation formulations according to Examples 8 and 9.

The manufacturing process of the solid composite-organic solvent wet granulation formulations of Examples 8 and 9 is shown in FIG. 3 .

lactose
(g) Chinese parsley extract - ion exchange resin
solid complex
(g) Example 8 9 One Example 9 3 One

< comparative example 1> lipophilicity containing a solubilizing agent middle hair extract

By the method described in the Examples of Korean Patent Publication No. 10-2020-0085024 'Selective Extraction Method of Natural Substances', an extract of P. chinensis containing a lipophilic solubilizing agent was prepared.

Specifically, as in the method described in the examples of Korean Patent Laid-open Publication No. 10-2020-0085024, the natural raw material, jungmeori grass (middle head chinensis), was obtained from Goesan Medicinal Herb Organic Agricultural Products Cooperative Association (https://natural-herbcokr). Vinegar (Middle Headgrass, Yeongcheon) was purchased, washed and dried, and 10 g of Middle Head Head hay was hot water extracted with 400 mL of 80% ethanol to obtain a primary extract. Thereafter, the primary extract was concentrated under reduced pressure to remove ethanol, and the primary extract concentrated under reduced pressure and the phase separation composition (nonionic surfactant, lipophilic solubilizer) were mixed, stirred for 10 minutes, and then allowed to stand for 60 minutes. The phase-separated supernatant was prepared by separating.

The extraction method disclosed in Korean Patent Publication No. 10-2020-0085024 is disclosed as providing a method for relatively easily extracting non-polar natural substances with high efficiency using a Dissolution-Emulsion Extract (DEE) method. , Since the liquid-liquid extraction method using toxic solvents is not used, steps such as drying can be omitted, and since the solvent is harmless to the human body, the extract containing natural substances is separated and immediately used as a product without any other steps. This is possible, and it is disclosed that the absorption rate of the product can be increased due to microemulsion or limiting micelle concentration.

< Experimental example 1> Evaluation of ion exchange resin binding rate and drug amount

Centella asiatica extract prepared in Example 1 to Example 6 - Centella asiatica extract of ion exchange resin solid complex - ion exchange resin binding rate was evaluated, and ion exchange resin extract according to the type and ratio of ion exchange resin - ion The drug binding ratio according to the exchange resin binding ratio and solubilization time was confirmed.

For the evaluation of the binding rate of ion exchange resin, the extract of tungsten chinensis was pre-solubilized for 12 or 24 hours, and then the concentration immediately before adding the resin was set as 100% standard concentration, and after adding the resin, the concentration decreased. The drug concentration was confirmed, and after stirring, 3 mL of the solution after 30 minutes, 1 hour, 2 hours, 4 hours, and 24 hours, respectively, was filtered using a membrane filter having 450 nm pores, and a solution obtained was used. In order to check the concentration of the drug bound to the resin for each time period, the concentration of the drug that decreases after the resin was added from the concentration before the resin was added was checked at each specific time.

(Concentration of the solution before inserting the resin) - (Concentration of the solution at the corresponding time after inserting the resin) = Concentration of the drug bound to the resin at the corresponding time

The bonding rate (%) confirmed through the above is shown in Table 3 below.

30 minutes 1 hours 2 hours 4 hours 24 hours Example 1 5.36±0.59 4.74±1.33 3.70±2.50 6.14±1.74 5.11±1.85 Example 2 11.08±3.27 11.64±3.73 10.86±4.48 13.06±3.74 22.34±3.00 Example 3 12.45±3.61 16.25±2.41 20.65±1.59 25.72±2.10 31.46±3.17 Example 4 19.65±0.36 26.04±0.95 33.38±0.35 39.80±0.50 51.22±1.66 Example 5 24.57±3.49 16.49±5.18 17.23±4.20 17.66±2.17 20.53±8.00 Example 6 38.77±5.59 33.96±5.53 32.59±5.46 32.94±5.28 33.62±3.74

As a result, when the weight ratio of the extract of P. chinensis and the ion exchange resin is the same and the stirring time is the same, the binding ratio between the extract of P. this was excellent In addition, the type of ion exchange resin and the pretreatment stirring time were the same, but the higher the weight ratio of the ion exchange resin to the quinoa extract, the better the bonding rate between the quinoa extract and the ion exchange resin. In addition, when the type of ion exchange resin and the weight ratio of the quinoa extract and the ion exchange resin were the same, as the pretreatment stirring time increased, the bonding ratio between the quinoa extract and the ion exchange resin was excellent.

Therefore, as shown in Table 3 below, the weight of the ion exchange resin relative to the quinoa extract is relatively higher and the ion exchange resin extract according to Example 6 having the longest solubilization time through pretreatment and stirring - ion exchange resin solid The composite had the highest bonding rate.

Next, the amount of yield of the extract-ion exchange resin solid composite prepared in Examples 1 to 6 and the amount of drug per 1 mg of the ion exchange resin were confirmed as follows.

First, 50 mg of each ion exchange resin drug was precisely weighed and put into a volumetric flask having a capacity of 50 mL, and completely dissolved using a mobile phase. Then, it was filtered using a membrane filter having a pore of 450 nm, and the concentration of the drug was measured using this as a sample solution. Based on the measured concentration of the drug, the amount of drug per weight of the ion exchange resin was calculated.

The results are shown in Table 4 below.

On the other hand, the drug contained in the extract of chinensis chinensis containing a lipophilic solubilizer prepared by the method described in the Examples of 'Selective Extraction Method of Natural Substances' of Korean Patent Laid-open Publication No. 10-2020-0085024 according to Comparative Example 1 ( The concentration of Brevilin A) is about 34.4 mg/mL.

yield
(g) Amount of drug per 1 mg of ion exchange resin
(μg) Example 1 1.2 1.84 Example 2 1.07 5.96 Example 3 2.16 2.56 Example 4 1.96 6.54 Example 5 1.19 7.91 Example 6 3.34 9.9

As a result,

In Table 3, Example 6, which had the highest bonding ratio between the Chinese parsley extract and the ion exchange resin, had the highest amount of drug per ion exchange resin, and Examples 5 and 4 had the next highest drug amounts.

because of this,

The extract-ion exchange resin solid composites according to Examples 1 to 6 of the present invention are produced by the manufacturing method according to the present invention and are combined with high efficiency, and contain Brevilin A, the main component of the extract of confirmed that

< Experimental example 1> middle hair Wet granulation formulation containing an extract and lipophilicity Evaluating the dissolution rate of the Chinese parsley extract containing a solubilizing agent

In order to evaluate the dissolution rate of the wet granulation formulation containing the extract of the parsley parsley and the extract of the parsley parsley containing the lipophilic solubilizing agent, extracts or wet extracts according to Comparative Examples 1 and 4 and Examples 6 to 9 The dissolution rate of the granule formulation was evaluated under pH 1.2 and pH 6.8 conditions, respectively. Each test was conducted according to the Korean Pharmacopoeia General Test Method - Dissolution Test Method 2, and was conducted under the conditions of 37 ° C. and 100 rpm. For each time, 3 mL of the eluate was taken and filtered using a membrane filter having a 0.45 μm pore, and the filtrate was used as the sample solution.

Brevilin A standard solution for dissolution evaluation was prepared as follows. First, 5 mg of Brevilin A standard was put into a 50 mL volumetric flask and diluted with the mobile phase to prepare a standard solution of 100 μg/mL. Then, it was diluted with an appropriate amount of mobile phase to prepare and analyze a calibration curve.

Brevilin A analysis conditions are as follows.

-Mobile phase: A 45:55 (v/v) mixture of 0.1% formic acid solution and methanol was used.

-Column: Aegispak 5 μm C18-L or similar column, 250 mm x 4.6 mm, 100 Å

Column temperature: 40 °C

Detector: UV 224 nm

Flow rate: 1.0 mL/min

Injection volume: 10 μL

The dissolution rate evaluation results under pH 1.2 conditions are shown in Table 5 and Figure 4, and the dissolution rate evaluation results under pH 6.8 conditions are shown in Table 6 and Figure 5 below.

10 minutes 20 minutes 30 minutes 1 hours 2 hours Comparative Example 1 14.65±2.48 31.90±4.06 46.68±4.80 67.36±2.83 79.58±1.04 Example 4 23.10±3.45 28.39±1.96 30.48±0.79 37.90±3.05 44.88±1.22 Example 6 39.97±2.26 47.80±1.06 47.61±0.26 46.84±0.56 46.13±0.92 Example 7 95.10±1.40 100.43±1.11 101.17±0.96 99.38±1.16 97.37±1.20 Example 8 95.04±0.83 102.82±0.68 104.14±0.66 103.87±2.43 101.56±0.91 Example 9 95.65±1.38 101.99±0.70 102.51±0.22 100.73±0.70 97.69±3.37

10 minutes 20 minutes 30 minutes 1 hours 2 hours Comparative Example 1 17.17±3.10 32.54±3.02 45.27±2.37 65.01±1.38 77.59±0.62 Example 4 26.05±0.35 27.63±0.60 29.51±0.16 32.40±0.52 35.55±0.37 Example 6 36.07±1.51 43.57±1.45 45.58±2.42 46.88±1.78 46.31±1.40 Example 7 88.67±0.66 94.02±1.02 95.38±0.70 93.19±0.94 91.44±1.58 Example 8 93.91±1.57 101.48±0.51 102.95±0.86 101.56±0.62 100.24±0.12 Example 9 91.07±1.47 96.98±0.27 97.02±0.54 96.85±0.60 96.13±0.92

As a result,

As can be seen in Table 5, Table 6, Figures 4 and 5, the wet granulation formulations containing the extracts of P. It was confirmed that the dissolution rate was excellently improved. In particular, the wet granulation formulation using the polypterus extract-ion exchange resin solid composite prepared according to Example 9 of the present invention showed the highest dissolution rate.

because of this,

The wet granulation formulation prepared through the method for preparing a wet granulation formulation containing an extract of Chinese parsley extract using an organic solvent according to the present invention has a higher dissolution rate than the extract prepared through the conventional manufacturing method of a parsley parsley extract according to Comparative Example 1 It can be seen that the improvement is excellent.

< Experimental example 3> Confirmation of dosage compliance through bitter taste evaluation

The lipophilic solubilizing agent, which is an extraction liquid used for extracting P. chinensis, shows high affinity with Brevilin A, which is the active ingredient in the extract, and has the advantage of easy extraction, but it is difficult to use because it has a strong bitter taste for oral use. Accordingly, in order to compare and evaluate the bitter taste of the wet granulation formulations according to Comparative Example 1 and Examples 7 to 9, the following experiments were conducted.

For Comparative Example 1 and Examples 7 to 9, a sensory test for bitter taste was conducted on 6 healthy adult men and women, and the results were evaluated according to the following evaluation criteria, and the test results are shown in Table 7 below. During evaluation, the total amount of the drug was all conducted the same, and the blinded state was maintained to the test subjects in all tests.

Evaluation standard

0 point: No bitterness at all.

1 point: Almost no bitterness.

2 points: There is a little bitterness.

3 points: There is a bitter taste.

4 points: Very bitter taste.

Comparative Example 1 Example 7 Example 8 Example 9 Subject #1 4 3 0 One Subject # 4 One 0 0 Subject # 4 3 0 2 Subject # 4 3 One One Subject # 4 2 0 One Subject # 4 One 0 0 average 4.0 2.2 0.2 0.8

As a result,

The Chinese parsley extract containing the lipophilic solubilizing agent according to Comparative Example 1 was evaluated to have a very bitter taste in all test groups, and the wet granulation formulation containing the Chinese parsley extract according to Example 7 was evaluated to have a slightly bitter taste on average It became. On the other hand, the wet granulation preparations containing the extract of P. quinoa according to Examples 8 and 9 were evaluated to have no or almost no bitter taste, with average scores of 0.2 and 0.8, respectively.

because of this,

It was confirmed that the wet granulation preparation containing the extract of burdock chinensis, prepared by the manufacturing method according to the present invention, has excellent taste masking effect and is effective for use as an oral preparation.

In the above, the present invention has been described in detail through preferred manufacturing examples, examples and experimental examples, but the scope of the present invention is not limited to specific examples, and should be interpreted by the appended claims. In addition, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (19)

1) Purified water was added to an extract of Centipeda minima containing Brevilin A, followed by stirring at 40 to 60 ° C. for 12 to 24 hours to obtain an extract of Centipeda minima;
2) adding 3 to 10 parts by weight of anion exchange resin to 1 part by weight of the extract of P. chinensis obtained in step 1), stirring for 20 to 28 hours, and obtaining ionic compounds in the lower layer; and
3) filtering and drying the ionic compound obtained in step 2) to obtain an extract-ion exchange resin solid complex; Characterized in that it comprises, A method for producing an extract-ion exchange resin solid composite.
According to claim 1,
In step 1),
(1) preparing a primary extract by extracting an extract of quinoa;
(2) performing secondary extraction by mixing the phase separation composition containing a lipophilic solubilizer and water with the primary extraction solution; and separating the upper layer of the phase-separated solution to obtain a non-polar natural material.

An extract-ion exchange resin solid complex, characterized in that it is obtained by the manufacturing method of claim 1.
1) adding purified water to an extract of Brevilin A and stirring it at 40 to 60° C. for 12 to 24 hours to obtain an extract of Brussels sprouts;
2) adding 3 to 10 parts by weight of anion exchange resin to 1 part by weight of the extract of P. chinensis obtained in step 1), stirring for 20 to 28 hours, and obtaining ionic compounds in the lower layer;
3) filtering and drying the ionic compound obtained in step 2) to obtain an extract-ion exchange resin solid complex;
4) obtaining a combined solution of the solid complex and the alcohol by adding alcohol to the quinoa extract-ion exchange resin solid complex obtained in step 3) and mixing for 1 to 10 minutes;
5) obtaining a mixture by mixing while adding the combined solution of the solid complex obtained in step 4) and alcohol to the excipient; and
6) sieving the mixture obtained in step 5) and drying it at 40 to 60° C. for 10 to 14 hours; A method for producing a wet granule formulation containing a burdock extract, characterized in that it comprises a.
According to claim 4,
The alcohol of step 4) is ethanol or methanol .
According to claim 4,
The excipient in step 5) is at least one selected from the group consisting of lactose, microcrystalline cellulose, cellulose, pregelatinized starch, mannitol, dicalcium phosphate, calcium sulfate and sodium chloride, A method for preparing a wet granule formulation.
A wet granulation preparation containing the extract of P. chinensis, characterized in that it is prepared by the manufacturing method of claim 4.
According to claim 7,
The wet granulation formulation is for oral use, a wet granulation formulation containing an extract of chinensis. delete delete delete delete delete delete delete delete delete delete delete

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