KR20090103000A - Pharmaceutical composition for the treatment of arthritis - Google Patents

Abstract

PURPOSE: A pharmaceutical composition for treating arthritis is provided to improved effects of suppressing analgesics and reducing side effects. CONSTITUTION: A therapeutic composition for arthritis comprises 5-20 weight% of first component and second component. The first component is selected from at least one components comprising Juniper berry extract, pycnogenol, Rubus coreanus Miquel extract, outer surface and seeds extract of grape, resveratrol, omega-3-fatty acid, DHA and EPA. The second component is selected from a group of celecoxib, aceteaminopene and folic acid.

Description

Pharmaceutical composition for the treatment of arthritis

The present invention relates to a composition for treating arthritis by combining one component of celecoxib, acetaminophen, or folic acid, which are widely used for the treatment of arthritis, and a natural composition having various functions. An object of the present invention is to provide a non-steroidal anti-inflammatory drugs, arthritis therapeutic composition with a disintegration rate, dissolution rate and analgesic inhibitory effect by complex administration of a natural composition having the functions of anti-inflammatory, antioxidant, anti-aging, blood circulation, etc. It is.

In general, arthritis is a disease name collectively referred to as an inflammatory change caused by any cause, and is caused by infection with synovial membrane or direct trauma. Arthritis symptoms include degenerative arthritis, rheumatoid arthritis, gout, neuroarthritis, and tumors, but the most common of these are degenerative arthritis mainly in the 40s and 50s. Degenerative arthritis is an arthritis caused by degenerative changes (such as whitening of the head and wrinkles on the face) of the cartilage and the surrounding bones among the various components of the joint. Severe pain in the shoulder joints, such as joints and hip joints, is difficult to move, and may cause deformation of the joints if left unattended. Rheumatoid arthritis refers to chronic inflammation of the synovial membrane of the joints in the human body, and chronic means that the inflammation of the synovial membrane lasts more than 6 weeks.

Drugs used for arthritis include aspirin, acetaminophen, steroids, nonsteroidal analgesic agents, and cox inhibitors. In general, nonsteroidal anti-inflammatory drugs used as therapeutic agents for arthritis have been widely used in the treatment of rheumatoid arthritis and related diseases by inhibiting the biosynthesis of prostaglandins, thereby exhibiting strong anti-inflammatory and analgesic effects. Nonsteroidal anti-inflammatory drugs include propionic acid-derived drugs such as ibuprofen, naproxen, flubiprofen, phenopropene, ketoprofen or phenylacetic acid celecoxib, diclofenac, amphenac, and oxycampus meloxycampin. .

Acetaminophen is a type of nonsteroidal analgesic anti-inflammatory drug with short half-life, which is not a big problem for the analgesic anti-inflammatory effect during short-term administration, but it requires a frequent administration for the treatment of analgesic and anti-inflammatory treatment of chronic diseases. . Acetaminophen is also an antipyretic analgesic used for pains such as headaches, toothaches, white crystals or crystalline powder, odorless and bitter. Soluble in ethanol or methanol, slightly soluble in water, soluble in sodium hydroxide solution, very difficult to dissolve in ether.

Celecoxib is hydrophobic as a COX-2 inhibitory drug and has low solubility in water. Celecoxib is exceptionally insoluble in aqueous media and, when administered orally in capsule form, is not readily dissolved and dispersed for rapid absorption in the gastrointestinal tract.

Folic acid is a type of vitamin that contributes to the formation of red blood cells, especially in patients with rheumatoid arthritis. Folic acid is found in meat, liver, green and yellow vegetables, beans and cereals.

Bokbunja extract (Blackberry) has been used for the treatment of diabetes, sexual decline. It is known to contain triterpenoid glycosides such as coreanoside F1, suaavissmoside, niga-ichigoside Fa and F2, and other components such as nannin, diterpene and catechin are known from plants of the genus Rubus. Niga-ichigoside F1, a component of Bokbunja, has been reported to be effective in formalin-induced pain model.

Pycnogenol, on the other hand, is derived from the Pinus maritima shell, which grows in the Bordeaux region in southwestern France. Dr. Marc Maseriee, an honorary professor at the University of Bordeaux, succeeded in discovering and extracting several functional ingredients, including OPC (Oligomeric Proantho cyanidin), a polyphenol, in the sea shell of France. OPC, the main component of Pycnogenol, is an antioxidant that pines protect themselves from environmental pollutants and climatic conditions. Pycnogenol is recognized as a material with excellent antioxidant activity (US patent, US Pat. No. 4,698,360) and vascular protection (US patent, US Pat. No. 5,720,956). Currently, health foods are used in many countries including the United States. It was approved as an anti-vascular drug in '68 and sold under the trade name 'Flavan'.

All grapes contain antioxidants. In particular, grape seed extract contains high amounts of proanthocyanidins, a type of bioflavonoid, which improves the functioning of connective tissue and eliminates the generator oxygen that causes cardiovascular disease, arthritis and cancer. To prevent tissue damage. In addition, proanthocyanidins in grape seeds and skin have antiviral, antibacterial, anti-inflammatory and anti-allergic functions. Grape seed extract can be effective in the body for about 3 days, the effect is 20 times of vitamin C, 50 times of vitamin E.

Resveratrol is an extract of grapes, and research on resveratrol has been conducted since the 1970s. Resveratrol is a polyphenolic substance that is a phytoalexin produced by plants when faced with harsh environments such as mold or pests. Anti-cancer, anti-viral, neuroprotective, anti-aging, anti-inflammatory, prolonged life is known to help a number of diseases of the human body. Toxic effects and adverse effects on the human body have not been studied, especially for long-term use. It activates a deacetylase called sir2 and inhibits quinone reductase (QR1) and cyclooxygenase (COX). It is found in grape skins, grape seeds and peanuts. It is insoluble in water and soluble in alcohol. Therefore, it is contained in alcohol more than wine. It is found in the roots of a species called Rheum rhaponticum in rhubarb. There are two types of trans resveratrol and cis resveratrol. Only trans resveratrol is believed to be effective. Trans resveratrol is converted to cis resveratrol by heat and ultraviolet rays. It is quickly metabolized in the body and metabolites are mainly sulfide derivatives and glucuronide derivatives. The pharmacological action of the derivatives is not yet known. In the United States, rasveratrol is sold as a dietary supplement in a 50 mg daily dose.

DHA (docosahexaenoic acid) is known to be an essential component of brain, nerve and eye tissue and is naturally consumed through breast milk. DHA is a major component of cell membranes such as muscle cells and brain cells. Eicosa- pentaenoeic acid (EPA) is known to reduce inflammation and coagulation in the cardiovascular system. DHA and EPA improves hair, prevents adult diseases of the circulatory system such as atherosclerosis, myocardial infarction and stroke, as well as diabetes, cancer, aging and dementia. Several clinical trials have shown that high intake of EPA is less susceptible to rheumatoid arthritis, Crohn's disease, asthma, multiple sclerosis and skin diseases. It is also known to help prevent bone damage and osteoporosis. It is a major constituent of cells that promotes collagen production and prevents skin aging.

The inventors of the present invention are juniper berry extract, pycnogenol, grape skin or grape seed extract, resveratrol, a component of celecoxib, acetaminophen or folic acid, a nonsteroidal anti-inflammatory analgesic drug, and a substance known for its anti-inflammatory, antioxidant and lipid metabolism functions in natural products. The arthritis therapeutic composition consisting of one or two or more of omega-3-fatty acid, DHA, and EPA was completed. This can provide the arthritis therapeutic composition with the disintegration, the dissolution rate and the pain suppression effect improved.

The present invention is a nonsteroidal anti-inflammatory drug, celecoxib, acetaminophen or folic acid, juniper berry extract, bokbunja extract, pycnogenol, grape skin or grape seed extract, resveratrol, omega-3-fatty acid, DHA, It is an object to provide new compositions containing simultaneously one or two or more components of EPA. It is also an object of the present invention to provide an arthritis therapeutic composition having improved disintegration, dissolution rate and pain suppression effect than conventional arthritis therapeutics.

According to a preferred embodiment of the present invention for solving the above problems, at least one selected from the group consisting of juniperberry extract, pycnogenol, bokbunja extract, grape skin and grape seed extract, resveratrol, omega-3-fatty acid, DHA and EPA Provided is a composition for treating arthritis, comprising one component and a second component selected from the group consisting of celecoxib, acetaminophen and folic acid.

According to another suitable embodiment of the present invention, the first component provides an arthritis therapeutic composition, characterized in that 5 to 20% by weight based on the total weight.

According to another suitable embodiment of the present invention, the second component is 10 to 20% by weight of celecoxib, 10 to 15% by weight of acetaminophen, or 0.1 to 0.5% by weight of folic acid. To provide a composition.

According to another suitable embodiment of the present invention, the omega-3 fatty acid provides a therapeutic composition for arthritis, characterized in that extracted from alpha tocopherol, soybean oil, partially hydrogenated vegetable oil, fractionated coconut oil or lecithin.

According to another suitable embodiment of the present invention, there is provided a soft capsule, capsule or tablet comprising the arthritis therapeutic composition.

The present invention contains at least one component of Juniperberry extract, Bokbunja extract, Pycnogenol, grape skin or grape seed extract, resveratrol, omega-3-fatty acid, DHA, EPA and natural ingredients of celecoxib, acetaminophen, folic acid It provides a new arthritis therapeutic composition to have an improved pain inhibitory effect and side effect reduction compared to conventional arthritis therapeutics.

The present invention, at least one selected from the group consisting of juniperberry extract, pycnogenol, bokbunja extract, grape skin and grape seed extract, resveratrol, omega-3-fatty acid, DHA and EPA and celecoxib, acetaminophen and folic acid Provided is an arthritis therapeutic composition comprising a second component selected from the group consisting of arthritis treatment specialty pharmaceutical ingredients.

The above arthritis treatment medicinal ingredients include celecoxib, acetaminophen, folic acid, aceclofenac, amlodipine besylate, azathioprine, calcium citrate, butyamine, deplazacoat, eferison, hydroxychloroquine sulfate, leflunoamide, Meloxycam, omeprazole, rabeprazole, simvastatin and the like can be used.

Juniper berry extract, pycnogenol, bokbunja extract, grape skin and grape seed extract, resveratrol, omega-3-fatty acid, DHA and EPA, which are the first components of the composition of the present invention, are 5-20 parts by weight of the total composition. It is good to be in the weight%, preferably 3 to 10% by weight, more preferably 3 to 8% by weight of natural products. In the most preferred component content, the composition of natural products and the effects of the existing arthritis preparations are maximized, so that the medicinal effect can be maximized and the side effects can be reduced.

Resveratrol of the natural product may be extracted from grape skin, grape seed, peony seed, blueberry, peanuts and the like.

Omega-3-fatty acid in the natural product may be extracted from alpha tocopherol, soybean oil, partially hydrogenated vegetable oil, fractionated coconut oil or lecithin.

The second component of the composition of the present invention is celecoxib, acetaminophen or folic acid. In the case where the second component contains selectoxib, the selectoxib is preferably 10 to 20% by weight based on the total weight of the composition. When the second component is acetaminophen, it is preferably 10 to 15% by weight. When the second component is folic acid, it is preferably 0.1 to 0.5% by weight.

The first component, which is a natural product component, may be used as 10 to 50% by weight based on the total weight when prepared alone.

According to the present invention, at least one component of juniper berry extract, bokbunja extract, pycnogenol, grape skin or grape seed extract, resveratrol, omega-3-fatty acid, DHA, EPA and natural ingredients of celecoxib, acetaminophen or folic acid The pharmaceutical compositions in combination may be prepared in encapsulation, tableting, emulsion or syrup for oral administration and may be prepared in tablets or capsules of sustained or controlled release, enteric, etc. for sustained release.

Pharmaceutically acceptable solid or liquid carriers may be added to stabilize or enhance the composition or to facilitate the preparation of the composition. As the liquid carrier, syrup, soybean oil, olive oil, glycerin, propylene glycol, polyethylene glycol, ethanol and water can be suitably used. The carrier may also comprise a series of release materials, such as glyceryl monostearate and glyceryl distearate, alone or in combination with waxes. The amount of solid carrier may vary but preferably from about 20 mg to about 1 g per dosage unit. Pharmaceutical preparation is carried out according to conventional preparations including grinding, mixing, granulating and, if necessary, compression processes for tablets, and grinding, mixing and filling for light gelatine capsules. If a liquid carrier is used, it can be prepared in the form of syrups, elixirs, emulsions or aqueous or non-aqueous suspensions. Such formulations may be administered either directly or filled in soft gelatin capsules.

The method for producing a soft capsule containing the pharmaceutical composition of the present invention will be described below. The composition component of the present invention may be solubilized to speed up the effect. The composition of the soft capsule solution for solubilization is as follows. 5-15% by weight of natural product functional ingredients (Juniperberry extract, Bokbunja extract, Pycnogenol, grape skin or grape seed extract, at least one component of resveratrol, omega-3-fatty acid, DHA, EPA); 10-20 wt% celecoxib, 10-15 wt% acetaminophen or 0.1-0.5 wt% folic acid; Excipients corresponding to 1060% by weight; Powder binder corresponding to 130% by weight; Lubricant corresponding to 0.52% by weight; A coating agent corresponding to 15% by weight; A preservative corresponding to 0.010.2% by weight.

Specifically, one of the nonsteroidal anti-inflammatory analgesics celecoxib, acetaminophen or folic acid and natural ingredients (juniperberry extract, bokbunja extract, pycnogenol, grape skin or grape seed extract, resveratrol, omega-3-fatty acid, DHA, EPA At least one component), such as polyethylene glycol, propylene glycol, diethylene glycol monoethyl ether, glycerol, triacetin, and the like; Surfactants such as polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polysorbates, polyethylene glycol-8 glyceryl caprylate, dimethyl isosorbide and poloxamer; Oil components such as fatty acids, monohydric alkanols and ester compounds, intermediate fatty acid triglycerides and fatty acid monoglycerides for preparing emulsion concentrates; In order to ensure the stability of the emulsion concentrate, lipophilic tocopherol, dibutylhydroxytoluene and butylhydroxyanisole and the like, and hydrophilic antioxidants such as ascorbic acid, sodium sulfite, sodium pyrosulfite and sodium hydrogen sulfite, pH 5.0-7.0 In order to adjust the pH, a pH adjusting agent is added, and in particular, an acidifying agent, such as citric acid, succinic acid, tartaric acid, formic acid and malic acid, may be added to solubilization to form a soft capsule formulation.

In the composition of the present invention, it is preferable that the active ingredient natural ingredients and selecoxib, acetaminophen or folic acid do not exceed 10 to 80% by weight based on the total weight. If more than 80% by weight of the active ingredient, solubility is drastically lowered, such as precipitation during storage or content may be poor stability, and if the active ingredient is added less than 10% by weight of the total weight solubility and There is a disadvantage that the stability is increased but the dosage can be increased.

The soft capsule film in the present invention was prepared by a conventional film production method using a general soft capsule manufacturing component containing a known gelatin, plasticizer. The coating composition includes 118 mg of gelatin, 32.8 mg of glycerin, 14.1 mg of sorbitol solution, 0.7 mg of ethyl vanillin, 0.35 mg of methyl paraoxybenzoate, 0.05 mg of paraoxybenzoic acid, etc. per capsule (166 mg).

Natural ingredients (Juniperberry Extract, Bokbunja Extract, Pycnogenol, Grape Skin or Grape Seed Extract, Resveratrol, Omega-3- Fatty Acid, DHA, EPA, or two or more ingredients) of the present invention and one of celecoxib, acetaminophen, folic acid Production of soft capsules containing ingredients is carried out in Oval # 6 by the usual filling method using rotary automatic charger which is generally used, and then it is made into prototype by drying and sorting process.

The compositions of the present invention are useful in the treatment and prevention of a wide range of disorders mediated by COX-2, including but not limited to disorders characterized by inflammation, pain and / or fever. Such compositions are particularly useful as anti-inflammatory agents in the treatment of arthritis, for example, and have significantly less harmful side effects than compositions of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) lacking selectivity for COX-2 over COX-1. Having has the additional advantage. In particular, the compositions of the present invention, compared to the compositions of conventional NSAIDs, reduce the likelihood of gastrointestinal toxicity and gastrointestinal irritation, including upper gastrointestinal ulcers and bleeding, such as a decrease in renal function resulting in fluid retention and worsening of hypertension. Reduces the likelihood of kidney side effects.

Dose units containing a specific amount of selective COX-2 inhibitory drug, preferably celecoxib, may be selected to provide any desired frequency of administration used to achieve the desired daily dose. The daily dose and frequency of administration, and thereby the selection of the appropriate dosage unit, depend on a number of factors, including the age, weight, sex and medical condition of the subject, and the nature and severity of the condition or disorder, and thus can vary widely. have.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are only for illustrating the present invention, but the scope of the present invention is not limited thereto.

EXAMPLE

Among the components shown in Tables 1 to 3, natural compositions (juniperberry extract, bokbunja extract, pycnogenol, grape skin or grape seed extract, resveratrol, omega-3-fatty acid, one or two or more components of DHA, EPA) and celecoxib , Except for one component of acetaminophen and folic acid, warm the mixture to about 5070 ℃ and stir until it is transparent. At the temperature of about 50 ° C., the main natural extract (Juniperberry extract, Bokbunja extract, Pycnogenol, grape skin or grape seed extract, at least one of resveratrol, omega-3-fatty acid, DHA, EPA), celecoxib, acetaminophen , One component of folic acid was slowly added to the mixed solution prepared above to completely dissolve it to prepare a liquid solution for soft capsule preparation. The compositions used in Examples 1 to 15 are shown in Tables 1 to 3, respectively.

TABLE 1 Preparation of celecoxib and soft capsule containing natural composition

[Table 2] Preparation of acetaminophen and soft capsule containing natural composition

Table 3 Preparation of Folic Acid and Soft Capsules Containing Natural Composition

Comparative Example 1

Soft capsules were prepared in the same manner by adding 100 mg of celecoxib instead of the natural ingredients of Table 1.

Comparative Example 2

Soft capsules were prepared in the same manner by adding 100 mg of acetaminophen instead of the natural ingredients of Table 2.

Comparative Example 3

Soft capsules were prepared in the same way by adding 100 mg of folic acid instead of the natural ingredients in Table 3.

Experimental Example 1

Disintegration Experiment

According to the disintegration test method of the Korean Pharmacopoeia, the disintegration comparison experiments were performed for Examples 1 to 15 and Comparative Examples. That is, put the auxiliary plate using purified water of 37 ± 2 ℃ as the test zone, take 6 specimens each time in the tester which reciprocates at 29 ~ 32 rotation for 1 minute, put them in the glass tube and move up and down for a certain time, and then the residue disappears in the glass tube. Measured the time.

[Table 4] Disintegration test results of the combination

Experimental Example 2

Dissolution Accumulation Rate Comparison Experiment

According to the dissolution test method of the Korean Pharmacopoeia dissolution cumulative experiments were compared to Examples 1 to 15 and Comparative Examples. In other words, the eluate was taken at a constant time using 900 mL of pH 5.8 phosphate buffer at 37 ± 0.2 ° C. at 50 rotations per minute according to the second method. This was filtered and analyzed by high-performance liquid chromatography, and the experimental results are shown in Table 5 below.

[Table 5] Comparison of elution accumulation rate of celecoxib formulations

Table 6 Results of elution accumulation rate of acetaminophen preparations

[Table 7] Comparison of elution accumulation rate of folic acid preparations

Experimental Example 3 Analgesic Inhibitory Effect Experiment

The compositions of Examples 1-5 were orally administered to 25-28 g of ICR male mice fasted 12 hours before the experiment. Intraperitoneally inject 0.7% acetic acid-saline solution (0.1mg / 10g b.wt.) 30 minutes after administration, and measure the number of occurrences of writhing for 10 minutes from 5 minutes after injection (Koster et al., 1959). Table 8 shows. Phenylbutazone was used as a positive control drug.

TABLE 8 Analgesic inhibitory effects of celecoxib-containing formulations

^* P <0.05, significantly different compared to control.

From the results of Table 8, it was confirmed that the analgesic effects of the natural products and celecoxib-containing formulations of Examples 1, 2, 3, 4, 5 and the control / comparative group all showed at least 57% analgesic inhibitory effect.

TABLE 9 Analgesic inhibitory effects of acetaminophen containing formulations

^* P <0.05, significantly different compared to control.

From the results of Table 9, it was confirmed that the analgesic effect comparison evaluation of the natural products and the acetaminophen-containing formulations of Examples 6, 7, 8, 9, 10 and the control group / comparison group showed more than 55% analgesic inhibitory effect.

TABLE 10 Analgesic inhibitory effects of folic acid-containing preparations

^* P <0.05, significantly different compared to control.

From the results of Table 10, it was confirmed that the analgesic inhibitory effect of the natural products and folic acid-containing formulations of Examples 11, 12, 13, 14, and 15 and the control group / comparison group showed 53% or more analgesic inhibitory effect.

In addition, each experimental group was administered the same inflammation-inducing substance as the control / comparison group mice, but observed a more stable behavior.

The present invention contains at least one component of Juniperberry extract, Bokbunja extract, Pycnogenol, grape skin or grape seed extract, resveratrol, omega-3-fatty acid, DHA, EPA and natural ingredients of celecoxib, acetaminophen, folic acid By providing a new arthritis therapeutic composition to provide an arthritis therapeutic agent having a side effect reducing effect and an improved pain inhibitory effect compared to conventional arthritis therapeutics.

Claims (5)

Juniper berry extract, pycnogenol, bokbunja extract, grape skin and grape seed extract, resveratrol, omega-3-fatty acid, at least one selected from the group consisting of DHA and EPA from the group consisting of celecoxib, acetaminophen and folic acid An arthritis therapeutic composition comprising one selected second component. According to claim 1, wherein the first component is an arthritis therapeutic composition, characterized in that 5 to 20% by weight based on the total weight. The composition of claim 1, wherein the second component is 10-20 wt% celecoxib, 10-15 wt% acetaminophen, or 0.1-0.5 wt% folic acid. The composition of claim 1, wherein the omega-3 fatty acid is extracted from alpha tocopherol, soybean oil, partially hydrogenated vegetable oil, fractionated coconut oil or lecithin. A soft capsule, capsule or tablet comprising the composition for treating arthritis according to any one of claims 1 to 4.