KR20120045121A - Composition for preventing and treating bone diseases - Google Patents

Abstract

PURPOSE: A pharmaceutical composition and health food containing trimebutine are provided to suppress differentiation and generation of osteoclast and to prevent and treat bone diseases. CONSTITUTION: A pharmaceutical composition for preventing and treating bone diseases contains trimebutine as an active ingredient. The bone diseases include osteoporosis, osteomalacia, osteopenia, bone atrophy, fibrous dysplasia, Paget's disease, hypercalcemia, or neoplastic destruction. A pharmaceutical composition for suppressing generation and differentiation of osteoclast contains trimebutane as an active ingredient. A health food for treating or relieving bone diseases contains trimebutine as an active ingredient.

Description

COMPOSITION FOR PREVENTING AND TREATING BONE DISEASES}

The present invention relates to a composition for preventing and treating bone diseases containing trimebbutine (Trimebutine).

Metabolic bone diseases include osteoporosis, osteomalacia, osteopenia, bone atrophy, fibrous dysplasia, Paget's disease, hypercalcemia, bone species Neoplastic destruction, cancer-related bone resorption diseases, osteolysis, osteoarthritis or rheumatoid arthritis.

Osteoporosis, a representative metabolic bone disease, is a disease caused by an osteostatic regulation imbalance between osteoclasts that absorb bone and osteoblasts that form bone, and is a skeletal disorder characterized by weakened bone strength that may increase the risk of fracture. (US National Institutes of Health Justice NIH, 2000). This is a systemic disease that decreases bone density and deteriorates the microstructure of bone tissue, increasing the risk of fracture. In other words, the bone density is maintained while the old bones are destroyed and the production of new bones is balanced. As the aging progresses, the replacement of new bones is not made smoothly, and the bones become thin and the process is repeated. The risk is increased. Bone strength is affected by two factors: bone density (BMD) and bone quality. The constituent elements of bone quality are bone structure, bone replacement rate, mineralization and microfracture, and collagen. Osteoporosis is a disease in which bone mass required for maintaining normal activity is reduced, such as a decrease in the amount of calcium in the bone, that is, bone density is reduced, and thus fracture is easily caused even by a light impact. On the other hand, the condition before osteoporosis is called osteopenia, and the bone is thinned and lightened, until the hole is opened. In addition, osteomalacia is a condition in which bones are bent in a state where calcium is not mixed and bones are formed when there is a renal disease in which vitamin D is deficient or calcium is excreted in a large amount, and bone atrophy is reduction of bone degeneration, That is, it means a symptom of reducing bone mass of bone tissue that has already been completed.

In addition, renal osteodystrophy, a bone disease caused by renal failure, metabolic bone disease in patients with chronic renal failure, a dynamic bone disease, which has recently increased in frequency, and inflammatory diseases caused by infection with purulent bacteria Infectious bone diseases, which are diseases, are included in bone diseases.

In the present invention, the above-mentioned metabolic bone diseases, osteoporosis, osteomalacia, osteopenia, osteopenia, bone atrophy, fibrous dysplasia, Paget's disease, hypercalcemia (hypercalcemia), neoplastic destruction of bone, cancer-related bone resorption diseases, osteolysis, osteoarthritis, rheumatoid arthritis, and their concurrent metabolic syndrome And diseases resulting from them are collectively named "bone diseases".

Such a bone disease is caused by the harmony between the activity of osteoblasts (osteoblast), which plays a role in producing bones, and osteoclasts (osteoclast), which plays a role in destroying bone, in the body. Osteoclasts are large, multinuclear cells that destroy or absorb bone tissue that has become unnecessary during bone growth. Mature osteoclasts are multinuclear cells and are derived from hematopoietic stem cells. Osteoblasts differentiated from mesenchymal stem cells survive for about 34 months, creating new bone where activated osteoclasts break down old bone. Many osteoblasts form bone matrix and gradually mineralize the matrix, ending bone formation. More than about 70% of osteoblasts are then killed and some of them differentiate into osteoblasts and bone lining cells to survive. Since the amount of bone is maintained by the balance between osteoclasts and osteoblasts, it is important to develop therapeutics targeting molecules that play an important role for osteoclasts. In other words, when the activity of osteoclasts that absorb bone increases, diseases such as osteoporosis, which promote bone breakdown, thinner and easily broken bones, occur, and thus, proteins that can regulate the activity of osteoclasts are used to treat bone diseases. (GregoryY R. Mundy, Journal of Bone and Mineral Metabolism (1996) 14: 59-64; Chad Deal, nature clinical practice RHEUMATOLOGY (2009) vol 5 no 1; Kalervo Vaananen, Advanced Drug Delivery Reviews 57 (2005) 959-971).

The present inventors have found that trimebutine inhibits the production and differentiation of osteoclasts, and has developed a pharmaceutical composition for preventing and treating bone diseases and health functional foods containing the same as an active ingredient.

Disclosure of Invention An object of the present invention is to provide a pharmaceutical composition for preventing and treating bone diseases and functional health disorders that effectively inhibits the production and differentiation of osteoclasts.

In order to achieve the above object, in one embodiment there is provided a pharmaceutical composition for the prevention and treatment of bone diseases containing a trimebutine (Trimebutine) as an active ingredient. In another embodiment, the bone disease of the embodiment is osteoporosis, osteomalacia, osteopenia, bone atrophy, fibrous dysplasia, Paget's disease, hypercalcemia (hypercalcemia), neoplastic destruction of bone, cancer-related bone resorption disease and osteolysis, the pharmaceutical composition for the prevention and treatment of bone diseases, characterized in that any one selected from the group consisting of to provide. In another embodiment, the bone disease of the embodiment provides a pharmaceutical composition for the prevention and treatment of bone diseases, characterized in that the osteoporosis (osteoporosis).

In one embodiment, the present invention provides a pharmaceutical composition, which contains trimebutine as an active ingredient and inhibits the production and differentiation of osteoclasts.

In one embodiment, it provides a dietary supplement for improving or alleviating the symptoms of bone disease containing a trimebutine (Trimebutine) as an active ingredient. In another embodiment, the bone disease of the embodiment is osteoporosis, osteomalacia, osteopenia, bone atrophy, fibrous dysplasia, Paget's disease, hypercalcemia health function for improving or alleviating symptoms of bone disease, characterized in that it is any one selected from the group consisting of hypercalcemia, neoplastic destruction of bone, cancer-related bone resorption diseases, and osteolysis. Provide food. In another embodiment, it provides a health functional food for amelioration or alleviation of bone disease symptoms, characterized in that the bone disease is osteoporosis.

In one embodiment, it provides a dietary supplement for the improvement or alleviation of bone disease symptoms, characterized in that containing trimebutine (Trimebutine) as an active ingredient and inhibits the production and differentiation of osteoclasts.

In one embodiment there is provided a method for preventing and treating bone diseases by administering an appropriate amount of a pharmaceutical composition for the prevention and treatment of bone diseases containing trimebbutine (Trimebutine) as an active ingredient.

In the present invention, the bone disease is not limited thereto, but osteoporosis, osteomalacia, osteoopenia, bone atrophy, fibrous dysplasia, Paget's disease, Hypercalcemia, neoplastic destruction of bone, cancer-related bone resorption diseases, osteolysis, osteoarthritis, rheumatoid arthritis.

Pharmaceutical composition and dietary supplement containing trimebutine (Trimebutine) according to the present invention has an excellent effect on inhibiting the differentiation and production of osteoclasts, useful as a preventive and therapeutic agent for bone disease and health functional food Can be used.

FIG. 1 shows the results of comparing osteoclast differentiation induction, in which Raw264.7 cells (ATCC-TIB71) were treated with a control group RANKL and a test group RANKL and Trimebutine together (Example 1).
FIG. 2 shows the results of comparing osteoclast differentiation by treating LPS (lipopolysaccharide) and LPS with Trimebutine on the skull tissue of ICR mice (Example 2).
Figure 3 is a graph comparing the effect on ovarian resection induced bone density by administering Trimebutine in OVX animal model (Example 3).

Hereinafter, the present invention will be described in detail by the following Examples and Experimental Examples. However, the following examples and experimental examples are illustrative of the present invention, and the content of the present invention is not limited by the following examples and experimental examples.

Example

Example  1: osteoclast differentiation experiment In Vitro )

Raw264.7 cells (ATCC-TIB71) were added to the alpha-MEM medium containing 10% FBS (fetal bovine serum), and RANKL (receptor activator of nuclear factor-kB ligand) was added as a control. Treatment with mebutin (Trimebutine) was incubated for 3 days while inducing differentiation into osteoclasts. Next, washed with PBS (phosphate buffer saline) and fixed with 10% formaldehyde and treated with 0.1% Triton X-100. Then, the degree of osteoclast differentiation was observed under a microscope by TRAP staining. As a result, as shown in Figure 1 Trimebutine was confirmed to effectively inhibit the differentiation of osteoclasts.

Example  2: osteoclast production experiment ( Ex Vivo )

The skulls of 3-day-old ICR mice were removed and tissues were removed from Hanks' balanced salt solution (HBSS) solution. Alpha-MEM culture medium containing 10% FBS (fetal bovine serum) was incubated for 7 days with LPS (lipopolysaccharide) as a control and LPS and Trimebutine as experimental groups. Next, washed with PBS (phosphate buffer saline) and fixed with 10% formaldehyde and treated with 0.1% Triton X-100. Then, the degree of osteoclast generation in the skull was confirmed by TRAP staining. As a result, it was confirmed that Trimebutine effectively inhibits the production of osteoclasts in the skull as shown in FIG.

Example  3: animal efficacy test In Vivo )

Twelve-week-old ICR females were housed in a kennel with a temperature of 20 ± 1 ° C, a humidity of 50 ± 10%, a contrast cycle of 12 hours, an illuminance of 150-300 Lux, and a ventilation environment of 10-20 times / hr. Feed was freely supplied from experimental animal solid feed from Polars International, Inc., and drinking water was freely ingested after autoclaving the tap water. Six 12-week-old ICR rats were divided into normal, ovarian ablation, and OVX + trimebutine groups. After 1 day of ovarian resection, test materials were dissolved in 0.5% methyl cellulose and administered for 6 weeks by forced oral administration. In addition, the same group was administered with the same amount of 0.5% methyl cellulose (methyl cellulose). After the end of the administration, the bone density (BMD) of the shin (Femur) was measured using a micro-CT (micro-CT). As a result, it was confirmed that Trimebutine effectively inhibits osteoporosis induced by ovarian ablation as shown in FIG. 3.

The composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredient for administration. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, antioxidants, buffers And other conventional additives such as bacteriostatic agents can be added. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, it may be preferably formulated according to each disease or component by a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.

The compositions of the present invention can be administered to humans or animals by a variety of routes, including parenteral, intraarterial, intradermal, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous, oral and intranasal routes of administration. Dosage ranges vary depending on the weight, age, sex, health status, diet, time of administration, method of administration, rate of excretion and severity of the patient. The daily dosage of the composition is about 10 ng / kg to 10 mg / kg, preferably about 80 to 400 ng / kg, and more preferably, administered once or several times a day.

Examples of preparations for the compositions of the present invention are illustrated below.

Formulation example  One: Powder  Produce

300 mg of Trimebutine from Example 1

Lactose 100 mg

Talc 10 mg

The above ingredients were mixed and filled in an airtight cloth to prepare a powder.

Formulation example  2: Preparation of tablets

50 mg of Trimebutine from Example 1

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components was prepared by tableting according to the conventional manufacturing method of the tablet.

Formulation example  3: Preparation of Capsule

50 mg of Trimebutine from Example 1

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

According to a conventional capsule preparation method, the above ingredients were mixed and filled into gelatin capsules to prepare capsules.

Formulation example  4: Preparation of injection

50 mg of Trimebutine from Example 1

Appropriate sterile distilled water for injection

pH adjuster

According to the conventional method for preparing an injection, the amount of the above ingredient was prepared per ampoule (2 ml).

Formulation example  5: Liquid  Produce

100 mg of Trimebutine from Example 1

10 g per isomer

5 g mannitol

Purified water quantity

According to the conventional method for preparing a liquid, each component is added and dissolved in purified water, lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by adding purified water, and then filled in a brown bottle. The solution was prepared by sterilization.

Formulation example  6: manufacture of health food

Trimebutine 1000 mg of Example 1

Vitamin mixture quantity

70 μg of Vitamin A Acetate

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

Vitamin B2 0.15 mg

Vitamin B6 0.5 mg

0.2 μg of vitamin B12

Vitamin C 10 mg

10 μg biotin

Nicotinic Acid 1.7 mg

50 μg folic acid

Calcium Pantothenate 0.5mg

Mineral mixture

Ferrous Sulfate 1.75 mg

Zinc Oxide 0.82 mg

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Dibasic calcium phosphate 55 mg

Potassium Citrate 90 mg

Calcium Carbonate 100 mg

Magnesium chloride 24.8 mg

Although the composition ratio of the above-mentioned vitamin and mineral mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified. The granules may be prepared and used for preparing a health food composition according to a conventional method.

Formulation example  7: manufacture of health drinks

Trimebutine 1000 mg of Example 1

Citric acid 1000 mg

100 g oligosaccharides

Plum concentrate 2 g

1 g of taurine

Add 900 ml of purified water

After mixing the above components according to a conventional healthy beverage manufacturing method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed and sterilized and then refrigerated and stored in the present invention It was used to prepare a healthy beverage composition.

Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.

While the invention has been described with reference to exemplary embodiments so far, those skilled in the art will appreciate that various changes can be made therein and equivalents may be substituted for elements thereof without departing from the scope of the invention. You will know. In addition, many modifications may be made to adapt a particular situation and material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the present invention not be limited to the particular embodiments disclosed as the best mode contemplated for carrying out the invention, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims (8)

Pharmaceutical composition for the prevention and treatment of bone diseases containing trimebutine (Trimebutine) as an active ingredient. The method of claim 1,
The bone disease is osteoporosis, osteomalacia, osteopenia, osteopenia, bone atrophy, fibrous dysplasia, Paget's disease, hypercalcemia, hypercalcemia, bone species Pharmaceutical composition for the prevention and treatment of bone diseases, characterized in that any one selected from the group consisting of neoplastic destruction, cancer-related aggregate absorption diseases and osteolysis. The method of claim 2,
Pharmaceutical composition for the prevention and treatment of bone diseases, characterized in that the bone disease is osteoporosis. Pharmaceutical composition, characterized in that containing trimebutine (Trimebutine) as an active ingredient and inhibits the production and differentiation of osteoclasts. Health functional food for improving or alleviating the symptoms of bone disease, containing trimebutine as an active ingredient. 6. The method of claim 5,
The bone disease is osteoporosis, osteomalacia, osteopenia, osteoopenia, bone atrophy, fibrous dysplasia, Paget's disease, hypercalcemia, hypercalcemia Health functional food for improving or alleviating bone disease symptoms, characterized in that any one selected from the group consisting of neoplastic destruction, cancer-related aggregate absorption diseases and osteolysis. The method of claim 6,
Health functional food for improving or alleviating bone disease symptoms, characterized in that the bone disease is osteoporosis. A dietary supplement for the improvement or alleviation of bone disease symptoms, which contains trimebutine as an active ingredient and inhibits the production and differentiation of osteoclasts.

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