WO2014171740A1

WO2014171740A1 - Pharmaceutical composition for treating or alleviating arthritis, containing aceclofenac or pharmaceutically acceptable salt thereof, and extract comprising clematis florida, paeonia lactiflora pall. and prunella vulgaris var. lilacina nakai

Info

Publication number: WO2014171740A1
Application number: PCT/KR2014/003316
Authority: WO
Inventors: 김관영; 이해인; 류근호; 신호철; 김용혁; 손현주; 황상욱; 김훈택
Original assignee: 에스케이케미칼주식회사
Priority date: 2013-04-17
Filing date: 2014-04-16
Publication date: 2014-10-23
Also published as: KR20140124729A; KR101488688B1

Abstract

The present invention relates to a pharmaceutical composition for treating or alleviating arthritis, or protecting joints, and contains two active ingredients comprising: aceclofenac or a pharmaceutically acceptable salt thereof; and a composite medicinal herb extract comprising Clematis florida, Paeonia lactiflora PALL. and Prunella vulgaris var. lilacina Nakai. The present invention can remarkably improve arthritis treatment and alleviation effects by simultaneously administering two active ingredients. Particularly, the two active ingredients can achieve remarkable effects even at a low dose, thereby having the great advantage of decreasing side effects which could occur when administering a large quantity of a single active ingredient.

Description

Aceclofenac or a pharmaceutically acceptable salt thereof

Contains extracts containing gastrointestinal tract, nectarine, and hazelnut

Pharmaceutical composition for the treatment or improvement of arthritis FIELD OF THE INVENTION The present invention relates to the treatment or improvement of arthritis, which contains aceclofenac or a pharmaceutically acceptable salt thereof, and a complex herbal extract comprising gastric acid, natural flower and algae as an active ingredient, and joints The present invention relates to a protective pharmaceutical composition, and more particularly, to a composite pharmaceutical composition which maximizes the therapeutic effect of arthritis and is highly effective in controlling inflammation as compared to a single component composition. Background Articular joints are areas where bones meet. Joints are composed of cartilage, articular capsule, synovial cord, ligaments, tendons, and muscles to smoothly move between bones, and absorb shocks generated by movement. Arthritis is an inflammation of the joint due to various causes, is represented by degenerative arthritis, rheumatoid arthritis, etc. The main symptoms are joint pain, accompanied by swelling or hot flashes. No definitive drug has been developed that can prevent or treat degenerative arthritis itself. However, many drugs with analgesic and anti-inflammatory action for alleviation of major symptoms have been developed and are currently in use. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs in this regard, but they can cause side effects on the digestive system and blood ulcers. need. Recently, the new side to reduce the side effects of the digestive system Although mechanisms of NSAIDs have been developed and used, these drugs have also been discussed for possible cardiovascular side effects. In addition, opioid-based drugs, which are a kind of synthetic analgesic anesthetics, are also used, but should be used with caution as they may cause side effects such as constipation and consciousness in older adults. Therefore, there is an urgent need for the development of new drugs with fewer side effects and excellent anti-inflammatory and analgesic effects.

In particular, degenerative arthritis is a chronic disease, so a drug that can be used for a long time without side effects is needed. The most widely used nonsteroidal anti-inflammatory drugs have adverse effects on the digestive and cardiovascular system, so the amount and duration of use are limited. Therefore, in order to minimize side effects in recent years, a low-dose long-term method has been developed, but pharmacological mechanisms and side effects mechanisms are directly related, so it is known that there is no definite income.

Therefore, the development of a new compound that can increase the efficacy without increasing the side effects when combined with NSAIDs, or the development of a new combination that can use low-dose NSAIDs will be a great help in improving the quality of life of the national medical care and patients. Several drugs can be administered in combination to enhance the therapeutic effect, but administration of multiple drugs does not necessarily increase drug efficacy and improve side effects at the same time.

In this regard, the "Circulation Guidelines for Circulatory Drug Complexes" (2006) of the Ministry of Food and Drug Safety, in determining the effectiveness of a combination of two or more drugs, sets the criteria for the validation of new combinations for different mechanisms. Suggesting that, as a criterion for determining the effectiveness of a combination (or co-administration), it should be demonstrated that the therapeutic effect is superior to the administration of a combination compared to the administration of a single agent. Since it is difficult to arithmetically evaluate the effectiveness of the combination, such a criterion may be an important criterion in evaluating the effectiveness of the combination. On the other hand, aceclofenac is 2-[(2,6-dichlorophenyl) amino] phenylacetoxy acetic acid (2- [(2, 6-di ch 1 or opheny 1) am i no] pheny 1 acet oxyace tic acid, NSAIDs with the chemical structure of 'ACF' have excellent effects on rheumatoid arthritis and osteoarthritis. It plays a role in reducing prostaglandin E2 in synovial fluid of patients with acute joint pain, and is known to inhibit the production of prostaglandin E2 by polymorphonuclear leukocytes and monocytes in patients with severe osteoarthritis. Aceclofenac is a relatively low gastrointestinal disorder among existing NSAIDs, but it is known that gastrointestinal side effects such as ulcers appear in patients with long-term use or increasing doses, especially in elderly patients.

Complex herbal extracts of gastric nectar, nectarine and hyacinth (hereinafter referred to as 'JIN') are known to have anti-inflammatory, analgesic, joint protection and immunosuppressive effects, and are widely used for the treatment of osteoarthritis and rheumatoid arthritis. In particular, the clinical dose is limited because existing NSAIDs cause gastrointestinal disorders by the inhibitory effect of cyclooxygenases 1 and 2, which are mechanisms of action. In order to prevent or treat gastrointestinal disorders, NSAIDs need to be combined with gastritis / gastric ulcer medications, whereas joins, which are complex herbal extracts of gastric and gastric ulcers and algae, do not cause gastrointestinal disorders. Has the action of protecting. Therefore, the present inventors have attempted to develop a new anti-inflammatory complex with improved side effects while increasing the anti-inflammatory effect through the combination of aceclofenac and joins, a representative drug of NSAIDs. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide pharmaceutical compositions which exhibit excellent effects on the treatment or amelioration of arthritis, and on joint protection while being less toxic and having reduced side effects such as gastrointestinal disorders. The present invention to achieve the above object is aceclofenac or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for the treatment or amelioration of arthritis, including as an active ingredient complex herbal extracts including yeongseon sun cheonhwa powder and hachicho.

In addition, the present invention is aceclofenac or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for protecting joints, comprising as an active ingredient complex herbal extracts including gastric glands, cheonhwabun and hachigo.

The present invention provides a pharmaceutical formulation comprising aceclofenac or a pharmaceutically acceptable salt thereof; And it provides a kit for the treatment or amelioration of arthritis, or a joint protection, comprising a pharmaceutical preparation comprising a complex herbal extract comprising gastric glands, cheonhwa minutes and hyacinth. The present invention comprises aceclofenac or a pharmaceutically acceptable salt thereof, and a composite herbal extract comprising a medicinal herb, nectarine, and hazelnut, for the treatment and improvement of arthritis, or a pharmaceutical composition for protecting joints To provide. The present invention can significantly increase the effects of treating and improving arthritis, including analgesic and anti-inflammatory, by simultaneously administering two active ingredients, and in particular, high effects can be achieved even when the two active ingredients are used in combination at low doses. There is a great advantage that can reduce the various side effects that can occur when a large amount of the component, for example, gastrointestinal disorders caused by aceclofenac. BRIEF DESCRIPTION OF THE DRAWINGS The above and other objects and features of the present invention will become apparent from the following description of the invention in conjunction with the accompanying drawings: 1 is a graph showing aceclofenac (ACF) alone, gastric ginseng, hwahwabun and complex herbal extract (JIN) alone, and TNF-α inhibitory activity according to the combination treatment thereof.

Figure 2 is a graph comparing the maximum inflammation inhibition rate according to ACF alone, JIN alone, and their combination treatment.

Figure 3 shows the inhibitory effect of the negative control, ACF alone, JIN alone, and their combination treatment for croton oil-induced acute inflammation (relative to the negative control, *: P <0.05, **: P < 0.01, ***: P <0.001 (t-test); compared to ACF (0.4 mg / kg) group, #: P <0.05, ##: P <0.01, 漏: P <0.001 (t-test); JIN +: P <0.05, ++: P <0.01, +++: P <0.001 (t-test)) compared to the (20, 40 and 80 mg / kg) administration group.

Figure 4 is a graph showing a comparison of the inhibition rate of inflammation according to the combination treatment of J IN and various NSAIDs.

Figure 5 shows the results of the anti-inflammatory effect duration test according to ACF alone, JIN alone, and their combination treatment.

6 shows autopsy results of individuals who died by ACF alone treatment.

7 is a score of the degree of gastric ulcer induced by the negative control group, ACF alone and ACF and JIN combination treatment.

FIG. 8 shows H & E staining pictures of ulcerated gastrointestinal tissues induced by negative control (A), ACF alone (B) and ACF and JIN combination treatment (C). DETAILED DESCRIPTION OF THE INVENTION The present invention provides aceclofenac or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for the treatment or amelioration of arthritis, comprising as an active ingredient a complex herbal extract comprising gastric glands, cheonhwabun and hachigo. The invention provides aceclofenac or a pharmaceutically acceptable salt thereof for the treatment and amelioration of arthritis, or for the protection of joints; And a combination of herbal extracts including gastrointestinal tract, nectarine and hyacinth, which is based on the surprising fact that it can dramatically increase the therapeutic effect of arthritis, including analgesic and anti-inflammatory, and the protective effect of the joint. One of the two active ingredients included in the pharmaceutical composition of the present invention is aceclofenac or a pharmaceutically acceptable salt thereof.

As used herein, the term “pharmaceutically acceptable salts” refers to salts that are prepared with less toxic or less acid or base. When the compounds of the present invention are relatively acidic, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base and a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, salts consisting of sodium, potassium, calcium, ammonium, magnesium or organic amino. Preferably amino acid salts can be used.

Aceclofenac or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention as an active ingredient may be present in an unsolvated form as well as a solvated form including a form of a hydrate, an ethanolate, or the like. have. Aceclofenac or a pharmaceutically acceptable salt thereof of the present invention may exist in crystalline or amorphous form, and all such physical forms are included in the scope of the present invention.

Complex herbal extracts including the gastric, ginseng and hyacinth contained as another active ingredient in the pharmaceutical composition of the present invention can be prepared using an extraction method well known to those skilled in the art to which the present invention pertains. have. For example, each of the medicines of the gastrointestinal tract, hwahwahwa or hyacinth, or a combination thereof, was extracted under reflux for 4 to 6 hours using a mixture solution of water or alcohol of 5 to 10 times the weight of the herbal medicine or as an extraction solvent and filtered. In each residue again 5-10 times the weight of the herbal weight of water or water and alcohol The mixture is added, warmed, re-extracted once or twice, filtered and then combined with the previous filtrate and concentrated. Purification of impurities such as unnecessary proteins, polysaccharides and fatty acids contained in the filtrate with saturated lower alcohols such as butyl alcohol or propyl alcohol, the alcohol solvent fraction obtained is concentrated under reduced pressure to 60 to 70 ^° C. Remove it. The complex herbal extract obtained after concentration is azeotropically concentrated two to three times with water of 25 to 50 times the total amount of the extract, and is then homogeneously suspended by adding the same amount of water and dried to obtain a powdery extract.

However, in order to minimize the side effects of the composite herbal extracts, it is preferable to use the composite herbal extracts of the gastric ginseng, cheonhwabun and hachicho prepared according to the preparation method of the extract disclosed in the Republic of Korea Patent Publication No. 10-2011-0006642. The weight ratio of the aceclofenac or pharmaceutically acceptable salts thereof, and the complex herbal extracts including the gastric glands, cheonhwabun and hachicho in the pharmaceutical composition of the present invention is 1: 0.01 to 1: 200, preferably 1: 0.01 to 1 : 100, more preferably 1: 0.1 to 1: 10, most preferably 1: 1 to 1: 5. The pharmaceutical composition of the present invention may be a solid preparation or a liquid preparation. Solid preparations include, but are not limited to, powders, granules, tablets, voxels, suppositories, and the like. Preferably, it may be a single dose formulation of tablets, granules or voxels.

The solid preparation may include, but is not limited to, a pharmaceutically acceptable additive consisting of excipients, flavoring agents, binders, preservatives, disintegrants, fluidizing agents, lubricants, stabilizers, fillers and coating agents.

For example, powders may be prepared by simply mixing the active ingredients of the present invention with suitable pharmaceutically acceptable excipients such as lactose, starch and microcrystalline cellulose. Granules are the active ingredients of the present invention; Pharmaceutically acceptable excipients; Starch sodium glycolate, Pharmaceutically acceptable disintegrants such as croscarmellose sodium, certain complex silicates, crospovidone and low-substituted hydroxypropylcelose; And a pharmaceutically acceptable binder such as polyvinylpyridone and hydroxypropyl cellulose, followed by a wet granulation method using a solvent such as water, ethane, isopropane, or a dry granulation method using a compressive force. It can be prepared using. Tablets may also be prepared by mixing the granules with a suitable pharmaceutically acceptable lubricant such as magnesium stearate and then tableting using a tableting machine.

The liquid preparation may include water, a solution such as a propylene glycol solution, a suspension, an emulsion, and the like, but is not limited thereto, and may be prepared by adding a suitable pharmaceutically acceptable colorant, flavoring agent, stabilizer, viscosity agent, or the like. Can be. The daily dose of the pharmaceutical composition for the treatment of arthritis as a complex herbal extract comprising aceclofenac, and gastrointestinal tract, cheonhwabun and hyacinth according to the present invention can be variously adjusted according to the age, symptoms, dosage form or drug type of the patient. , Preferably from 1 to 500 mg, more preferably from 20 to 200 rag as aceclofenac, preferably from 2 to 2,000 rag and more preferably from 60 to 2,000 rag . In addition, the present invention is aceclofenac or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for protecting joints, comprising as an active ingredient complex herbal extracts including gastric glands, cheonhwabun and haejucho.

In the present invention, "joint protection" refers to treating or preventing cartilage degeneration of the joint, cartilage damage, inflammation or pain, muscle or joint tissue, maintaining cartilage regeneration or cartilage, or maintaining joint health.

Diseases requiring such joint protection by causing pain and inflammation in the joints include, for example, rheumatoid arthritis, spondyloarthropathies, gout arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute joint pain, degenerative joint disease, Periarthritis, rheumatoid polymyalgia, anti-acute arthritis, arthrosis, traumatic arthritis, scleroderma, polymyositis, skin myositis, atrophic polyarthritis, Sjogren's syndrome, Still's syndrome, Pelti's syndrome, multiple sclerosis, acute encephalomyelitis, synoviitis, chuck Subjective stenosis, tendonitis, fibromyalgia, chronic foot and ankle pain, heel syndrome, neuralgia, foot pain, toe toe occlusion, ankylosing spondylitis, and combinations thereof. Preferably it may be a disease selected from the group consisting of osteoarthritis, degenerative joint disease, acute arthralgia, rheumatoid arthritis and combinations thereof. Therefore, in the present invention, the pharmaceutical composition for protecting joints may be recognized as a pharmaceutical composition for preventing, treating or improving a disease requiring joint protection as mentioned above. The invention also provides a pharmaceutical formulation comprising (i) aceclofenac or a pharmaceutically acceptable salt thereof; And (Π) a kit for the treatment or amelioration of arthritis, or a kit-type product for the protection of arthritis, comprising two preparations of a pharmaceutical preparation comprising a complex herbal extract comprising gastric glands, nectarine, and hyacinth. Such a kit-type product includes instructions for taking the (i) formulation and the (Π) formulation at the same time or taking another formulation within a certain time after administration of the other formulation.

The present invention also relates to a complex of herbal extracts comprising aceclofenac or its pharmaceutically acceptable salts and gastrointestinal tracts, honeysuckle, and hazelnuts in human patients or animals other than humans that need to treat or improve arthritis or require a joint protective effect. Provided are methods of treating or ameliorating arthritis or a condition requiring joint protection, comprising administering a combination pharmaceutical agent in a therapeutically or prophylactically effective amount.

EXAMPLE

Hereinafter, examples and the like will be described in detail in order to help the understanding of the present invention. However, the embodiments according to the present invention are various other It may be modified in the form, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art. The composite herbal extract containing the gastric gland, cheonhwabun and hyacinth used in the following Experimental Examples and Examples was prepared according to the composite herbal extract preparation method described in the example of Korean Patent No. 10-0483707. Experimental Example 1 Measurement of Cytokines Associated with Immune Suppression in Human Peripheral Blood Mononuclear Cells

TNF-α is a signaling substance produced by the immune system to increase the risk of salt infection, but induces the death of cancer cells, but causes excessive inflammation, which negatively affects inflammatory diseases such as arthritis, psoriasis and lupus. In addition, it is known that TNF-a and its receptors are over-formed in cartilage and synovial fluid of osteoarthritis patients, promote cartilage damage, and the major components of cartilage inhibit proteoglycan production. In addition, the administration of TNF-a antibody to osteoarthritis patients is known to prolong the pain suppression effect, TNF-a is a major cytokine involved in inflammation, cartilage damage and pain in osteoarthritis patients. NSAIDs increase TNF-a production (Theresa H. Page et al., Journal of Immunology, 2010; 185: 3694-3701), or inhibit the production (Syggelos et al., Osteoarthritis and Cartilage. 2007 15: 531-542) Although the effect is inconsistent, complex herbal extracts containing gastric gland, nectarine and hyacinth are known to significantly inhibit the production of TNF-α in amounts of 250 pg / ml ( A Hartog et al. 'Phytomedicine, 2008; 15: 313-320). In this experiment, aceclofenac alone gastric gland, hwahwahwa and Inhibitory activity of TNF-α, which is a major arthritis inducing agent, was confirmed as follows.

Human peripheral blood mononuclear cells (hPBMCs) were isolated from healthy human blood and dispensed at 25 x 104 cells / well in 48-well plates. Herbal extract (hereinafter 'JIN') 3 / g / ml, aceclofenac (hereinafter 'ACF') 1 ^ g / ml or the same concentration of ACF and J IN in combination (hereinafter 'ACF + JIN'). After one hour lipopolysaccharide (LPS) was added 0.5 // g / ml based on the final concentration, and incubated at 37 ^° C for 24 hours. Subsequently, the supernatant was collected by centrifugation to separate the medium. T Fa was quantified using TNF-α EL ISA kit, and TNF-a inhibition rate (¾) in ACF alone, JIN alone, and their combination compared to control (untreated group) was calculated and the results are shown. 1 is shown.

As shown in Figure 1, the TNF-a inhibition rate of the ACF + JIN combination treatment group increased more than three times to a statistically significant level compared to each alone treatment group. These results indicate that when aceclofenac and the combined herbal extracts are administered in combination in inflammatory diseases such as arthritis, synergistically inhibits TNF-a as compared to the case where they are administered alone.

On the other hand, osteoarthritis is known to over-produce TNF-a and promote cartilage destruction (FC Breedvel, Rheumatology, 2004; 43 (Sup l. 1): i4- i8), and NSAIDs inhibit TNF-a. It is known that the anti-inflammatory effect is shown by the mechanism of inhibiting prostaglandin E2 in the body fluid rather than the mechanism. In this experiment, there was almost no TNF-a inhibitory effect in the ACF alone and JIN alone groups, while the inhibitory effect was statistically significant in the combination treatment group. This is the existing effect on the osteoarthritis of the NSAIDs, and the complex herbal extracts including the gastrointestinal tract, nectarine and hyacinth is shown by the inhibitory mechanism of PGE2, and when combined, the inhibitory effect of TNF-a can be simultaneously shown. Medicinal effect Suggests that you can.

Experimental Example 2 Measurement of Maximum Inhibitory Effect on Acute Inflammation In the present experiment, the following experiment was performed to confirm the maximum effect on anti-inflammatory activity compared to the single administration when ACF and JIN were administered in combination.

ICR (Institute of Cancer Research) mice were treated orally with ACF (0.2-6.4 mg / kg) alone, JIN (40-1000 mg / kg) alone, or a combination of both, and 2.5% croton oil (1 hour later). 0.025 croton oil was evenly applied to the right ear to induce inflammation. 0.5% methyl cellulose (methyl cellulose, MC) was used as a negative control.

After 4 hours, left and right ear edema were measured to calculate the incidence rate (%) and inhibition rate (%) compared to the negative control. In this case, the ACF alone and JIN alone administration group, starting from a low dose and administered to a significantly higher dose of toxic levels were evaluated for inhibition of inflammation, and the results are shown in FIG. 2.

As shown in Figure 2 JIN 40 to 1000 mg / kg, ACF 0.2 to

When administered alone to high doses of 6.4 mg / kg of toxicity, the inhibition rate of each drug was limited to a maximum of 40%. On the other hand, the combination of each active ingredient at a low dose (ACF 0.4 mg / kg + JIN 80 mg / kg), significantly higher than the inhibition rate (40%) when administered alone.

These results indicate that in order to achieve the maximum effect when each drug is administered alone, ultra high doses of toxic levels must be administered, whereas even lower doses in combination doses may have more than the maximum effect of the drug alone. It also suggests that fewer doses of each drug are likely to have much fewer side effects. Experimental Example 3 Measurement of Inhibitory Effect on Acute Inflammation

The combination of ACF and JIN was evaluated as follows to show whether the anti-inflammatory effect was superior to that of the administration alone.

After the negative control, ACF alone J IN alone or in combination thereof in the same manner as described in Experimental Example 2, acute inflammation was induced in mice using croton oil. The degree of inhibition of ear edema induced by croton oil was compared with that of the negative control, and each administration group and the incidence rate 00 are shown in FIG. 3.

As shown in Figure 3, about 81.6%, ACF ^stage, dock, or JIN exhibits a low of about 48 to 66¾> Discharge rate than the case of 60 to 75% for the single administration group, a combination administration group of JIN and ACF For the negative control It was found that co-administration of the active ingredients is useful for suppressing acute inflammation.

Experimental Example 4 Determination of Inflammatory Inhibitory Effects of NSAIDs in Acute Inflammation Models The anti-inflammatory effects of acute inflammatory models were examined for representative drugs of NSAIDs, which are widely used as a therapeutic agent for arthritis. The effects were compared.

Commercially available diclofenac (DCF), ibuprofen (IBF), and naproxen (NPX) were selected as representative NSAIDs, and celecoxif (CCX) was selected as a comparative drug as a C0X-2 selective inhibitor. It was.

Inflammation was induced in mice in the same manner as described in Experimental Example 3, and the inhibition rate of inflammation (%) compared to the negative control was evaluated. For the dose of each drug, anti-inflammation when NSAIDs 0.4 mg / kg and JIN 80 mg / kg were administered in combination with reference to the dose combination performed in Experimental Example 2 above The effects were compared. The results are shown in FIG.

As shown in Figure 4, aceclofenac, celecoxif and naproxen showed a high anti-inflammatory effect when administered in combination compared to the case of administering each alone. However, in the case of drugs other than aceclofenac, the effects of JIN and co-administration did not show a significant increase than the effects of single administration. In the case of aceclofenac only showed a statistically significant increase in the combined administration, it can be seen that there is no additional concomitant effect exceeding the maximum inhibition rate in the acute inflammation model for other drugs.

In addition, the clinical doses of aceclofenac, celecoxif and naproxen in osteoarthritis ileus were 100 to 200 mg / day, 200 mg / day and 250 to 1000 mg / day, respectively. Given the dosage (200-600 mg / day), it is preferable in view of the ease of administration of the patient to select a drug with a smaller dosage when choosing a combination of the two drugs. Therefore, on the basis of the results of the present experiment it can be seen that the combination of ACF and JIN can not only show an excellent anti-inflammatory effect but also improve the ease of taking the patient.

Experimental Example 5 Measurement of Duration of Anti-inflammatory Effect in Acute Inflammation Model

In this experiment, we confirmed the prolonged effect of anti-inflammatory effect when ACF and JIN were administered in acute inflammation model.

ACF (0.2 mg / kg or 0.4 mg / kg) alone, J IN (40 mg / kg or 80 mg / kg) alone, or both (ACF 0.4 mg / kg + JIN 80 mg / kg) in ICR mice ACF 0.2 mg / kg + JIN 40 mg / kg) was orally administered at one time and inflamed inflammation was evenly applied to the right ear with 0.025 μη £ of 2.5% croton oil each hour for 3 hours. Left and right ear edema was measured after 4 hours. Inhibition rate of inflammation induced by croton oil was negative in each dose group (0.5¾> It is shown in FIG. 5 as a percentage compared to MC).

As shown in FIG. 5, in contrast to the inhibition rate of inflammation for 1 hour when ACF and J IN were administered alone, the combination inhibition group was confirmed to maintain the same or higher inhibition rate for up to 3 hours.

Experimental Example 6 Subchronic Toxicity Test In rat repeated dose toxicity test model, the difference between the toxicity and side effects expression was observed when ACF alone and J IN were administered.

The 6-week-old male and female rats of the SD strain were divided into 10 rats (5 male and female males) per group, and classified into ACF alone group and ACF and JIN combination group (ACF: JIN = 1: 3 (w / w)). Was dissolved in a 0.5% MC solution (prepared), followed by oral administration once daily at the same morning time for 13 weeks. At this time, the ACF alone group was administered in an amount of 3.75 mg / kg to 5 mg / kg, and the ACF and J IN combination group were administered in an amount of 15 mg / kg to 20 mg / kg. Thereafter, death was observed for general symptoms, weight change, feed and water intake, urinalysis, hematology and blood biochemistry, autopsy findings, organ weight and histopathological findings.

As a result, one of the females treated with ACF alone died during the test period, and no mortality occurred in the ACF and JIN co-administered groups. Histopathologically, submucosal inflamed atory cell foci was observed in the cecum of females treated with ACF5 mg / kg alone. In addition, when an autopsy was performed on a deceased subject, peritonitis and long-term stenosis were observed as shown in FIG. 6, and gastric ulcer lesions were identified at the gastric portion during gastrectomy. There were no significant changes in clinical symptoms, feed intake, hematology, and organ weight.

The important fact that can be seen from the above results, despite the combination of three times the JF of the same dose of ACF, toxic symptoms compared to the ACF alone administration group Confirmed to be relatively low

Experimental Example 7 Evaluation of Improvement of Gastrointestinal Side Effects Side Effects In general, NSAIDs such as ACF are known to cause gastrointestinal disorders by the inhibitory effect of cyclooxygenases 1 and 2 on the mechanism of action. JIN, on the other hand, did not cause gastric mucosal damage even at high doses (2 g / kg) in animal studies of gastrointestinal damage. As described in Experiment 6, gastrointestinal toxicity was confirmed by ACF administration, but when the ACF and JIN were administered in combination, gastrointestinal toxicity was lowered. Thus, animal experiments were performed as follows to determine whether side effects such as gastrointestinal disorders expressed by ACF were improved by JIN administration.

Male rats (Sprague Dawley) commonly used in gastric ulcer induction test were used, and the dose of ACF was set to 40 mg / kg so that gastric ulcer could be induced by a single administration.

In the test method, overnight fasting was performed from the evening before the test to the morning of the test, so that food in the digestive system including the stomach of the test animal was removed. On the day of the test, rats were administered 10% Labrasol (negative control), ACF alone, or a combination of ACF and JIN (ACF 40 mg / kg + JIN 300 mg / kg). In this case, the combination administration group was administered by oral administration of ACF (po), followed by intraperitoneal administration (ip) of JIN. After 8 hours of administration, rats were euthanized with C0 ₂ , and the stomach was removed and visually observed. Gastroenterological lesions were also scored according to Table 1 below with reference to L. Laine et al., Gastroenterology, 1988; 94: 1254-1262. The results are shown in FIG. TABLE 1

As shown in FIG. 7, gastric ulceration was rarely induced when the negative control group was administered, but significant gastric ulceration was induced at about 3.9 points when ACF alone was administered. In addition, the administration of JIN lowered the gastric ulcer induction score to about 1.5, indicating that the degree of gastric ulcer induction was significantly decreased. In addition, the stomach of the rat extracted through the above procedure was fixed with neutral buffered formal in, and cut to a certain size for histological examination and stained with hemaroxylin & eosin (hematoxylin & eosin, H & E) for tissue slides. Prepared. The glandular stomach, except for the forestomach, of the rats in the tissue slides was read according to the Covance Glossary of Toxic Pathology Glossary and the results are shown in FIG. 8. At this time, the focal (superficial discontinuity) of the surface, which is a slight change in the erosion / ulcer reading process, was excluded from the threshold in the reading process.

As a result of reading the tissue slide of the stained rat apical region shown in FIG. 8, a normal rat apical structure was observed in the negative administration group (A) and no specific finding was observed, but in the ACF 40 mg / kg administration group (B) Ulceration, necrosis and inflammatory cell infiltration foci) was well observed (refer to the arrow on the right diagram of FIG. 8), and mucosal epithelial cells were eroded around the lesion, and only a single dose of 40 mg / kg ACF was applied. It was confirmed that gastric ulcer induction occurred well.

On the other hand, after a single administration of ACF 40 mg / kg, in the combined administration group (C) administered JIN 300 mg / kg, the degree of ulceration area was reduced compared to the ACF alone administration group (Fig. 8 ( C) See the circle on the left dotted line). Example 1 Preparation of Complex Solid Formulation 1 Using the ingredients and contents shown in Table 2, a complex herbal formulation including a gastric herbaceous ginseng, hwahwabun and hyacinth extract, and aceclofenac were prepared.

TABLE 2

First, the compound herbal extract containing the gastric glands, cheonhwabun and hyacinth, hard silicic anhydride, microcrystalline cellulose, low-substituted hydroxypropylcellose and sodium starch glycolate were passed through a No. 30 sieve, followed by a high speed stirrer (YC -SEP-SMG-3J, Yenchen) and mixed for 3 minutes. Thereafter, an appropriate amount of anhydrous ethanol was added thereto, followed by granulation for 3 minutes. The high speed stirrer was opened, the base wall was scraped, and then further combined for 2 minutes, dried in a 55 ^° C. dryer, and sieved to a No. 18 sieve to prepare a composite herbal extract formulation including a gastric nectar, a hwahwahwa and a vinegar. The formulation was mixed in a mixer and mixed for 10 minutes, and then magnesium stearate was added as a lubricant, followed by mixing for 5 minutes, thereby preparing a composite herbal extract granule part (hereinafter, JIN granule part) including a gastric gland, cheonhwa flour and algae.

Separately, aceclofenac and lactose hydrate were passed through a No. ₃₀ sieve, placed in a high speed stirrer, and mixed for 3 minutes. Then, anhydrous ethane was added to the binding solution in which povidone was dissolved, followed by assembling for 3 minutes. The high speed stirrer was opened, the base wall was scraped, and then further combined for 2 minutes, and then dried in a 551: dryer and sieved to No. 18 to prepare aceclofenac. The sieved material was added to a mixer, and then mixed with microcrystalline cellulose and croscarmellose sodium for 10 minutes, and then added with magnesium stearate as a lubricant, followed by mixing for 5 minutes, to prepare aceclofenac granules (hereinafter, ACF granules).

Each granule prepared above is a rotary tableting machine (PR-3543, PTK

Korea) was used to prepare the two-layer tablet by sequentially tableting. Subsequently, Opadry Yellow was dissolved in 80% ethanol as a coating agent to prepare a film coating solution, and then the tablets were coated using a coating machine (SFC-30N, Sejong Machinery) to obtain a film coating tablet.

Example 2: Preparation of Composite Solid Formulation 2

By using the ingredients and contents shown in Table 3 above, A composite herbal extract comprising haejucho, and a complex solid preparation comprising aceclofenac were prepared.

TABLE 3

Pass the complex herbal extract, hardened silicic acid, microcrystalline cellulose, and corn starch, including the gastric nectar, nectar, and vinegar, through a No. 30 sieve, and place it in a high speed stirrer (YC-SEP-SMG-3J, Yenchen) for 3 minutes. Mixed. Thereafter, an appropriate amount of anhydrous ethane was added to a binder solution in which povidone was dissolved, and then assembled by combining for 3 minutes. The high speed stirrer was opened, the base wall was scraped, and then further combined for 2 minutes, dried in a 55 ^° C. dryer, and sieved to a No. 18 sieve to prepare a composite herbal extract formulation including a gastric nectar, a hwahwahwa and a vinegar. The sieved material and croscarmellose sodium were added to a mixer, mixed for 10 minutes, magnesium stearate as a lubricant, and mixed for 5 minutes to prepare JIN granules.

Separately, aceclofenac and lactose monohydrate were passed through No. 30 sieve. Fully mixed. The whole mixture, microcrystalline cellulose and sodium croscarmellose sodium prepared above were added to a mixer and mixed for 10 minutes, and then magnesium stearate was added as a lubricant and mixed for 5 minutes to prepare ACF granules.

Subsequently, ACF granules were placed in a mixer containing JIN granules and mixed for 5 minutes. The mixture was then prepared in the form of a single tablet using a rotary tablet press (PR-3543, PTK Korea). After dissolving Opadry Yellow as a coating base in 80% ethanol solution to prepare a film coating solution, the tablet was coated using a coating machine (SFC-30N, Sejong Machinery) to obtain a film coating tablet. Although the present invention has been described in connection with the specific embodiments described above, those skilled in the art can variously modify and change the present invention within the scope of the present invention as defined by the appended claims.

Claims

Scope of claim

1. (a) aceclofenac or a pharmaceutically acceptable salt thereof; And

(B) a pharmaceutical composition for treating or ameliorating arthritis, comprising as an active ingredient a complex herbal extract comprising gastric glands, cheonhwabun and hachigo.

2. The method of paragraph 1,

The composition is formulated as a single dose formulation of tablets, granules or capsules, the pharmaceutical composition for the treatment or amelioration of arthritis.

3. Clause 1,

The composition comprises aceclofenac or a pharmaceutically acceptable salt thereof and a complex herbal extract comprising gastric glands, cheonhwabun and haegocho in a weight ratio of 1: 0.01 to 1: 200, the pharmaceutical composition for treating or improving arthritis.

4. (a) aceclofenac or a pharmaceutically acceptable salt thereof; And

(b) comprising a complex herbal extract containing gastric gland, cheonhwahwa and hachigori as an active ingredient, a pharmaceutical composition for protecting joints.

5. The method of clause 4,

The composition may include rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus, pediatric arthritis, acute arthralgia, degenerative joint disease, shoulder periarthritis, rheumatoid arthritis, rheumatoid arthritis, arthrosis, traumatic arthritis, scleroderma , Multiple myositis, Dermatitis, Atrophic polyarthritis, Sjogren's syndrome, Still's syndrome, Pelti's syndrome, Multiple sclerosis, Acute Diseases requiring joint protection selected from the group consisting of encephalomyelitis, cystitis, spinal stenosis, tendonitis, fibromyalgia, chronic foot and ankle pain, heel protrusion syndrome, neuralgia, foot pain, toe toe occlusion, ankylosing spondylitis, and combinations thereof Preventing, treating or ameliorating, pharmaceutical composition for joint protection.

6. The method of clause 4,

The composition comprises aceclofenac or a pharmaceutically acceptable salt thereof, and complex herbal extracts including gastric glands, cheonhwabun and haegocho in a weight ratio of 1: 0.01 to 1: 200, a pharmaceutical composition for protecting joints.

7. (i) a pharmaceutical formulation comprising aceclofenac or a pharmaceutically acceptable salt thereof, and

(ii) a kit for the treatment or amelioration of arthritis, comprising a pharmaceutical preparation comprising a complex herbal extract comprising gastric gland, nectarine and hyacinth.

8. (i) a pharmaceutical formulation comprising aceclofenac or a pharmaceutically acceptable salt of ah, and

(ii) A kit for protecting joints, comprising a pharmaceutical formulation comprising a complex herbal extract comprising a gastric gland, a ragweed and a hyacinth.