KR100736901B1 - Liquid formulation of herbal composition comprising inclusive compound of hesperidin and beta-cyclodextrin and the process for preparing them - Google Patents

Abstract

The present invention relates to an herbal medicine with improved solubility of hesperidin which is an index component of dermis softening extract currently used as a pharmaceutical raw material. More specifically, the present invention contains 0.1 ~ 1.85 w / v% of the beta-cyclodextrin in herbal medicine to form the hesperidin clathrate in the dermis soft extract, inhibiting precipitation formation through improving the solubility of hesperidin and improved herbal medicine It is about.

Dermis soft extract, hesperidin, beta-cyclodextrin, clathrate, precipitation, herbal solution

Description

Herbal formulations containing clathrate compounds of hesperidin and beta-cyclodextrin, which are indicators of dermis softening extract, and a method for preparing the same {Liquid formulation of herbal composition comprising inclusive compound of hesperidin and beta-cyclodextrin and the process for preparing them}

1 is a diagram showing an increase in the solubility of hesperidin which is an indicator component of dermal soft extract by the addition of beta-cyclodextrin. Is,

Figures 2a to 2d is a comparison of the hesperidin clathrate (2a) produced by the method of the present invention, the hesperidin clathrate (2b) by solvent evaporation, a simple mixture of hesperidin and beta-cyclodextrin (2c), 2b and 2c ( IR chart of 2d) shows the possibility of inclusion complex formation by the method of the present invention by reducing skeletal vibrations of ketone bands and rings,

3 is a diagram showing the optimum reaction conditions for the solubilization of hesperidin through the formation of a clathrate of hesperidin and beta-cyclodextrin, which is an index component of dermal soft extract, and shows that the reaction is performed at 90 ° C. for 1 hour or more.

4 is a diagram showing the hesperidin content for the dermal soft extract containing liquid formulations, showing an excellent increase in the hesperidin content due to the addition of beta-cyclodextrin,

5 is a view showing a specific result of the transparency for the dermal soft-core extract containing, showing the effect of inhibiting precipitation formation and increase the transparency by the formation of hesperidin inclusion complex due to the addition of beta-cyclodextrin.

The present invention relates to a herbal medicine with improved solubility of hesperidin, which is an indicator component of dermis softening extract, currently used as a pharmaceutical raw material, and a preparation method thereof.

More specifically, the present invention contains 0.1 ~ 1.85 w / v% of beta-cyclodextrin to form a hesperidin inclusion complex in the dermis soft extract, inhibiting precipitation formation through improving the solubility of hesperidin, and the content and drug efficacy in the herbal medicines improved It is about.

In general, the following items should be considered to sell herbal liquids containing dermis soft extract as a commercial product.

(1) Uniformity of dermis soft extract content-The dermis soft extract extracts hesperidin, an indicator component, during cooling and concentration, which may result in a lack of uniformity of the active ingredient content, as well as a filtration process during manufacture for commercial use. Hesperidin precipitated from is often removed, resulting in a significant amount of analysis of commercially available dermis softener extracts.

(2) Precipitation formation of hesperidin in dermal softening extract-After liquid solution is prepared and dispensed into each package for commercial use, precipitation may precipitate due to reaction between components. Hesperidin, which is an index component of X, is included, and thus there is a problem that the product cannot sufficiently exhibit the pharmacological effects of the product.

As mentioned above, hesperidin, an indicator component of dermis soft extract, has low solubility in the amount of 1 g dissolved in 50 l of water (see Merck index), which is why the other ingredients added after dispensing each package for commercial use Problems such as the formation of hesperidin precipitation due to interactions and other changes in conditions have caused difficulties in developing high-quality drugs as well as drug efficacy.

Among the problems caused by the liquid formulation of dermis soft extract X, the most important and difficult to solve problem is to increase the aesthetic value or to maintain the aesthetic sense and to improve the solubility of hesperidin, which is an indicator ingredient and an active ingredient. Prevention of precipitation through.

In the conventional herbal preparations, suspending agents such as gelatin, casein, carboxymethyl cellulose, polyvinylpyrrolidone, arabic gum, or carbomer, floxamer, etc. are used for the purpose of preventing precipitation. You can find it in the paper. As sweeteners to improve the taste and specific odor, perfumes such as honey, syrup, white sugar, glucose, high fructose, cyclodextrin and orange oil, peppermint oil, rose oil, cinnamon oil, lavenda oil, menthol, vanilla, ethyl vanillin, etc. were used. . However, the method of using a suspending agent (thickener) does not prevent the formation of a substance causing precipitation, and it can not be a fundamental solution by suppressing precipitation by floating it in the liquid phase. In many cases, it did not get a satisfactory effect. In addition, as a conventional method of preventing precipitation and improving taste and specific odor, the effect of preventing precipitation or masking bitter or irritating odor from the dermis softening extract itself during the use and storage period of the herbal liquid was insufficient.

In addition, some methods using cyclodextrin solutions, derivatives of poloxamers or cyclodextrins have been patented, but the preparation method is not clear and the results are described according to very subjective criteria, making it difficult to objectively verify the effects. . Therefore, a method of using various additives has been attempted to improve the above-mentioned disadvantages of herbal extracts containing dermis softening extract. However, a method of remarkably improving has not been developed yet.

Accordingly, the present inventors have conducted intensive research to find a component that can improve the disadvantages of the herbal liquids described above with respect to various additives used in the field of synthetic pharmaceuticals, and especially in the field of synthetic pharmaceuticals. The study was carried out on cyclodextrins that are used for various purposes and are known to be safe, and more detailed studies on beta-cyclodextrins, which are most effective, were carried out.

Cyclodextrins, ie, cyclodextrin alpha, beta, or gamma, or complexes thereof, have been introduced into the field of synthetic pharmaceuticals under other names, such as Shardinger dextrins, Cycloamyloses, and Cyclologcans, to prostaglandins, It is applied to dissolution aids such as steroids and barbitals, chemical stabilizers such as aspirin, epinephrine and vitamins, and taste and odor improving agents such as prostaglandins and alkyl parabens. Typically, when a cyclodextrin solution in use on the cyclodextrin alpha, beta, and a medium containing starch as a complex of a gamma-cyclodextrin trans-glycosidase produced by the action of an enzyme agent, a LD ₅₀ value of 10 rats in oral administration High levels of g / kg and higher have been reported, and since only a small amount is absorbed in the gastrointestinal tract, it is a stable material with little toxicity. Beta-cyclodextrin is generally the most widely used substance in the pharmaceutical and food fields, and its safety, etc. is recognized in the US Pharmacopoeia (USP). The LD ₅₀ value of oral administration to rats and mice is 12, Above 12.5 g / kg this is also a safe substance.

Cyclodextrins, which are widely used as solubilizers for poorly water-soluble drugs, include lyophilization (Kurozumi M. et al., Chem. Pharm. Bull. , 23 , p3062, 1975), and solvent evaporation (Tsuruoka M.). et al., Journal of Pharmaceutical Society of Japan , 101 , p360, 1981), coprecipitation with ethanol (Tsuruoka M., et al., Journal of Pharmaceutical Society of Japan , 101 , p360, 1981), copolyester with ether Acupuncture (Kurozumi M. et al., Chem. Pharm. Bull. , 23 , p3062, 1975) and the ethanol method (Pitha J., et . Al . , Int. J. Pharm. , 80 , p253, 1992) are known.

In general, the above method may be used to form a beta-cyclodextrin inclusion complex. However, in the case of a liquid preparation, the above method may be used in addition to the use portion of an organic solvent or a general liquid preparation facility, for example, lyophilization. Equipment such as equipment is required, and when the product is made from the hesperidin and beta-cyclodextrin clathrate in the dermis soft extract thus manufactured, the aesthetics of the product are lowered compared to the existing construction products, which makes it difficult to sell the product. It is true.

Through various experiments, the inventors of the present invention can effectively prevent the precipitation of hesperidin, which is a problem of liquid preparations in which beta-cyclodextrin includes herbal extracts, especially dermis soft extracts, and effectively prevent precipitation due to precipitation. It was confirmed that there are various effects such as a synergistic effect of the aesthetic by masking the unpleasant taste, and completed the present invention.

It is an object of the present invention to form a hesperidin clathrate using only dermis soft extract and beta-cyclodextrin in a general liquid preparation ratio without the use of an organic solvent or ammonia, solubilizing most of the hesperidin in the dermal soft extract, resulting in precipitation derived from hesperidin. It is to provide a method of manufacturing a herbal liquid to suppress the occurrence of the increase in transparency when manufacturing the construction product, there is no deterioration of taste and the taste is increased due to the sweetness effect of beta-cyclodextrin to improve the overall quality of the product.

In order to achieve the above object, the present invention provides a herbal liquid composition containing dermis soft extract, characterized in that it contains a beta-cyclodextrin and the conjugate of hesperidin which is an index component of dermis soft extract.

Specifically, the liquid composition of the present invention is a beta-cyclodextrin is about 0.01 to 2 w / v%, preferably 0.1 to 1.85 w / v%, more preferably 0.60 to 1.35 w / v relative to the total liquid composition volume It is provided by the amount of% to provide a herbal liquid composition containing the dermis soft extract, characterized in that to form a clathrate compound with hesperidin which is an indicator component of the dermis soft extract.

The clathrate compound of beta-cyclodextrin and hesperidin prevents precipitation formation by solubilizing the hesperidin component in the dermis softening extract, and improves the herbal composition of the dermis by preventing the synergistic effect of the aesthetics by masking the bitter and unpleasant taste of the dermis softening extract. To provide.

In the present invention, by adding beta-cyclodextrin as the object of the present invention to obtain the effect of improving the solubility of hesperidin in the dermis soft extract is not particularly limited, 1/5, 1/2 or 1 It is irrelevant to the degree of enrichment of dermis softening extract having a concentration ratio such as / 1, and the same or similar effect is applied to a product using only hesperidin as a main ingredient, so the herbal liquid preparations in the present invention are dermis containing hesperidin as an index component. It includes all herbal liquids containing soft extract as an active ingredient.

Specific examples of such herbal medicines may include, but are not limited to, prescription formulations such as K company's S products and C's products, J's K products, which are already commercialized in Korea.

More specifically, the present invention provides a method for preparing the above-described herbal liquid composition, wherein the beta-cyclodextrin forms a clathrate compound with hesperidin which is an index component of dermal softening extract. do.

For example, the present invention is obtained by adding an extraction solvent to the herbal raw medicine containing dermis soft extract extract to obtain a herbal extract and filtered the herbal extract, and then concentrated the extract filtrate to 1/5 to 1/1 A dermal soft extract was prepared, and about 0.1-1.85 weight ratio (w / v%) of beta-cyclodextrin was added to this dermal soft extract, and purified water was added to dissolve it for about 30 minutes to 2 hours at 90 ° C. or more. The herbal liquid composition containing the hesperidin clathrate can be manufactured through the manufacturing process.

More specifically, the present invention is capable of preparing herbal medicines such as ethanol, alcohol, or the like in about 1 to 20 times the volume of the raw material, preferably about 5 to 15 times the volume of the raw material in herbal herbal medicine containing dermis soft extract. A first step of extracting a herbal extract by adding an extraction solvent and extracting at 80 to 100 ° C., preferably at 90 to 95 ° C. for 1 to 12 hours, preferably 1 to 8 hours; A second step of passing the herbal extract through 200-500 mesh, preferably 300 mesh filter paper and about 0.5-2, preferably 1 μm filter paper to obtain an extract filtrate; A third step of concentrating the extract filtrate to 1/5 to 1/1 by using a concentrator to obtain a soft extract; About 0.01 to 2 w / v%, preferably 0.1 to 1.85 w / v%, more preferably 0.60 to 1.35 w / v% of beta-cyclodextrin is added to the concentrated soft lead extract to an appropriate amount. A fourth step of reacting the hesperidin clathrate compound in the concentrated dermis extract extract after heating, dissolving, mixing and adding purified water at 80 to 100 ° C, preferably at least 90 ° C; It provides a manufacturing process comprising a fifth step of producing a final liquid composition by sterilizing the liquid formulation and adding purified water.

In the fourth step, the beta-cyclodextrin has a solubility in water of 1.85 w / v% and is re-precipitated according to changes in temperature conditions, etc. when added to a liquid formulation, so that beta-cyclodextrin itself is a source of precipitation. The weight ratio may not exceed 1.85 w / v% because it may act, and the liquid may be buried around the bottle cap, causing the plug to be hardly picked. In addition, it is preferable that the reaction temperature of beta-cyclodextrin and hesperidine is reacted at 90 ° C. or more, which shortens the time for reaching the peak.

Specific examples of the beta-cyclodextrins used in the present invention include CAVAMAX W7 PHARMA and Peak Chem CO., Ltd., China, of ISP Technologies. Inc., Germany, Beta-cyclodextrin commercial products manufactured from Shandong Xinda Fine Chem Co, Ltd, China and Biosynth AG, Switzerland may be mentioned, but are not particularly limited thereto.

Therefore, according to the present invention, hesperidine in the dermal soft extract is formed by forming the hesperidin inclusion complex using only the dermis soft extract and 0.1 to 1.85 w / v% of beta-cyclodextrin as a general liquid preparation without using an organic solvent or ammonia. Mostly solubilized to suppress the occurrence of hesperidin-induced precipitation, which increases the transparency when manufactured as a construction product, there is no deterioration of taste and the taste is increased due to the sweetening effect of beta-cyclodextrin, resulting in improved overall quality of the product. Advantages are provided.

The dermal soft extract containing herbal medicine prepared according to the present invention is a problem of the product currently being sold as a construction product, namely, the problem of precipitation caused by reprecipitation due to poor solubility of hesperidin in the main ingredient of dermis soft extract and due to the precipitation The turbidity of the construction products, the consumer's claims due to the deposits on the bottom of the product, and the damage of the manufacturer's image resulting from this were solved by the inclusion of hesperidin and beta-cyclodextrin in the dermis softening extract to increase the solubility. It prevents the bleeding and the formation of deposits on the bottom, which not only improves the quality of the product but also solves the problem of deterioration of aesthetics caused by the reprecipitation of hesperidin.

In addition, the present invention does not require additional equipment in the preparation of the dermal soft-core extract containing liquid and also provides an advantage that the method of forming a clathrate is easy to apply to the production and can be directly applied.

Hereinafter, the present invention will be described in detail by the following Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples and Experimental Examples.

Comparative Example 1.

An excess of hesperidin (Hesperidin 30.0 mg, Acros, min 98.0%, UK), an indicator component of dermis soft extract, was placed in a 1000 ml container and 700 ml of purified water was heated. The purified water was reacted for 4 hours while the purified water was maintained at 90 ° C. or higher, and the purified water was added to a total amount of 1000 ml, followed by filtering with a 5 μm filter to prepare a sample.

Comparative Example 2.

In order to determine whether the conjugate of hesperidin and beta-cyclodextrin, which are indicators of the dermal soft extract in Example 1, was formed, the inclusion complex of hesperidin and beta-cyclodextrin was optionally prepared by solvent evaporation.

Comparative Example 3.

Samples were prepared by preparing a simple mixture of hesperidin and beta-cyclodextrin, which are indicator components of dermis soft extract.

Comparative Example 4.

       Take 20 mg of dermis soft extract from the raw material of the dermis soft extract containing Table 1, add 23 ml of purified water to the preparation tank, warm it to 90 ℃ or more, add the dermis soft extract extracted beforehand, and stir for 1 hour. After the reaction, purified water was added so that the total amount was 53 ml, and each of the remaining raw materials in Table 1 was added, mixed, stirred, and dissolved, and then purified water was added so that the total amount was 75 ml. Filled in a brown glass bottle to a ml.

Example 1.

Hesperidin excess (Hesperidin 30.0 mg, Acros, min 98.0%, UK), an indicator component of dermis soft extract, was placed in a 1000 ml container, 700 ml of purified water was added, and the purified water was warmed to 90 ° C. or more. 5 g of beta-cyclodextrin was added thereto, the reaction was carried out for 4 hours while maintaining at 90 ° C. or higher, and then purified water was added thereto so that the total amount thereof was 1000 ml, and then filtered through a 5 μm filter to prepare a sample.

Example 2.

Take the dermis soft extract 20 mg and beta-cyclodextrin 0.1 g of the raw material of the dermis soft extract X-containing herbal liquid of Table 1, put 23 ml purified water in the preparation tank, warmed to 90 ℃ or more, and the dermis softened in advance X was added and stirred for 1 hour to react, and then purified water was added so that the total amount was 53 ml. Then, the remaining raw materials in Table 1 were added, mixed, stirred, and dissolved, and then purified water was added so that the total amount was 75 ml. Sterilized for at least 10 minutes and filled into a brown glass bottle so that the total amount was 75 ml.

Example 3.

Take the dermis soft extract extract 20 mg and beta - cyclodextrin 0.25 g in the raw material of the dermis soft extract extract containing the Table 1, add 23 ml purified water to the preparation tank, warmed to 90 ℃ or more and the dermis soft drink X was added and stirred for 1 hour to react, and then purified water was added so that the total amount was 53 ml. Then, the remaining raw materials in Table 1 were added, mixed, stirred, and dissolved, and then purified water was added so that the total amount was 75 ml. Sterilized for at least 10 minutes and filled into a brown glass bottle so that the total amount was 75 ml.

Example 4.

Take the dermis soft extract 20 mg and beta-cyclodextrin 0.5 g of the raw material of the dermis soft extract X-containing herbal medicine of Table 1, put 23 ㎖ purified water in the preparation tank and warmed to 90 ℃ or more and the dermis softened After stirring for 1 hour, the reaction mixture was stirred for 1 hour, and then purified water was added so that the total amount thereof was 53 ml. Then, each of the remaining raw materials shown in Table 1 was added, mixed, stirred, and dissolved, and then purified water was added so that the total amount was 75 ml. Sterilized for at least 10 minutes and filled into a brown glass bottle so that the total amount was 75 ml.

Example 5.

Take the dermis soft extract 20 mg and beta-cyclodextrin 1.0 g of the raw material of the dermis soft extract X-containing herbal solution of Table 1, put 23 ml purified water in the preparation tank, warmed to 90 ℃ or more, and the dermis softened in advance X was added and stirred for 1 hour to react, and then purified water was added so that the total amount was 53 ml. Then, the remaining raw materials in Table 1 were added, mixed, stirred, and dissolved, and then purified water was added so that the total amount was 75 ml. Sterilized for at least 10 minutes and filled into a brown glass bottle so that the total amount was 75 ml.

Example 6.

Take the dermis soft extract 20 mg and beta-cyclodextrin 1.8 g of the raw material of the dermis soft extract X-containing herbal solution of Table 1, put 23 ml purified water in the preparation tank, and warmed to 90 ℃ or more dermis soft bath X was added and stirred for 1 hour to react, and then purified water was added so that the total amount was 53 ml. Then, the remaining raw materials in Table 1 were added, mixed, stirred, and dissolved, and then purified water was added so that the total amount was 75 ml. Sterilized for at least 10 minutes in a brown glass bottle was filled so that the total amount is 75 ml.

Ingredients (75mL) Comparative Example 4 Example 2 Example 3 Example 4 Example 5 Example 6 Ginseng Drying Extract 20mg 20mg 20mg 20mg 20mg 20mg Health Tink 225 μl 225 μl 225 μl 225 μl 225 μl 225 μl Cinnamon Tink 250 μl 250 μl 250 μl 250 μl 250 μl 250 μl Dermis Soft X 20mg 20mg 20mg 20mg 20mg 20mg DL-carnitine hydrochloride 150mg 150mg 150mg 150mg 150mg 150mg Sodium benzoate 75 mg 75 mg 75 mg 75 mg 75 mg 75 mg High fructose 10,000mg 10,000mg 10,000mg 10,000mg 10,000mg 10,000mg Citric acid 80 mg 80 mg 80 mg 80 mg 80 mg 80 mg Sodium citrate 40mg 40mg 40mg 40mg 40mg 40mg β-cyclodextrin  - 0.1g 0.25g 0.5g 1.0 g 1.8g

Experimental Example 1. Formation of a clathrate between hesperidin and beta-cyclodextrin

In order to find out whether clathrate formation of hesperidin and beta-cyclodextrin, which are indicators of dermal soft extract, is an object of the present invention, the contents are compared and analyzed using an infrared spectrometer (IR; FTS-2000MX SCIMITAR, DIGILAB). It was confirmed whether the inclusion body was formed.

As a result, as can be seen in Figure 1, the addition of beta-cyclodextrin of Example 1 clearly shows an excellent increase in the solubility of hesperidin, an index component of dermis soft extract, which is confirmed in the IR chart of Figures 2a to 2d As compared with Comparative Example 3 (FIG. 2C), which is a simple mixture, both Example 1, which is a conjugate prepared by the method of the present invention, and Comparative Example 2, which is a conjugate of hesperidin and beta-cyclodextrin prepared by solvent evaporation, were used. In both (FIG. 2D), it was confirmed that skeletal vibrations of the ketone band around 1624 cm ⁻¹ and the ring around 1450 cm ⁻¹ were reduced, thereby making it possible to form a clathrate by the method of the present invention.

Experimental Example 2. Optimization of solubilization of hesperidin

To determine the optimum reaction conditions for solubilization of hesperidin by inclusion complexes of hesperidin and beta-cyclodextrin, which are the indicators of dermis softening extract, the reaction time was measured under the conditions of 50 ℃, 70 ℃ and 90 ℃, respectively. After changing to minutes, 30 minutes, 60 minutes, 120 minutes and 180 minutes, the remaining main ingredients and excipients were added and prepared, and the liquid volume was adjusted so that the total liquid amount was 75 ml. The experiment was carried out. As shown in FIG. 3 below, the reaction at 50 ° C. and 70 ° C. proceeds slowly while the reaction at 90 ° C. reaches a peak in 1 hour (60 minutes), resulting in a reaction temperature of 90 ° C. or higher and a reaction time of 1 hour. The reaction was confirmed to be the optimum conditions, and thus the experiments were conducted under the conditions of the samples obtained from the comparative examples and examples. However, the amount of beta-cyclodextrin was 0.5 g / 75 ml, and the amount was fixed at 30% of the total amount.

    As a result of the experiment, as shown in Figure 4 below, the dermal soft extract containing herbal solution containing 0.1 to 1.8% of beta-cyclodextrin (Examples 2 to 6) compared with Comparative Example 4 containing no beta-cyclodextrin When it contained a high concentration of hesperidin. In addition, as can be seen in Figure 5, the dermal soft extract containing herbal medicines (Examples 2 to 6) containing 0.1 to 1.8% of beta-cyclodextrin compared to Comparative Example 4 containing no beta-cyclodextrin compared to beta-cyclo As the dextrin content increased, it showed better sedimentation inhibitory effect. This demonstrated the effect of inhibiting precipitation formation due to the inclusion complex formation of beta-cyclodextrin and hesperidin. As can be seen in FIG. 5 below, the addition of beta-cyclodextrin to the dermal soft extract-containing liquid formulation showed precipitation formation and reprecipitation inhibition through the formation of hesperidin inclusion complex, thereby increasing transparency.

The herbal softener containing dermal soft extract prepared according to the present invention solves the problems of the product currently being sold as a construction product and prevents the turbidity of the construction product or the formation of deposits at the bottom, thereby improving the quality of the product as well as re-precipitation of hesperidin. In addition to solving the problem of deterioration of the aesthetics caused by the present invention, the present invention does not require any additional equipment in preparing a liquid extract containing dermal soft-core, and also has an advantage that the method of forming a clathrate is easy to apply to production and can be immediately applied. This is provided.

Claims (5)

        A herbal liquid composition containing dermis soft extract, characterized in that it contains a conjugate of 0.60 to 1.35 w / v% of beta-cyclodextrin and hesperidin which is an index component of dermis soft extract. delete delete delete A first step of obtaining a herbal extract by adding 1 to 20 times the volume of purified water, ethanol or alcohol to the herbal raw medicine containing dermis soft extract to extract at 80 to 100 ° C. for 1 to 12 hours; A second step of passing the herbal extract through 200-500 mesh and 0.5-2 μm filter paper to obtain an extract filtrate; A third step of concentrating the extract filtrate to 1/5 to 1/1 by using a concentrator to obtain a soft extract; A fourth step of reacting the hesperidin clathrate compound in the extract filtrate by adding 0.01-2 w / v% of beta-cyclodextrin to purified water to the concentrated soft extract extract in warm water and dissolving the mixture at 90 ° C. or more. ; Method for producing a herbal liquid composition containing the hesperidin inclusion complex of claim 1, characterized in that it comprises a fifth step of sterilizing the liquid formulation and adding purified water to produce a final liquid composition.

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