KR101779513B1

KR101779513B1 - Pharmaceutical composition comprising the isopropanol extract of artemisia

Info

Publication number: KR101779513B1
Application number: KR1020150090032A
Authority: KR
Inventors: 신용관; 이종현; 홍일기; 임종재; 박상욱; 조상호; 송세현; 손세일; 이홍우
Original assignee: 대원제약주식회사
Priority date: 2015-06-24
Filing date: 2015-06-24
Publication date: 2017-09-19
Also published as: WO2016208926A1; KR20170000907A

Abstract

A pharmaceutical composition comprising an isopropanol extract of Leaf as an active ingredient is provided, which comprises a polymer substance and a disintegrant and has a specific dissolution rate.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING THE ISOPROPANOL EXTRACT OF ARTEMISIA [0002]

The present invention relates to a pharmaceutical composition containing an isopropanol extract of lobster. The present invention relates to a pharmaceutical composition comprising an isoflavone extract of a leaf, as an active ingredient, and capable of solubilization without using a surfactant. More specifically, in the case of using a combination of a specific polymer with a specific disintegrant and a pH adjusting agent in a pharmaceutical composition containing an isopropanol extract of a leaf as an active ingredient, the isopropanol extract of the leaf can be obtained without using a surfactant The present invention relates to a pharmaceutical composition which can be solubilized effectively.

Further, the present invention relates to a unit dosage form for the treatment of gastrointestinal diseases, which comprises 90 mg of isoflavone extract of lobule per unit dosage form and is taken twice a day.

Artemisia mongolica, A. asiatica, A. princeps var. Orientalis, A. argyi, A. montana, etc.) are perennial herbs belonging to Asteraceae and have been used as antiseptic drugs for gynecological diseases, gynecological diseases and diarrhea since ancient times, Include isocoumarin, coumarin, diterpene lactone, and the like. In the Korean Pharmacopoeia (Herbal Medicine) Specification Collection, the leaves and young stems of the mugwort are also referred to as "Artemisiae argyi Herb".

It has been confirmed that the leaf extract contains flavonoids such as yupatilin and oriental osteidine. Such a single ingredient alone has been known to have gastrointestinal protective action and gastritis treatment. However, There is a large difference in the effect of treatment of gastrointestinal diseases among unipolar individuals. There are many unknown compounds that have not yet been revealed in the extract of lobster, and it is thought that the synergistic interaction of these components shows the therapeutic effect of gastrointestinal diseases .

Particularly, pharmaceutical compositions containing an extract of Leucocybe as an active ingredient are known, and medicines containing an extract of Leucifer extract are commercially available. These drugs use an ethanol extract of Leaf leaf and an isopropanol extract of Leaf leaf as effective ingredients. However, in the case of natural products, there are many cases in which the content of the indicator component is different depending on which solvent is extracted. Therefore, the therapeutic effect also varies. For this reason, the Food and Drug Administration Even after receiving this license, patients are required to carry out Phase 3 clinical trials in the approval process for medicines containing isoflavone extract of Leaf as an active ingredient. It is also clear that if there is a difference in the content of the indicator component and the therapeutic effect between the ethanol extract of the leaf leaf and the isopropanol extract of the leaf leaf, the physicochemical properties affecting the formulation process of the leaf extract and the leaf leaf may be different.

Until recently, many technological advances and numerous patent applications have been filed on lentil extracts. Representative examples are as follows.

Patent No. 127777 discloses that eupatilin, a flavonoid component contained in the leaves, has an effect of treating gastrointestinal diseases. Patent No. 181751 discloses that another component, puosenicin, also has an effect of treating gastrointestinal diseases .

In patent No. 181751, the anti-gastritis effect of mugwort extract itself is more excellent than the anti-gastritis effect of refined oil tilline or postural oscidine from mugwort, and unknown substances in the extract increase the anti-gastritis effect.

In patent application No. 1000951, mugwort contains a blood coagulation inhibiting component, that is, coumarin, among which dicoumarol is included in the extraction process, and in order to remove such components / RTI >

On the other hand, the lobster extract is known as a poorly soluble drug, and accordingly, a suitable solubilizing means is indispensably required in order to formulate it. Accordingly, Japanese Patent No. 1100942 discloses a disadvantage in that the dissolution rate of the leaf extract in the gastrointestinal tract is very low, about 40 to 50%, and the bioavailability is low due to low biomembrane permeability, and as a solubilizing means for solving the problem, Transport system (SMEDDS), which essentially comprises a surfactant.

In addition, Japanese Patent No. 908193 discloses a means for solubilizing a leaf extract as in the above patent, but it also proposes the use of poloxamer, which is a kind of surfactant.

However, the present inventors have found that the surfactant used as a means for solubilizing the extract of the leaf extract in the above-mentioned patent documents solubilizes the leaf extract, but has a problem of stimulating the gastric mucosa (Contact Dermatitis 1995 Oct; ): 217-25). In particular, considering the fact that the indications of the extracts of lobules are the treatment of gastrointestinal diseases, when surfactants are used to solubilize the extracts of lobules, The results of this study are as follows. Thus, it was realized that there is a high need to reduce the risk of accelerating gastric wall damage by solubilizing the leaf extract without using a surfactant.

In particular, in patients with gastrointestinal diseases, every time a meal is taken, it is troublesome and uncomfortable to eat it every time. Therefore, there have been steady efforts to improve the compliance of medicines by improving the existing medicines that are taken three times a day twice a day. For example, Patent No. 1050015 discloses a pharmaceutical composition of a leaf extract using GRT and a sustained-release oral preparation using the same, wherein a swelling polymer, a bubbler, a release-controlling polymer, A dissolution aid is used, and a surfactant is used as a dissolution aid. That is, in any of the conventional patent documents, it is known that a surfactant is used to achieve solubilization and / or sustained release of the extract of the ladybug. In the pharmaceuticals containing the ladybug extract as an active ingredient for the treatment of gastrointestinal diseases , And the use of a surfactant capable of damaging the gastrointestinal mucosa is undesirable as mentioned above.

Accordingly, the present inventors have intensively studied as a means for solubilizing a leaf extract, a technique of not using a surfactant, and have proposed a pharmaceutical composition containing a leaf extract as a combination of a specific polymer and a specific disintegrant, The present invention provides a pharmaceutical composition which can be solubilized.

Patent No. 1100942 Patent No. 908193

The present invention provides a pharmaceutical composition in which an isopropanol extract of a leaf is solubilized without containing a surfactant in order to reduce adverse effects adversely affecting the gastrointestinal tract of gastrointestinal disease patients, such as damaging gastric wall cells . More specifically, it is intended to provide a pharmaceutical composition solubilized by using a combination of an isopropanol extract of a leaf, a specific polymer and a specific disintegrant, and a pH adjusting agent.

In the present invention, a pharmaceutical composition for treating gastrointestinal diseases comprising an isoflavone extract of a leaf as an active ingredient, which comprises a polymer substance and a disintegrant, is disclosed.

Also disclosed is a pharmaceutical composition as described above, wherein the polymeric material is HPC and the disintegrant is croscarmellose sodium.

Also disclosed is a pharmaceutical composition, wherein the pharmaceutical composition comprises a pH adjusting agent.

Also disclosed is a pharmaceutical composition characterized in that, in the pharmaceutical composition, the elution of the phosphatylline satisfies the following conditions.

Further, the pharmaceutical composition exhibits a dissolution rate of 5 to 45% at 15 minutes and 65% or more at 60 minutes in a pH 1.2 buffer supplemented with 0.5% sodium lauryl sulfate (SLS).

In particular, according to the present invention, there is provided a unit dosage form for the treatment of gastrointestinal diseases which comprises 90 mg of isoflavone extract of lobule per unit dosage form and can be taken twice a day.

According to the present invention, there is provided a pharmaceutical composition capable of solubilizing the isoflavone extract of leaf livers and having a high bioavailability and being prepared as a sustained release agent. In addition, by not using a surfactant, a pharmaceutical composition without gastrointestinal disorder can be provided.

Fig. 1 is a graph showing dissolution rates of Example 1 of the present invention and Comparative Examples 3 to 7. Fig.
2 is a photograph of a stomach-like motion image of Example 1 of the present invention.
3 is a photograph of a stomach-like motion picture of a commercial product.
4 is a graph showing the effect of ethanol-induced gastritis treatment in rats of Example 1 of the present invention.
5 is a graph showing the effect of indomethacin-induced gastritis treatment in the rat of Example 1 of the present invention.

Unlike a single component compound, a mixture of compounds such as a leaf extract is not easy to define its physical and chemical properties. This is because, in the case of extracts extracted from natural products, each of the monomers constituting the extract as a mixture of many single compounds having different physical and chemical properties will have unique physicochemical properties, and it is very difficult to specify easily to be.

In particular, in the case of the leaf extract, it is known that the gastrointestinal disease effect when the leaf extract is used as a whole is superior to the effect of the gastrointestinal disease represented by the ephedrine or postural oocidine, which is known as an indicator component, It is reasonable to understand that the physicochemical properties of the leaf extract are also greatly influenced by the unknown components.

Therefore, deriving a means for solubilizing the leaf extract, which is known to be poorly soluble, can not be expected to be solubilized by applying a conventional solubilization method because it is not of a property that can be explained uniformly by a certain theory.

In addition, in the case of natural product extracts, various physical and chemical properties that occur in the formulation process as well as the therapeutic effect differ depending on the solvent in which the same natural product is extracted. In the case of the leaf extract, the ethanol extract of the leaf leaf and the isopropanol extract of leaf leaf have a different therapeutic effect including the indicator component and the optimum solubilization method will not be the same.

The inventors of the present invention have found that, under such circumstances, by incorporating a specific polymer substance and a specific combination of a disintegrant into a pharmaceutical composition containing an isopropanol extract of a leaf, and further including a pH adjusting agent, .

In the case of natural extracts, the extract has a large number of unknown components that are not yet known, and therefore, a uniform solubilization method can not be applied. Thus, achieving solubilization by combination of a specific polymer substance and a specific disintegration means that a person skilled in the art Is difficult to predict.

Means derived by the present inventor for solubilizing isoflavone extract of leaves is a combination of hydroxypropylcellulose (HPC) as a polymer substance and croscarmellose sodium as a disintegrant.

The HPC may include 0.01 to 0.2 part by weight of the isopropanol extract of the leaf, and the croscarmellose sodium may include 0.01 to 0.3 part by weight of the isopropanol extract of the leaf leaf, based on 1 part by weight of the leaf extract.

It is usually difficult to predict that such disintegrants will affect solubilization ability, since disintegrants, in the case of oral solid preparations, serve to promote the disintegration of the formulation upon administration to the body. However, in the case of isopropanol extract of Leaf, the solubilization effect is increased by using HPC and disintegrant croscarmellose sodium in the process of granule production, and in addition to HPC, other combinations other than croscarmellose sodium as a disintegrant It is presumed that the solubilization ability is promoted by the organic action of such a combination of the disintegrant and the polymer.

Further, the composition may comprise a substance for controlling the pH. By incorporating a pH adjusting agent into the present composition, the isopropanol extract of the leaf is solubilized, and further, the sustained release can be achieved. Specific examples of the pH adjusting agent include calcium hydroxide, ethanolamine, potassium hydrogen carbonate, potassium citrate, sodium hydrogen carbonate, sodium hydroxide citrate, calcium silicate, sodium hydroxide, arginine, magnesium oxide, calcium carbonate, magnesium carbonate, magnesium hydroxide , Magnesium silicate, magnesium aluminum hydroxide, sodium borate, and meglumine can be used. In particular, an alkalizing agent selected from the group consisting of sodium hydrogencarbonate, magnesium oxide, meglumine, and sodium carbonate is used .

In the pharmaceutical composition of the present invention, the amount of the pH adjusting agent may be varied, but may include 0.1 to 1 part by weight based on 1 part by weight of the isopropanol extract of the leaf.

In addition, the pharmaceutical composition comprising the extract of the present invention may contain 10 to 50% by weight of the isopropanol extract of the leaf, based on the total weight of the composition.

Further, the compositions of the present invention may generally comprise one or more pharmaceutically acceptable excipients, carriers or diluents. In general, tablet formulations containing herbal extracts comprise materials such as diluents, lubricants and mixtures thereof. The present invention may include excipients, lubricants, and the like, which are any of the ingredients commonly used in the manufacture of tablet formulations in the pharmaceutical arts, including lactose, starch, lactose, mannitol, powdered sugar, and powdered cellulose derivatives And it is preferable to add a substance which is commonly used in pharmaceuticals within the range not adversely affecting the drug efficacy as an additive in a usual amount.

Hereinafter, the present invention will be described more specifically with reference to Examples. However, the present invention is not limited to the examples.

Example 1

90 mg of isopropanol extract and 10 mg of hydroxypropylcellulose were dissolved in ethanol to prepare a binding solution, and 10 mg of calcium silicate, 48 mg of lactose, 54 mg of microcrystalline cellulose, 60 mg of sodium hydrogencarbonate, 20 mg of croscarmellose sodium And the granules were prepared by adding the binding solution. After drying the granules, 30 mg of carbomer and 20 mg of hyphromellose were mixed. Then, talc, magnesium laurate, and magnesium stearate were mixed and then tableted to prepare tablets. A film-coated tablet was prepared by coating the nylon with a base containing HPMC.

Comparative Examples 1 to 2

Comparative Example 1 was prepared in the same manner as in Example 1 except that ethanol extract was used instead of isopropanol extract as an active ingredient in Example 1 and Comparative Example 2 was supplemented with poloxamer as a surfactant.

Experimental Example 1

A solubility test was conducted on Example 1 and Comparative Examples 1 and 2. The solubility test was conducted by measuring the solubility of each of the tablets of Examples and Comparative Examples in accordance with the solubility test method described in Korean Patent No. 1100942. The solubility (%) is a relative value based on the solubility of Comparative Example 1.

division Solubility (μg / mL) Solubility (%) Example 1 6.5 203 Comparative Example 1 3.2 100 Comparative Example 2 6.0 188

As can be seen from Table 1, in Example 1, solubilization was possible by including a combination of HPC and croscarmellose sodium. However, in the case of the ethanol extract of the leaf lobes, solubilization was observed even when the combination of HPC and croscarmellose sodium was included (Comparative Example 1), and a surfactant was required (Comparative Example 2).

Comparative Example 3

90 mg of isopropanol extract of Leaf lard was dissolved in ethanol to make a binding solution, and 10 mg of calcium silicate, 48 mg of lactose hydrate, 54 mg of microcrystalline cellulose and 60 mg of sodium bicarbonate were mixed and granulation was made by adding a binding solution. After drying the granules, 30 mg of carbomer and 20 mg of hyphromellose were mixed and kneaded to prepare tablets. A film-coated tablet was prepared by coating the nylon with a base containing HPMC.

Comparative Example 4

90 mg of isopropanol extract of Leucocephalus was dissolved in ethanol to prepare a binding solution. After mixing 10 mg of calcium silicate, 48 mg of lactose hydrate, 54 mg of microcrystalline cellulose, 60 mg of sodium hydrogencarbonate and 20 mg of croscarmellose sodium, To form granules. After drying the granules, 30 mg of carbomer and 20 mg of hyphromellose were mixed and kneaded to prepare tablets. A film-coated tablet was prepared by coating the nylon with a base containing HPMC.

Comparative Example 5

90 mg of isopropanol extract and 10 mg of hydroxypropylcellulose were dissolved in ethanol to prepare a binding solution. 10 mg of calcium silicate, 48 mg of lactose, 48 mg of microcrystalline cellulose and 60 mg of sodium bicarbonate were mixed, I made the sun granules. After drying the granules, 30 mg of carbomer and 20 mg of hyphromellose were mixed and kneaded to prepare tablets. A film-coated tablet was prepared by coating the nylon with a base containing HPMC.

Comparative Example 6

90 mg of isopropanol extract of the leaves was dissolved in ethanol to prepare a binding solution, and 10 mg of calcium silicate, 48 mg of lactose hydrate, 54 mg of microcrystalline cellulose and 60 mg of sodium bicarbonate were mixed and granulation was made by adding a binding solution. After drying the granules, 30 mg of carbomer and 20 mg of hyporomelose were mixed and kneaded to prepare tablets. A film-coated tablet was prepared by coating the nylon with a base containing HPMC.

Comparative Example 7

Experimental Example 2

The dissolution tests of Example 1 and Comparative Examples 3 to 7 were carried out, and the results are shown in Table 2.

The dissolution test was carried out in a pH 1.2 buffer solution containing 0.5% of sodium lauryl sulfate (SLS) under the condition of 100 rpm by the pharmacopoeial paddle method, and the dissolution rate of the tiline was confirmed (unit:%).

division 0 minutes 15 minutes 30 minutes 45 minutes 60 minutes Example 1 0 24.4 47.1 72.0 89.6 Comparative Example 3 0 15.1 28.3 36.6 45.7 Comparative Example 4 0 11.4 27.5 44.2 55.1 Comparative Example 5 0 2.2 4.7 7.8 11.0 Comparative Example 6 0 13.7 25.3 42.7 54.9 Comparative Example 7 0 17.6 34.6 52.0 61.2

As can be seen from the above Table 2, in comparison with the examples of the present invention using a combination of HPC and croscarmellose sodium, Comparative Examples 3 to 7, which did not use these combinations, showed poor solubilization ability, It was found that it was bad.

Example 2

90 mg of isopropanol extract and 12 mg of hydroxypropylcellulose were dissolved in ethanol to prepare a binding solution, and 10 mg of calcium silicate, 48 mg of lactose, 54 mg of microcrystalline cellulose, 13 mg of magnesium oxide and 20 mg of croscarmellose sodium After mixing, the binding solution was added to make granules. After drying the granules, 30 mg of carbomer and 20 mg of hyphromellose were mixed and kneaded to prepare tablets. A film-coated tablet was prepared by coating the nylon with a base containing HPMC.

Example 3

90 mg of isopropanol extract and 12 mg of hydroxypropylcellulose were dissolved in ethanol to prepare a binding solution, and 10 mg of calcium silicate, 48 mg of lactose hydrate, 54 mg of microcrystalline cellulose, 82 mg of meglumine, 20 mg of croscarmellose sodium And the granules were prepared by adding the binding solution. After drying the granules, 30 mg of carbomer and 20 mg of hyphromellose were mixed and kneaded to prepare tablets. A film-coated tablet was prepared by coating the nylon with a base containing HPMC.

Example 4

90 mg of isopropanol extract and 12 mg of hydroxypropylcellulose were dissolved in ethanol to prepare a binding solution, and 10 mg of calcium silicate, 48 mg of lactose, 54 mg of microcrystalline cellulose, 60 mg of sodium carbonate and 20 mg of croscarmellose sodium were mixed After the addition of the binding solution, granules were made. After drying the granules, 30 mg of carbomer and 20 mg of hyphromellose were mixed and kneaded to prepare tablets. A film-coated tablet was prepared by coating the nylon with a base containing HPMC.

Comparative Example 8

90 mg of isopropanol extract of Leaflets and 12 mg of hydroxypropylcellulose were dissolved in ethanol to prepare a binding solution, and 10 mg of calcium silicate, 48 mg of lactose hydrate, 54 mg of microcrystalline cellulose and 20 mg of croscarmellose sodium were mixed, To make granules. After drying the granules, 30 mg of carbomer and 20 mg of hyphromellose were mixed and kneaded to prepare tablets. A film-coated tablet was prepared by coating the nylon with a base containing HPMC.

Experimental Example 3

The dissolution tests of Example 1 and Comparative Examples 8 to 10 were carried out, and the results are shown in Table 3.

division 0 minutes 15 minutes 30 minutes 45 minutes 60 minutes Example 1 0 24.4 47.1 72.0 89.6 Example 2 0 32.4 53.6 79.9 92.2 Example 3 0 26.7 42.8 68.2 86.9 Example 4 0 25.3 48.5 73.3 88.4 Comparative Example 8 0 8.8 20.3 34.2 40.1

As can be seen from the above Table 3, when sodium hydrogencarbonate, magnesium oxide, meglumine, and sodium carbonate were used as pH adjusting agents, it was found that the solubilizing ability was excellent.

Experimental Example 4

The commercially available three-times-a-day formulation containing the extract of Example 1 of the present invention and 60 mg of isopropanol extract as an active ingredient was orally administered to beagle dogs to confirm the gastric behavior.

The beagle dog was orally administered with Example 1, and after confirming that it was swallowed, about 10 mL of water was fed, and the position and shape of the tablet were measured for 5 minutes using a C-Arm (Model: Aroadis Vario, Simens co. 10 minutes, 15 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes, 130 minutes, 140 minutes, 150 minutes, 180 minutes . FIG. 3 and FIG. 4 show photographs taken by Example 1 and oral administration of commercially available preparations to beagle dogs.

FIG. 3 shows that when the intragastric behavior was confirmed after oral administration of Example 1, it was observed that the tablet remained on the surface even after 120 minutes had elapsed. However, in the case of the commercial formulation shown in FIG. 4, Respectively. Thus, it can be seen that Example 1 according to the present invention remained longer than the commercial three-times-a-day formulation.

Experimental Example 5

Animal experiments were conducted to evaluate the effect of Example 1 on stomach damage. Sprague-Dawey rats were treated with ethanol to induce acute gastric injury and then Example 1 was administered. Experimental animals in this study used Crf: CD (SD) as a specific pathogen member (SPF) rat. Experimental animals were refined for 7 days after ingestion, and the weight of the animals determined to be healthy during the refinement period was distributed by a random method so that the average weight was distributed as evenly as possible.

For Example 1 and rebamipide (a gastritis treatment), an appropriate amount was weighed and suspended in 0.5% CMC. 70% ethanol (v / v) was used as the damage inducing substance. All animals were fasted for 48 hours before the administration of Example 1 and rebamipide, and ethanol prepared in advance was orally administered at a dose of 80 mg / kg. Animals were anesthetized with Zoletil 50 (VIRBAC, France) and xylazine (Rompun®, Bayer AG, Germany) at 4 hours after ethanol administration, and then the upper pyloric section was ligated. 30 minutes after ligation, Example 1 and rebamipide were orally administered. At 10 and 120 minutes after administration, the stomach was anesthetized with diethyl ether, and the gastric mucosa was photographed with a digital camera. The area of the damaged area was analyzed using Image software (NIH, Bethesda, MD).

Test group Lesion area (mm ² ) Lesion inhibition rate (%) G1 Trace - G2 61.3 ± 6.4 - G3 41.3 ± 4.6 * 32.6 G4 43.2 ± 4.9 * 29.5 G5 Trace - G6 63.8 ± 6.6 - G7 29.0 + - 4.7 ^& 54.5 G8 28.3 ± 2.9 ^{# $} 55.6

(G1: normal treat with 90 mg / kg Example 1: G2: ethanol treated only G3: ethanol + 100 mg / kg rebamipide G4: ethanol + Example 1 G1-G4: Gastric retention time 10 minutes; G5-G8: Gastric retention time 10 minutes Example 1 G6: ethanol treated only G7: ethanol + 100 mg / kg Rebamipide G8: ethanol + * P <0.05 vs the ethanol treated group (G2). # P <0.05 vs the ethanol treated group (G6 Treated group (G3). $ P <0.05 vs. Treated group (G4).

In the experiment for the treatment of stomach injury with 70% ethanol, Example 1 showed a 26.1% improvement in the therapeutic effect upon staying for 120 minutes than staying for 10 minutes. Rebamipide showed 21.9% And the improvement of the therapeutic effect was confirmed. Therefore, it was found that the treatment effect of the residence time of 120 minutes of Example 1 was further improved than that of rebamipide.

Experimental Example 6

The effect of the indomethacin on the acute gastric injury Sprague-Dawey rat model on the lesion area after administration of Example 1 was evaluated.

Experimental animals in this study used Crf: CD (SD) as a specific pathogen member (SPF) rat. Experimental animals were refined for 7 days after ingestion, and the weight of the animals determined to be healthy during the refinement period was distributed by a random method so that the average weight was distributed as evenly as possible.

For Example 1 and rebamipide, the titrant was weighed and suspended in 0.5% CMC. In the case of indomethacin, which is the causative agent of injury, diluted with sodium bicarbonate (8.4%), weighed in an appropriate amount and placed in a diluted excipient, followed by oral administration. All animals were fasted for 48 hours prior to the administration of the experiment 1 and rebamipide, and then the indomethacin prepared in advance was orally administered at a dose of 80 mg / kg. Animals were anesthetized with zoletil 50 (VIRBAC, France) and xylazine (Rompun®, Bayer AG, Germany) at 4 hours after indomethacin administration and then laparotomy was performed. 30 minutes after ligation, Example 1 and rebamipide were orally administered. The animals were anesthetized with diethyl ether at 10 minutes and 120 minutes after the administration, and then the stomach was removed and the gastric mucosal surface was photographed with a digital camera. The area of the damaged area was analyzed using Image software (NIH, Bethesda, MD).

Test group Lesion area (mm ² ) Lesion inhibition rate (%) G1 Trace - G2 32.7 ± 3.6 - G3 6.5 ± 1.2 * 80.1 G4 6.5 ± 1.5 * 80.1 G5 Trace - G6 31.2 ± 2.9 - G7 6.9 ± 1.1 ^# 77.9 G8 1.8 ± 0.1 ^{# $} 94.2

(G1: normal treat with 90 mg / kg Example 1; G2: indomethacin treated only G3: indomethacin + 100 mg / kg rebamipide G4: indomethacin + Example 1 G1-G4: gastric retention time 10 minutes; G5-G8: indomethacin + 100 mg / kg Example 1 G6: indomethacin treated only G7: indomethacin + 100 mg / kg Rebamipide G8: indomethacin + (P <0.05 compared to indomethacin treated group (G6). P < 0.05 compared to Example 1 < RTI ID = 0.0 > treated group (G4). $ P <0.05 compared to treated group (G7).

In the experiment for the treatment of stomach damage by indomethacin, Example 1 showed a 14.1% improvement in the therapeutic effect when stood for 120 minutes rather than staying for 10 minutes, and the improvement of the therapeutic effect was confirmed by standing for 10 minutes and 120 minutes I could not. Therefore, it can be seen that the therapeutic effect by staying for 120 minutes in Example 1 is further improved than rebamipide.

Experimental Example 7

The efficacy of the tablet of Example 1 was evaluated in patients who were diagnosed with acute and chronic gastritis by administering one tablet twice a day, once per day. The subjects were 230 patients who were diagnosed with acute and chronic gastritis with erosion of 1 or more, and received the preparation manufactured according to Example 1 twice a day twice a day for one time. The gastroscopy was assessed by the same instrument as the same examiner for each possible test subject. Analysis was performed on the efficacy rate of gastroscopy, cure rate on stomach endoscopy, improvement rate of subjective symptoms, edema and redness on stomach endoscopy, and bleeding rate.

The efficacy and cure rate in gastroscopy were evaluated according to the number of erosions according to Table 6, and the improvement rate was calculated and evaluated.

Score Number of erosion 1 point none 2 points 1-2 3 points 3 to 5 4 points More than 6

According to the subjective symptom frequency classification, the improvement rate was calculated for the subjects who had symptoms before the test by the questionnaire survey according to Table 7 below.

Score Symptom 0 point No symptoms 1 point Less than once a week 2 points More than once a week 3 points If you get symptoms every day

Edema and erythema were evaluated according to the endoscopic findings according to the following Tables 8 and 9, and the improvement rate was calculated.

Score opinion 1 point none 2 points The mucosa is somewhat pale, with a white ancestral line, with a hexagonal upper quadrant markedly elevated and slightly elevated

Score opinion 1 point none 2 points There is a clear change in hues 3 points There is a more pronounced and stronger hue change. 4 points Red beige like beef

Score opinion 1 point No bleeding mucosa 2 points One bleeding lesion 3 points 2-5 bleeding lesions 4 points 6-10 bleeding lesions 5 points More than 10 hemorrhagic lesions

The efficacy rate of gastric endoscopy was 45.5%, which was significantly improved from 4.30 to 1.90, as compared with before administration of the drug for clinical use. . In addition, the cure rate, which was observed to be completely erased after administration compared to before administration of the drug for clinical trial, was analyzed and the cure rate improved to 41.1%. Of the subjects who had symptoms before the clinical trial, 71.3% of them had a 50% or more decrease in their subjective symptom scores. Of the subjects with edema at the gastroscopy, 41.9% were cured of edema. 40.1% of the patients who had focal findings on gastroscopy were improved after the administration of the test drug, and 63.0% of the subjects who had bleeding findings improved.

Based on these results, Example 1 is considered to be a drug that can improve the convenience of taking the patient by reducing the number of administrations even though it has statistically significant gastritis treatment efficacy when taking two weeks.

Claims

A pharmaceutical composition comprising an isopropanol extract of a leaf, comprising hydroxypropyl cellulose (HPC), croscarmellose sodium and a pH adjusting agent, wherein the pH adjusting agent is sodium hydrogencarbonate, magnesium oxide, meglumine or sodium carbonate, Characterized in that the dissolution rate of the pha tilin in the pH 1.2 buffer solution containing 0.5% of lauryl sulfate (SLS) is 5 to 45% in 15 minutes and more than 65% in 60 minutes.

delete

(HPC), croscarmellose sodium and a pH adjusting agent, the pH adjusting agent is sodium hydrogencarbonate, magnesium oxide, meglumine or sodium carbonate, and contains 1 mg of isopropanol extract of 1 Unit dosage form for the treatment of gastrointestinal disorders which can be taken twice a day.