KR20050098441A - Rapid-acting emulsion concentration composition of artemisia extract and oral formulation thereof - Google Patents

Abstract

The present invention relates to a fast-acting emulsion concentrate composition of leaf extracts and improved fast-acting oral preparations containing the same, wherein the leaf extracts and oils are effective for the treatment of gastrointestinal diseases. The present invention relates to a fast-acting emulsion concentrate composition of a leaf extract consisting of a surfactant and a cosolvent, and a fast-acting oral preparation of a leaf extract containing the same.

The fast-acting emulsion concentrate of the leaf extract of the invention according to the present invention and the fast-acting oral preparation of the leaf extract containing the same have improved solubility, dissolution rate, oral absorption rate and bioavailability in the gastrointestinal tract than the pharmaceutical composition of the conventional leaf extract, and thus the stomach is improved. It is an agent that exhibits an immediate effect on disease.

Description

Fast-acting emulsion concentrate composition of leaf extracts and fast-acting oral preparations of leaf extracts containing same {RAPID-ACTING EMULSION CONCENTRATION COMPOSITION OF ARTEMISIA EXTRACT AND ORAL FORMULATION THEREOF}

The present invention relates to a fast-acting emulsion concentrate composition of a leaf extract, and a fast-acting oral preparation of leaf extracts containing the same, which have improved elution rate, absorption rate and bioavailability.

The leaf lobe used in the present invention is a perennial herbaceous plant belonging to the family of compositae , the leaf leaf extract extends the blood coagulation time (Pharmaceutical Journal 28 (2): 69-77, 1984), and the flavone extracted from the leaf Anticancer activity ( Chem. Pharm. Bull. 32 (2): 723; 1984), platelet aggregation inhibitory activity ( Zhongguo Zhongyao Zazhi , 17 (6): 353, 1992), antifungal activity ( J. of Chemical Ecology , 19 (11) ), 1993), and its anti-complementary effect helps the host's defenses to treat allergies and inflammations ( Chem. Pharm. Bull. 33 (5): 2028-2034, 1985). It has been reported to work ( Indian J. Med. Res. 60, 1972). In addition, eupatilin extracted from the leaf lobe can be used for antitumor (WO 8803805), psoriasis treatment (WO 8803800), allergy treatment (JP 84155314) and aphthous ulcer treatment (CA 2065496 AA) It is known.

The present inventors found that eupatillin extracted from the leaf lobe has an effect on gastrointestinal diseases in addition to the above-described antitumor and anti-allergic effects, and patented the use of eupatillin as a therapeutic agent for gastrointestinal diseases (Korean Patent Application No. 94-00147). In a continuing study, pharmacologically active jaceosidin, which is another pharmacologically active ingredient, was isolated from the leaves and patented for its preparation and its use as a therapeutic agent for gastrointestinal diseases (Korean Patent Application No. 94-39337). Petal extract containing tilin and postiosidine was found to be effective against inflammatory bowel disease, and a patent application for inflammatory bowel disease treatment (Korean Patent Application No. 96-28230).

In addition, the present inventors have recently removed the harmful components while maintaining the active ingredient of the leaf extract as it is, the prevention or treatment effect of gastrointestinal diseases or inflammatory bowel disease is significantly superior to the conventional leaf extract that does not remove the harmful components The extraction method was developed and patented for its manufacturing method (Korean Patent Application No. 2003-41628).

However, even though the leaf extract has an excellent effect on the prevention or treatment of gastrointestinal diseases or inflammatory bowel diseases, the dissolution rate in the gastrointestinal tract is about 40-50%. Although the solubility and dissolution rate in E. coli and the permeability of biomembrane are low, the absorption of drug is delayed, the bioavailability is low. However, there is no prior art for the solubilization method and the specific formulation of the preparation containing the leaf extract. .

Moreover, the prevention or treatment of gastrointestinal diseases or inflammatory bowel disease should be taken in the long run, but patients should take medications in response to symptomatic symptoms such as heartburn, stomach pain, or random discontinuation of medication due to medication insufficiency. As a result, there is a problem in that gastrointestinal diseases are not treated and relapse, and therefore, a fast-acting formulation which is administered in combination with a sustained release formulation has been required.

In order to solve the above problems, the present inventors have conducted a number of studies to formulate fast-acting oral preparations to increase the bioavailability by excellent dissolution rate and oral absorption rate of leaf extracts that have an excellent effect in the prevention or treatment of gastrointestinal diseases or inflammatory bowel disease. It was. As a result, when the emulsion concentrate composition of the leaf extract is administered to the human body, a self-microemulsifying drug delivery system (SMEDDS) is used by the digestive or bodily fluid to form a microemulsion, which is absorbed into a living body, thereby extracting the leaf extract. It was confirmed that the dissolution rate, oral absorption rate and bioavailability can be improved, and the present invention was completed by preparing a fast-acting oral preparation of a leaf extract.

Accordingly, an object of the present invention is to provide an emulsion concentrate composition of a leaf extract, which microemulsifies the leaf extract using a self-emulsifying drug delivery system.

In addition, an object of the present invention is to provide a fast-acting oral preparation of a leaf extract, which can elute the leaf extract quickly and have an excellent oral absorption rate.

In order to achieve the above object, the present invention provides an emulsion concentrate composition of leaf extract, containing leaf extract, oil, surfactant, and cosolvent.

The present invention also provides a fast-acting oral preparation containing the emulsion concentrate composition of the leaf extract.

Hereinafter, the present invention will be described in detail.

The present invention provides an emulsion concentrate composition of the leaf extract, which essentially contains leaf extract, oil, surfactant and cosolvent. The emulsion concentration composition of the leaf extract prepared in the present invention is used by the self-emulsifying drug delivery system by digestion or body fluid in the gastrointestinal tract to form a microemulsion to be absorbed in vivo to increase the dissolution rate, oral absorption rate and bioavailability of the leaf extract Can be.

The leaf extract can be used for extracting the leaf leaves obtained by a conventional extraction method, in addition to

1) extracting the leaf leaves with an alcohol or an aqueous alcohol solution (step 1);

2) adding an alkaline solution to the extract obtained in step 1 and reacting at 80 ° C. for at least 12 hours (step 2);

3) a method of preparing a leaf extract, which comprises the step (step 3) of neutralizing by adding an acidic solution to the extract obtained in step 2, or

4) The extract obtained in step 3 may be obtained through a method for producing a leaf extract, which comprises the step of freezing and drying (step 4) after concentration under reduced pressure.

Through this preparation method, the leaf extract can be prepared by selectively removing only the harmful component dicoumarol without losing the contents of the eutectilin and postiosidine in the leaf extract, and the method of extracting the leaf extract is It is described in detail in Korean Patent Application No. 2003-41628 filed by.

The leaf extract used in the present invention is known to have an excellent effect in the treatment of gastrointestinal diseases, gastritis and gastric ulcer, the effective dose is 60mg once, 180mg per day.

The oil used in the present invention is mixed with a surface extract, such as surfactant, co-solvent to form an emulsion concentrate close to the liquid phase and when the emulsion preconcentrate is in contact with an aqueous medium such as water or gastrointestinal tract to form an oil-in-water microemulsion It plays a role. That is, the emulsion preconcentrate formed by the oil automatically forms an oil-in-water microemulsion by an aqueous medium such as gastrointestinal fluid, small intestine, etc. to maximize the solubility and dissolution rate of the drug, and increase the fat solubility of the drug and decrease the drug particle size. By increasing the membrane permeability, the absorption rate and bioavailability of the leaf extract can be significantly increased. In addition, the oil forms an emulsion to block the contact of the drug with moisture in the air to play a role in maintaining physical and chemical stability. In addition, in the present invention, a minimum amount of oil is used to facilitate taking.

The oil used in the present invention is glyceryl stearate, glyceryl monooleate, captylic / capric triglyceride, cetyl octanoleate, isopropyl myristate (isopropyl myristate), isopropyl 2- ethylene carbonate as pel (2-ethylene isopelagonate), di -C aged _12-13 alkyl maleate _{(di-C 12-13 alkyl malate)} , Te naphthyl octanoate ( ceteatyl octanoate, butylene glycol dicaptylate / dicaprate, propylene glycol monocapreate, isononyl isostearate, isostearyl isostearate isostearate, coco-captylate / caprate, cetyl octanoate, octyldodecyl myristate, cetyl Thermal switch current (cetyl esters), C _10-30 cholesterol / lanosterol esters _{(C 10-30 cholesterol / lanosterol ester)} , hydrogenated castor oil (hydrogenated castor oil), a monoglyceride (mono-glycerides), diglycerides esters such as diglycerides and triglycerides; Beeswax, canauba wax, suctose distearate, propylene glycol-8 biswax, candelilla (euphorbia cerifera) wax, etc. Hydrocarbons of; Minerals such as ceresin and ozokerite; Corn oil, sesame oil, soybean oil, bean oil, olive oil, jojoba oil, grapeseed oil, macadamia ternifolia nut oil, hydrogenated high Hydrogenated hi-erucic acid rape seed oil, safflower oil, hybrid sunflower (Helian thus annuus) oil, neen (melia azadirachta) seed oil or wild rose Plants, such as dog rose (rosa canina) lips oil, etc. can be used.

Preferably, the oils include vegetable oils such as corn oil, sesame oil, soybean oil, and olive oil, captylic / capric triglycerides, glyceryl stearate, glyceryl monooleate, propylene glycol monocapriate, monoglycerides and diglycerides. Ester, such as a lide and a triglyceride, can be selected.

The surfactant used in the present invention is to reduce the interfacial tension between the oil layer and the aqueous solution and biological fluid in which the drug is dissolved when the pre-emulsion concentrate of the leaf extracts dissolved in oil is exposed to the aqueous solution and biological fluid. It helps to easily mix the aqueous solution and the biological fluid so that the self-emulsifying drug delivery system that automatically forms the microemulsion is used to maximize the solubility and dissolution rate of the leaf extract, and improve the biomembrane permeability while simultaneously It is responsible for maintaining stability. In the present invention, a minimum amount of surfactant is used to facilitate the administration.

The surfactant may be used various surfactants including pharmaceutically acceptable anionic, cationic, nonionic or amphoteric surfactants. Specifically, polyoxyethylene sorbitan fatty acid ester (tween), sorbitan fatty acid ester (span), polyoxyethylene fatty acid ester (polyoxyethylene fatty acid ester, myriad) (Myrj), polyoxyethylene polyoxypropylene block copolymer, poloxamer, polyoxyethylene polyoxypropylene copolymer, pluronic, natural or hydrogenated vegetable oil Reactant of natural or hydrogenated vegetable oil and ethylene glycol, cremophor, sodium dioctylsulfosuccinic acid sodium salt, lauryl sulfonic acid sodium salt, phospholipid , Propylene glycol mono or di fatty acid esters fatty acid esters, Miglyol, trans-esterification of natural vegetable oil triglycerides and polyalkylene polyols, labrafil M Mixtures of mono-, di- or triglycerides and mono- or di-fatty esters of polyethylene glycol, labrasol, mono Mixtures of mono-, di- or mono / di glycerides, imbitols, propylene glycol mono or di fatty acid esters with mono-, di- or mono / diglycerides (mixture of mono- or di- fatty acid esters of propylene glycol and mono-, di- or glycerides) and derivatives thereof.

Preferably the surfactant is a polyoxyethylene polyoxypropylene block copolymer, a reaction product of natural or hydrogenated vegetable oils with ethylene glycol, polyoxyethylene sorbitan fatty acid esters and propylene glycol mono or di fatty acid esters with mono-, di- Or a mixture of mono / diglycerides.

In the present invention, a cosolvent may be used as a solvent to improve the absorption rate of the leaf extract, and as the cosolvent, propylene carbonate, propylene glycol, ethanol, diethylene glycol mono Group consisting of ethylglycol monoethyl ether, transcutol, glycofurol, polyethylene glycol, dimethylisosorbide and N-methyl pyrrolidone Use the one selected from

Preferably, as the cosolvent, one selected from the group consisting of propylene carbonate, diethylene glycol monoethyl ether, propylene glycol and polyethylene glycol is used.

The emulsion concentrate composition of the present invention is 1: 0.5 to 50: 0.1 to 50: 0.1 to 50 by weight ratio of leaf extract, oil, surfactant and cosolvent, preferably 1: 0.5 to 10: 0.1 to 10: 0.1 to 10 weight ratio It is prepared by mixing.

In addition, the emulsion concentrate composition of the present invention increases the solubility and absorption in the gastrointestinal tract of substances commonly used in pharmaceuticals, for example, leaf extracts, within the range that does not adversely affect the medicinal effects and dispersed with water upon oral administration and Emulsifiers, such as fatty acids or fatty alcohols, which can be widely used to increase dissolution and improve bioavailability, sugars such as white sugar, macion syrup, white sugar, gelatin, sugar and starch syrup, magnesium stearate, talc, colloidal silicon dioxide and Lubricating agents, microcrystalline cellulose, calcium dihydrogen phosphate, starch, excipients such as mannitol, polyvinylpyrrolidone, sodium starch glycolate, crospovidone, low-substituted hydroxypropylcellulose, calcium Disintegrants such as carboxymethylcellulose, antioxidants that prevent the formulation from oxidizing, Fragrance, preservatives, fragrances, and can further comprise a sweetener, colorant, pH adjusting agent and viscosity agent, it is preferably added in an ordinary amount to be used in a conventional against aeyeop extract.

Fatty acids or fatty alcohols that may be used in the emulsion concentrate composition of the present invention include citric acid, oleic acid, stearyl alcohol, stearyl alcohol, myristic acid, linoleic acid or Lauric acid, capric acid, caprylic acid, caproic acid, and the like may be used, but is not limited thereto.

Antioxidants that can be used in the emulsion concentrate composition of the present invention are butylated hydroxytoluene, sodium bisulfite, alpha-tocopherol, vitamin C (ascorbic acid), beta Β-carotin, tocopherol acetate, fumaric acid, nalic acid, butylated hydroxyanisole, propyl galate and sodium Ascorbate may be used, but is not limited thereto.

Flavoring agents that can be used in the emulsion concentrate composition of the present invention may be mixed fruit flavor, apple flavor, strawberry flavor, cherry flavor, peppermint flavor, vanilla flavor, yogurt flavor, drink flavor and the like, but is not limited thereto.

Preservatives that can be used in the emulsion concentrate composition of the present invention may be used, but are not limited to benzoic acid, sodium benzoate, ethyl paraben, methyl paraben, propyl paraben and the like.

Perfume which can be used in the emulsion concentrate composition of the present invention may be used, but not limited to, peppermint brain, peppermint oil, orange oil, clove oil, cinnamon oil, strawberry essence and other common fruit flavor and plant essence.

Sweeteners that can be used in the emulsion concentrate composition of the present invention may be used, but are not limited to white sugar, glucose, fructose, aspartame, stevioside, sorbitol, mannitol, oligosaccharide, syrup, macion syrup, and the like.

The pigments that can be used in the emulsion concentrate composition of the present invention are green No. 3, red No. 2, red No. 3, blue No. 1, blue No. 2, yellow No. 4, yellow No. 5, water-soluble mannitol, caramel, titanium oxide, ferric oxide Etc. may be used, but is not limited thereto.

PH adjusting agents that can be used in the emulsion concentrate composition of the present invention may be used, but is not limited to sodium carbonate, sodium hydroxide, potassium hydroxide, triethanolamine, monoethanolamine and the like.

Viscosity modifiers that can be used in the emulsion concentrate composition of the present invention hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), ethyl cellulose (ethylcellulose), methyl cellulose (Methylcellulose), Carboxymethyl cellulose, acacia, bentonite, alginic acid, propylene glycol alginate, polyvinylpyrrolidon, polyvinyl alcohol, and carboyl Carbopol, polycarbopil, tragacanth, xanthan gum, and the like may be used, but are not limited thereto.

The present invention also provides a fast-acting oral preparation containing the emulsion concentrate composition of the leaf extract.

The oral preparations are oral solutions, suspensions containing tablets, pills, hard capsules, soft capsules and aqueous solutions, and the preferred oral preparations of the present invention are soft capsules. The fast-acting oral preparations according to the present invention are formulated into a fast-acting oral preparation of juniper extracts by a conventional formulation method of an emulsion concentrate composition prepared by mixing a leaf extract, oil, a surfactant and a cosolvent and heating and dissolving at 80 ° C. can do.

Hereinafter, the present invention will be described in detail by examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited by the examples.

Example 1 Fast-acting oral preparation containing leaf extract

In accordance with the method described in Korean Patent Application No. 2003-41628, 60 mg of leaf extract extracted from harmful components, 100 mg of propylene glycol monocapriate, 20 mg of polyoxyethylene polyoxypropylene block copolymer, and 20 mg of propylene carbonate were mixed. 80 mg of Cremopoa RH40 and 30 mg of Labrasol were added to the mixed solution, and heated at 80 ° C. to dissolve until clear, thereby preparing an emulsion concentrate composition. The emulsion concentrate composition was formulated by filling in soft capsules.

ingredient Quantity (mg / capsule) Leaf extract 60 Propylene Glycol Monocapriate 100 Polyoxyethylene Polyoxypropylene Block Copolymer 20 Propylene carbonate 20 Cremopoa RH40 80 Labrasol 30

Example 2 Fast-acting Oral Formulation Containing Lobules Extract 2

The leaf extract 60 mg prepared in the same manner as in Example 1, propylene glycol monocapriate 100 mg, polyoxyethylene polyoxypropylene block copolymer 30 mg, propylene glycol 50 mg was mixed. 50 mg of Labrasol was added to the mixed solution, and heated to 80 ° C. to dissolve until clear, thereby preparing an emulsion concentrated composition. The emulsion concentrate composition was formulated by filling into a soft capsule.

ingredient Quantity (mg / capsule) Leaf extract 60 Propylene Glycol Monocapriate 100 Polyoxyethylene Polyoxypropylene Block Copolymer 30 Propylene glycol 50 Labrasol 50

Example 3 Fast-acting Oral Formulation Containing Lobules Extract 3

The leaf extract 60 mg, propylene glycol monocapriate 100 mg, polyoxyethylene polyoxypropylene block copolymer 20 mg, and propylene carbonate 20 mg which were prepared in the same manner as in Example 1 were mixed. 150 mg of polyoxyethylene sorbitan fatty acid ester and 80 mg of Labrasol were added to the mixed solution, and heated to 80 ° so as to be dissolved until it was transparent, thereby preparing an emulsion concentrate composition. The emulsion concentrate composition was formulated by filling into a soft capsule.

ingredient Quantity (mg / capsule) Leaf extract 60 Propylene Glycol Monocapriate 100 Polyoxyethylene Polyoxypropylene Block Copolymer 20 Polyoxyethylene Sorbitan Fatty Acid Ester 150 Propylene carbonate 20 Labrasol 80

Example 4 Fast-acting Oral Formulations Containing Lobules Extracts 4

The leaf extract 60 mg, propylene glycol monocapriate 150 mg, polyoxyethylene polyoxypropylene block copolymer 30 mg, and propylene carbonate 30 mg which were prepared in the same manner as in Example 1 were mixed. 150 mg of polyglyceryl-6-dioleate and 150 mg of Cremophor RH40 were added to the mixed solution, and heated at 80 ° C. to dissolve until clear to prepare an emulsion concentrate composition. The emulsion concentrate composition was formulated by filling in a soft capsule.

ingredient Quantity (mg / capsule) Leaf extract 60 Propylene Glycol Monocapriate 150 Polyoxyethylene Polyoxypropylene Block Copolymer 30 Propylene carbonate 30 Polyglyceryl-6-Dioleate 150 Cremopoa RH40 150

Example 5 Fast-acting Oral Formulation Containing Lobules Extract 5

The leaf extract 60 mg, propylene glycol monocapriate 150 mg, polyoxyethylene polyoxypropylene block copolymer 20 mg, and propylene carbonate 50 mg which were prepared in the same manner as in Example 1 were mixed. 200 mg of Cremophor RH40 was added to the mixed solution, and heated to 80 ° C. to dissolve until it was clear, thereby preparing an emulsion concentrated composition. The emulsion concentrate composition was formulated by filling into a soft capsule.

ingredient Quantity (mg / capsule) Leaf extract 60 Propylene Glycol Monocapriate 150 Polyoxyethylene Polyoxypropylene Block Copolymer 20 Propylene carbonate 50 Cremopoa RH40 200

Example 6 Fast-acting Oral Formulation Containing Lobules Extract 6

The leaf extract 60 mg, glyceryl monooleate 150 mg, polyoxyethylene polyoxypropylene block copolymer 30 mg, and propylene carbonate 30 mg which were prepared in the same manner as in Example 1 were mixed. 100 mg of Cremopoa RH40 and 50 mg of Labrasol were added to the mixed solution, and heated to 80 ° C. to dissolve until clear to prepare an emulsion concentrate composition. The emulsion concentrate composition was formulated by filling into a soft capsule.

ingredient Quantity (mg / capsule) Leaf extract 60 Glyceryl Monooleate 150 Polyoxyethylene Polyoxypropylene Block Copolymer 30 Propylene carbonate 30 Cremopoa RH40 100 Labrasol 50

Example 7 Fast-acting Oral Formulation Containing Lobules Extract 7

The leaf extract 60 mg, glyceryl monooleate 150 mg, polyoxyethylene polyoxypropylene block copolymer 30 mg, and propylene glycol 30 mg which were prepared in the same manner as in Example 1 were mixed. 150 mg of Labrasol was added to the mixture, and the mixture was heated at 80 ° C. and dissolved until it was transparent, thereby preparing an emulsion concentrate composition. The emulsion concentrate composition was formulated by filling into a soft capsule.

ingredient Quantity (mg / capsule) Leaf extract 60 Glyceryl Monooleate 150 Polyoxyethylene Polyoxypropylene Block Copolymer 30 Propylene glycol 30 Labrasol 150

Example 8 Fast-acting Oral Formulations Containing Lobules Extracts 8

The leaf extract 60 mg, glyceryl monooleate 150 mg, polyoxyethylene polyoxypropylene block copolymer 30 mg, and propylene carbonate 30 mg which were prepared in the same manner as in Example 1 were mixed. 150 mg of polyoxyethylene sorbitan fatty acid ester and 150 mg of Labrasol were added to the mixed solution, and heated to 80 ° C. to dissolve until clear, thereby preparing an emulsion concentrate composition. The emulsion concentrate composition was formulated by filling into a soft capsule.

ingredient Quantity (mg / capsule) Leaf extract 60 Glyceryl Monooleate 150 Polyoxyethylene Polyoxypropylene Block Copolymer 30 Propylene carbonate 30 Polyoxyethylene sorbitan fatty acid ester 150 Labrasol 150

Example 9 Fast-acting Oral Formulations Containing Lobules Extracts 9

The leaf extract 60 mg, glyceryl monooleate 150 mg, polyoxyethylene polyoxypropylene block copolymer 30 mg, and propylene carbonate 30 mg which were prepared in the same manner as in Example 1 were mixed. 150 mg of polyglyceryl-6-dioleate and 150 mg of Cremophor RH40 were added to the mixed solution, and heated to 80 ° C. to dissolve until clear to prepare an emulsion concentrate composition. The emulsion concentrate composition was formulated by filling in a soft capsule.

ingredient Quantity (mg / capsule) Leaf extract 60 Glyceryl Monooleate 150 Polyoxyethylene Polyoxypropylene Block Copolymer 30 Propylene carbonate 30 Polyglyceryl-6-Dioleate 150 Cremophor RH40 150

Example 10 Fast-acting Oral Formulation Containing Lobules Extract 10

The leaf extract of 60 mg, propylene glycol monocapriate 150 mg, polyoxyethylene polyoxypropylene block copolymer 30 mg, and propylene carbonate 30 mg, which were prepared in the same manner as in Example 1, were mixed. The mixture was heated at 80 ° C. and dissolved until it was transparent to prepare an emulsion concentrated composition. The emulsion concentrate composition was formulated by filling into a soft capsule.

ingredient Quantity (mg / capsule) Leaf extract 60 Propylene Glycol Monocapriate 150 Polyoxyethylene Polyoxypropylene Block Copolymer 30 Propylene carbonate 30

Example 11 Fast-acting Oral Formulation Containing Lobules Extract 11

The leaf extract 60 mg prepared in the same manner as in Example 1, 300 mg of propylene glycol monocapriate and 100 mg of polyoxyethylene polyoxypropylene block copolymer and 20 mg of propylene glycol were mixed. 150 mg of Cremopoa RH40 and 150 mg of Labrasol were added to the mixed solution, and heated at 80 ° C. to dissolve until clear to prepare an emulsion concentrate composition. To the emulsion concentrated composition, 1,000 mg of white sugar, 30 mg of citric acid, and 5 mg of flavoring (mixed fruit flavor) were added and dissolved, and then sterilized by using an appropriate amount of purified water. After sterilization was completed, the bottles were filled and formulated into liquid formulations.

ingredient Quantity (mg / capsule) Leaf extract 60 Propylene Glycol Monocapriate 300 Polyoxyethylene Polyoxypropylene Block Copolymer 100 Propylene glycol 20 White sugar 1,000 Citric acid 30 Spices (mixed fruits) 5 Purified water Quantity

Example 12 Fast-acting Oral Formulation Containing Lobules Extract 12

Emulsion concentrate composition was prepared by mixing 60 mg of leaf extracts prepared in the same manner as in Example 1, 30 mg of propylene glycol monocapriate, 20 mg of polyoxyethylene polyoxypropylene block copolymer, and 20 mg of Cremopoa RH40. 80 mg of microcrystalline cellulose, 60 mg of polyvinylpyrrolidone (collidone CL), 3 mg of magnesium stearate, and 2.5 mg of colloidal silicon dioxide (aerosil 200) were added to the emulsion concentrated composition, followed by tableting to obtain tablets. .

ingredient Quantity (mg / capsule) Leaf extract 60 Propylene Glycol Monocapriate 30 Polyoxyethylene Polyoxypropylene Block Copolymer 20 Cremopoa RH40 20 Microcrystalline cellulose 80 Polyvinylpyrrolidone 60 Magnesium Stearate 3 Colloidal silicon dioxide 2.5

Comparative Example

8 kg of lactose and 4 kg of corn starch were mixed in a high speed mixer. This mixture was mixed with 3 Kg of leaf extracts prepared in the same manner as in Example 1, combined in a coalescer, and assembled into No. 20 sieves. After hot-air drying at 60 degreeC, it granulated in No. 20 sieve and obtained granules. The granules were prepared by filling the granules into an automatic capsule filling machine.

Experimental Example 1 Solubility Comparison Experiment

Pharmaceuticals of fast-acting oral preparations containing emulsion concentrate compositions of leaf extracts according to the invention and leaf extracts without such a system The solubility of oral formulations containing the composition was measured and compared.

Specifically, pH conditions (pH = 1.2) in the gastrointestinal tract and pH conditions in the small intestine and the large intestine (pH = 6.8) of the short-acting oral soft capsule containing the leaf extract prepared from Example 1 and the granule extract-containing granules prepared from the comparative example. The solubility of the drug was measured at.

The experimental method is as follows.

Take an amount corresponding to 60 mg of leaf extract in the oral preparations prepared in Example 1 and Comparative Example, and the buffer solution of pH 1.2 and pH 6.8 (KEPCO Revision 8; pH 1.2 solution-2.0 g sodium chloride 7.0 ml and Add water to 1 L. pH 6.8 solution-250 mol of 0.2 mol / L potassium dihydrogen phosphate solution 118 ml of 0.2 mol / L sodium hydroxide solution and 1 L of water) were added to 150 ml, respectively. After the solution was stirred at 37 ° C. for 1 hour, the solubility was measured. Solubility was measured using HPLC after centrifugation.

The results are shown in Table 1.

Solubility and Comparison at pH = 1.2 and pH = 6.8 Formulation Solubility (µg / mL) pH = 1.2 pH = 6.8 Example 1 (Test formulation) 8.4 8.8 Comparative Example (Comparative) 1.5 3.4 Solubility Comparison (Example 1 / Comparative Example) 5.6 2.6

As can be seen in Table 1, the solubility of the fast-acting oral preparation of the leaf extract prepared from Example 1 of the present invention was 8.4 µg / ml and 8.8 µg / ml at pH = 1.2 and pH = 6.8, respectively, and compared. The solubility of the oral preparations prepared from the examples was 1.5 μg / ml and 3.4 μg / ml, respectively. In addition, when comparing the solubility it can be seen that the solubility of the fast-acting oral preparation of the leaf extract according to the present invention is 5.6 times and 2.6 times higher at pH = 1.2 and pH = 6.8, respectively.

Therefore, the fast-acting oral preparation of the leaf extract according to the present invention can be seen that the solubility is very high at the pH conditions of the small intestine and the large intestine in the gastrointestinal tract, compared to the preparation prepared by the conventional method, it is constantly dissolved in various pH conditions Can be.

Experimental Example 2 Dissolution Rate Comparison Experiment

The dissolution rate of the fast-acting oral preparation of the leaf extract according to the present invention and the oral preparation containing the pharmaceutical composition of the leaf extract without such a system was measured and compared.

The experimental method is as follows.

Taking an amount corresponding to 60 mg of leaf extract in the oral preparation containing the pharmaceutical composition of the leaf extract prepared from Example 1 and Comparative Example, buffering pH = 1.2 and pH = 6.8 prepared in the same manner as in Experiment 1 500 ml of solution was added and stirred at 100 rpm. Samples were taken at 10, 20, 30, 40, 50 and 60 minutes of agitation by paddle method to determine the content of the leaf extract extracted therefrom. The dissolution rate was 100% of the leaf extracts contained in the oral preparation and measured in% using the leaf extracts measured from the sample.

The dissolution rate measured at pH = 1.2 is shown in FIG. 1, and the dissolution rate measured at pH = 6.8 is shown in FIG. 2.

As can be seen in Figure 1, the fast-acting oral preparations (test preparations) of the leaf extract prepared from Example 1 of the present invention showed a dissolution rate of more than 70% for 10 minutes, a constant dissolution rate for 20 minutes to 60 minutes Showed. On the other hand, the oral preparation prepared in Comparative Example (comparative) showed a lower dissolution rate for each stirring time compared to the oral preparation prepared in Example 1.

Therefore, it can be seen that the fast-acting oral preparation of the leaf extract according to the present invention has a high dissolution rate in the pH = 1.2 buffer solution. In addition, it can be seen that the fast-acting oral preparation of the leaf extract according to the present invention shows a rapid increase in dissolution rate during the stirring time of 10 minutes.

As can be seen in Figure 2, the fast-acting oral preparations (test preparations) of the leaf extract prepared from Example 1 of the present invention showed a dissolution rate of more than 70% for 10 minutes, a constant dissolution rate for 20 minutes to 60 minutes Showed. On the other hand, the oral preparation prepared in Comparative Example (comparative) showed a lower dissolution rate for each stirring time compared to the oral preparation prepared in Example 1.

Therefore, it can be seen that the fast-acting oral preparation of the leaf extract according to the present invention has a high dissolution rate in the pH = 6.8 buffer solution.

As can be seen in Figures 1 and 2 it can be seen that the fast-acting oral preparation of the leaf extract according to the present invention has a higher dissolution rate at pH = 1.2 and pH = 6.8 than the oral preparation prepared from the comparative example. In addition, the dissolution rate is similar in shape, it can be seen that it has a constant dissolution rate at various pH.

Experimental Example 3 Blood Concentration Comparison Experiment

When the rats were administered the fast-acting oral preparation of the leaf extract according to the present invention and the oral preparation prepared from the comparative example, the blood concentration was measured and compared.

The experimental method is as follows.

250-300 g of male white rats (Sprague-Dawely series) purchased from the National Institutes of Health were used for the experiment after adapting for about 1 to 2 weeks. Mice fasted for at least 24 hours prior to the start of the experiment were anesthetized with ether and the canal of the left femoral artery was inserted to insert a tube to which a 50 IU / ml heparin-filled syringe was connected. After about 2 hours, when the rat awakes from anesthesia, the fast-acting soft capsule formulation of the leaf extract obtained from Example 1 and the formulation prepared from the comparative example were administered with a dose of 20 mg / kg of eupatillin using an oral sonde. It was. 0, 5, 10, 20, 30, 1, 2, 4, 6 and 8 hours after administration of the formulation, blood was drawn from the left femoral artery and centrifuged at 3,500 rpm for 10 minutes. The plasma was separated and stored at −20 ° C. until analysis.

The content of eupatillin in the blood was quantified using HPLC. First, 100 μl of blood is added to a microtube, and 100 μl of acetate buffer and 20 μl of beta-glucuronidase are added, followed by reaction at 37 ° C. for 2 hours. 100 μl of biochainin A and 1.5 mL of ether were added and then vortexed for 2 minutes. After centrifugation at 12,000 rpm for 2 minutes, the supernatant is separated and evaporated under nitrogen gas. 130 μl of the mobile phase was added and vortexed for 1 minute, and 100 μl of which was injected into HPLC. Analytical conditions are the column is a mixture of Hichrom RPB (250 * 4.6mm, particle size: 5㎛), analysis wavelength 350nm, mobile phase 0.5% acetic acid buffer and acetonitrile in a volume ratio of 50:50. The flow rate of the mobile phase was 1 ml / min, and the sample injection amount was 100 µl. Eupatillin was quantified as area ratio with internal standard.

The results are shown in FIG.

As can be seen in Figure 3, the blood concentration when the fast-acting soft capsule (test preparation) of the leaf extracts prepared in Example 1 of the present invention was administered to the rat prepared from the comparative (preparative) It can be seen that it is higher than the blood concentration at the time of administration. In addition, the quick-acting soft capsule formulation of the leaf extract according to the present invention can be seen that it has more than two times the highest blood concentration and 10 times more blood concentration area (AUC) than the preparation prepared from the comparative example.

In addition, the preparation prepared from the comparative example had a blood concentration of 0 after 4 hours after administration to the rat, but the fast-acting soft capsule preparation of the leaf extract according to the present invention had a blood concentration of 0 after 12 hours.

Therefore, it can be seen that the fast-acting soft capsule preparation of the leaf extract according to the present invention exists for a longer time in the blood. Through such experiments, it can be seen that the fast-acting soft capsule preparation of the leaf extract according to the present invention has a higher bioavailability than the preparation prepared from the comparative example.

As described above, the present invention provides a fast-acting emulsion concentrate composition of leaf extracts and improved fast-acting oral preparations containing the same, which has improved dissolution rate, oral absorption rate and bioavailability, thereby increasing solubility and dissolution rate in the gastrointestinal tract. By enhancing the biomembrane permeability, it can be rapidly absorbed in vivo, thereby significantly increasing the bioavailability.

In addition, by presenting a solubilizing method and a specific formulation method of the preparation containing the leaf lobe extract to coexist with the sustained release formulation in the prevention or treatment of diseases of the gastrointestinal tract or inflammatory bowel disease to treat the underlying gastrointestinal diseases.

1 is a fast-acting soft capsule preparation (test preparation) of a leaf extract according to the present invention containing 60 mg of leaf extracts in a pH = 1.2 buffer solution of Experimental Example 2 and a time after stirring the preparation according to a comparative example (comparative). The dissolution rate according to

Figure 2 is a time-effective soft capsule formulation of the leaf extract according to the present invention containing a leaf extract 60mg in the pH = 6.8 buffer solution of Experimental Example 2 (test preparation) and the preparation according to the comparative example (comparison preparation) at a time after stirring The dissolution rate according to

Figure 3 is a fast-acting soft capsule preparation (test preparation) according to the invention containing 20 mg of eupatillin of Experimental Example 3 (preparative formulation) and the preparation prepared from the comparative example (comparative formulation) in the blood over time after oral administration to the rat The concentrations are compared.

Claims (7)

A quick-acting emulsion concentrate composition of a leaf extract using a self-emulsifying drug delivery system, comprising a leaf extract, oil, a surfactant, and a cosolvent in a weight ratio of 1: 0.5 to 50: 0.1? 50: 0.1 ?? 50. The method of claim 1, wherein the oil is glyceryl stearate, glyceryl monooleate, captylic / capric triglycerides, cetyl octanolate, isopropyl myristate, 2-ethylene isofelonate, di-C _{12 -13} alkylmaleates, ceteathyl octanoate, butylene glycol dicaptylate / dicaprate, propylene glycol monocapriate, isononyl isostearate, isostearyl isostearate, coco-captylate / caprate Esters such as cetyl octanoate, octyldodecyl myristate, cetyl esters, C _10-30 cholesterol / lanosterol esters, hydrogenated castor oils, monoglycerides, diglycerides, triglycerides; Hydrocarbons such as biswax, carnauba wax, succitose distearate, propylene glycol-8 biswax and candelilla wax; Minerals such as ceresin and ozokerite; At least one selected from the group consisting of corn oil, sesame oil, soybean oil, olive oil, jojoba oil, grape seed oil, macadamia oil, hydrogenated high-erucic acid rapeseed oil, safflower oil, hybrid sunflower oil, ninse oil or wild rose oil. Fast-acting emulsion concentrate composition of the leaf extract. The method of claim 1 wherein the surfactant is a polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene polyoxypropylene copolymer, natural or Reaction products of hydrogenated vegetable oils and ethylene glycol, sodium dioctyl sulfosuccinate, sodium lauryl sulfonate, phospholipids, propylene glycol mono or di fatty acid esters, trans-esterification products of natural vegetable oil triglycerides and polyalkylenepolyols, mono -Mixtures of di- or triglycerides with polyethylene glycol mono or di fatty acid esters, mono-, di- or mono / diglycerides, propylene glycol mono or fatty acid esters with mono-, di-, or mono / diglycerides Mixtures and derivatives thereof Fast-acting emulsion concentrate composition of the leaf extract, characterized in that at least one selected from the group consisting of. The method of claim 1, wherein the cosolvent is at least one selected from the group consisting of propylene carbonate, propylene glycol, ethanol, diethylene glycol monoethyl ether, glycofurol, polyethylene glycol, dimethyl isosorbide and N-methyl pyrrolidone Fast-acting emulsion concentrated composition of the leaf extract, characterized in that. The method of claim 1, wherein the leaf extract, oil, surfactant and co-solvent is 1: 0.5 ~ 10: 0.1 ?? 10: 0.1 ?? 10 weight ratio of the leaf extract that can use a self-emulsifying drug delivery system Fast-acting emulsion concentrate. A fast-acting oral preparation of a leaf extract containing the emulsion concentrate composition of the leaf extract which can use the self-emulsifying drug delivery system according to claim 1. 7. The fast-acting oral preparation of juniper extract according to claim 6, wherein the fast-acting oral preparation is selected from the group consisting of tablets, pills, hard capsules, soft capsules and oral solutions containing aqueous solutions, and suspensions. .