KR101802212B1 - Pharmaceutical composition for increasing of bone regeneration containing Asiatic acid or pharmaceutically acceptable salts thereof as an active ingredient - Google Patents
Pharmaceutical composition for increasing of bone regeneration containing Asiatic acid or pharmaceutically acceptable salts thereof as an active ingredient Download PDFInfo
- Publication number
- KR101802212B1 KR101802212B1 KR1020150172712A KR20150172712A KR101802212B1 KR 101802212 B1 KR101802212 B1 KR 101802212B1 KR 1020150172712 A KR1020150172712 A KR 1020150172712A KR 20150172712 A KR20150172712 A KR 20150172712A KR 101802212 B1 KR101802212 B1 KR 101802212B1
- Authority
- KR
- South Korea
- Prior art keywords
- bone
- acid
- asialic
- pharmaceutical composition
- pharmaceutically acceptable
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims abstract description 31
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- LBGFKBYMNRAMFC-PYSQTNCISA-N asiatic acid Natural products C[C@@H]1CC[C@@]2(CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@@]34C)[C@]2(C)[C@H]1C)C(=O)O LBGFKBYMNRAMFC-PYSQTNCISA-N 0.000 title claims abstract description 28
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
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Abstract
The present invention relates to a composition for promoting bone regeneration comprising asiatic acid or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the asialic acid of the present invention is used for the proliferation of cells of human alveolar bone marrow derived mesenchymal stem cells (Collagen type I α), ALP, and osteocalcin, which are known as osteoblast differentiation markers, increase the activity of basic alkaline phosphatase (APL) activity, which is known as an indicator enzyme of bone cell activity during osteoblast differentiation, , And BSP (bone sialoprotein), the bone marrow-derived mesenchymal stem cells are remarkably promoted in their ability to differentiate and bone regeneration through bone grafting treatment, May be useful as an effective ingredient of a transplantation adjuvant.
Description
The present invention relates to a pharmaceutical composition for regenerating a bone defect such as a bone tissue, a fracture or a bone defect destroyed by periodontal disease containing asiatic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
Reconstructive surgery through bone regeneration has been extensively carried out in orthopedics and plastic surgeons as well as in dentistry to restore the inherent and acquired damaged bone structure. Currently, the materials used for bone regeneration are classified into three categories according to the osteogenesis ability: osteogenesis, osteoconduction, and osteoinduction.
The bone-forming material is a self-made bone that can make bone by itself by preparing cells and growth enzymes necessary for bone regeneration by themselves. In contrast, the bone conduction material is absorbed after serving as a scaffold necessary for bone regeneration, and includes various allografts, heterogeneous bone, and xenografts. Finally, bone-derived material is a material capable of differentiating mesenchymal cells into bone cells to produce bone.
In the early days, the bone-inducing substance was limited to the Demineralized Bone Matrix (DBM). However, recently, various growth factors have been studied and applied so that not only bone differentiation but also vascularization and macrophage function involved in bone healing It is reaching to the regulating ground. In 2001, Clokie and Sandor et al. Described "osteoactive agents" for the Bone Morphogenetic Protein (BMP), Platelet Rich Protein (PRP), and Plasma Rich in Growth Factor (PRGR) I have defined it.
In the regenerative procedure applied to the periodontal region, various bone grafts are used to form neonatal cementum, periodontal ligament fibers and new bone in the lost periodontal tissue and to achieve renal adhesion. To date, autogenous bone grafting has shown the greatest amount of bone regeneration, but there is a limitation in the amount of additional surgery and acquisition of the donor site, and complications such as osseointegration and root resorption may occur. Therefore, there is a great increase in interest and application of a bone inducing substance having a superior bone forming ability and less restriction of a donating part.
Recently, BMP, which has been under much interest and studied, was first introduced by Urist in 1965 as a member of the Transforming Growth Factor (TGF-β) superfamily, and was first isolated in the DBM of rabbits and cows in 1980. Since the recombinant Human Bone Morphogenetic Protein (rhBMP) has been synthesized, known BMPs have been found in about 20 species. They are 30 ~ 38 kDa homodimers, synthesized in prepropetides composed of 400 ~ 525 amino acids, . It is known to induce cartilage and bone formation and to provide a basic environment for functional bone marrow formation during bone formation. In particular, BMP-2 is able to develop directly neuronal cells, and has the ability to induce chondroblasts and osteoblasts, differentiates the surrounding immature mesenchymal cells into osteogenic cells, and stimulates and regulates osteogenesis .
BMP has recently been approved by the US FDA and has been commercialized, and various attempts have been made to make it easier to apply to clinical practice, but so far it has been supplied in liquid form. Therefore, when the BMP alone is applied, not only the operability is poor but also it is difficult to induce bone formation because it spreads to the implantation site and is quickly absorbed.
Asiatic acid is a natural organic compound isolated from Centella asiatica . It has been developed as a skin cream and has been already proven in human body. It has been reported that it has anti-inflammatory function. J Agric Food Chem, 1, 63 (12): 12-24. [CrossRef], [Web of Science ®] View all references). In addition to the antioxidative and antiinflammatory activities of asiatic acid, glycyrrhizic acid and oleanolic acid in human bronchial epithelial cells, 3196-204), the bone regeneration effect of asialic acid is not known at present.
Accordingly, the present inventors have made efforts to develop a material for bone regeneration derived from a natural product safe to human body, and as a result, it has been found that asiatic acid inhibits cell proliferation effect on mesenchymal stem cells derived from human alveolar bone marrow, (Collagen type I α), ALP, osteocalcin (BSP), and bone sialoprotein (BSP), known as osteoblast differentiation markers, by increasing the activity of Alkaline phosphatase (APL) The inventors of the present invention have completed the present invention by confirming that the asymtric acid of the present invention or a pharmaceutically acceptable salt thereof can be used as an effective ingredient of a bone regeneration composition by confirming that the bone differentiation ability of cells is remarkably promoted.
It is an object of the present invention to provide a composition for promoting bone regeneration comprising asiatic acid or a pharmaceutically acceptable salt thereof as an active ingredient, and a bone grafting aid.
In order to achieve the above object, the present invention provides a pharmaceutical composition for promoting bone regeneration comprising asiatic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also provides a health food for promoting bone regeneration comprising asialic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
In addition, the present invention provides a bone grafting aid comprising asialic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
Asiatic acid of the present invention or a pharmaceutically acceptable salt thereof is useful as a cell proliferation effect on mesenchymal stem cells derived from human alveolar bone marrow, a basic phosphatase (Collagen type I α), ALP, osteocalcin (BSP), and bone sialoprotein (BSP), known as osteoblast differentiation markers, by increasing the activity of Alkaline phosphatase (APL) It significantly enhances the bone differentiation ability of the cells and shows the effect of increasing the bone regeneration through the combination treatment of the bone graft materials and thus can be effectively used as an effective component of the bone regeneration composition or bone grafting aid.
1 shows the effect of inducing osteoblast proliferation of asiatic acid (cw7)
negative: no treatment control;
low dose: treated with 1 ㎍ / mL of asialic acid;
high dose: treated with 10 ㎍ / mL of asialic acid; And
positive: Osteoporotic stimulant treatment group.
2 is a diagram showing the activity of APL (Alkaline phosphatase) of asialic acid:
negative: no treatment control;
positive: group treated with osteoblast-inducing stimulants;
low con asiatic acid: treated with 1 ㎍ / mL of asialic acid;
high con asiatic acid: treated with 10 ㎍ / mL of asialic acid;
negative control: untreated control group;
positive control: treatment group for induction of osteoblast;
low dose: treated with 1 ㎍ / mL of asialic acid; And
high dose: 10 ㎍ / mL of asiatic acid.
FIG. 3 shows the calcium accumulation effect of asialic acid:
negative: no treatment control;
positive: group treated with osteoblast-inducing stimulants;
low dose: treated with 1 ㎍ / mL of asialic acid; And
high dose: 10 ㎍ / mL of asiatic acid.
4 shows the effect of the asialic acid on the osteoblast differentiation markers:
egative: untreated control group;
positive: group treated with osteoblast-inducing stimulants;
low dose: treated with 1 ㎍ / mL of asialic acid; And
high dose: 10 ㎍ / mL of asiatic acid.
FIG. 5 is a view showing the effect of inducing osteogenic formation of asialic acid in an animal model.
Hereinafter, the present invention will be described in more detail.
The present invention provides a pharmaceutical composition for promoting bone regeneration comprising asiatic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
The asialic acid may be separated from Centella asiatica and used in combination.
The abovementioned acidic acid is a compound represented by the following formula (1).
[Chemical Formula 1]
The asialic acid induces differentiation of osteoblast-derived mesenchymal stem cells into osteoblasts, increases alkaline phosphatase (APL) activity in the process of differentiating into osteoblasts, It is desirable to increase expression of ColI alpha (collagen type I alpha), ALP, osteocalcin, and bone sialoprotein (BSP), which are known as cell differentiation markers.
It is preferable that the bone regeneration has bone regeneration effect on bone defect due to various bone tissue damage, fracture, bone damage, bone necrosis, osteoarthritis, osteoarthritis or osteoporosis as well as bone tissue and bone damage destroyed by periodontal disease.
In a specific example of the present invention, the inventors of the present invention conducted a study to determine the effect of inducing the proliferation of hAD-BMSC of the asialic acid into osteoblasts, from alveolar bone marrow aspirates (0.5-1.0 cc) As a result of treatment with asialic acid after obtaining leaf stem cells (hAD-BMSC), it was confirmed that asialic acid significantly induces osteoblast proliferation in a culture-dependent manner (see Fig. 1).
Furthermore, the present inventors have confirmed the effect of accelerating the bone differentiation ability of hAD-BMSC of asialic acid. As a result, the acidic acid increases the activity of basic alkaline phosphatase (APL) known as an indicator enzyme of bone cell activity (see FIG. 2 ), Increased calcium accumulation (see FIG. 3), increased expression of ColIα (Collagen type I α), ALP, OCN (osteocalcin) and BSP (bone sialoprotein) known as osteoblast differentiation markers It was confirmed that bone marrow differentiation ability of human alveolar bone marrow derived mesenchymal stem cells was significantly promoted.
Therefore, the asialic acid of the present invention can be used as a prophylactic or therapeutic agent for the treatment of osteoarthritis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, , And bone sialoprotein (BSP), the bone marrow-derived mesenchymal stem cells can be effectively used as an effective ingredient of a pharmaceutical composition for bone regeneration.
The present invention encompasses not only the asialic acid represented by the formula (1) but also its pharmaceutically acceptable salts, possible solvates, hydrates, racemates or stereoisomers thereof which can be prepared therefrom.
The acidic acid represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Sulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulphonate, naphthalene-1-sulphonate, , Naphthalene-2-sulfonate or mandelate.
The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving the asymmetric acid represented by the formula (1) in an excess amount of an acid aqueous solution, and then mixing the salt with a water-miscible organic solvent such as methanol, ethanol, Followed by precipitation using nitrile. It is also possible to prepare the mixture by evaporating a solvent or an excess acid in the mixture, or by suction filtration of the precipitated salt.
In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).
When the composition is formulated, it is prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are usually used.
Solid formulations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which may contain one or more excipients, such as one or more excipients, Starch, calcium carbonate, sucrose or lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .
Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.
The composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
Specifically, the effective amount of the compound according to the present invention may vary depending on the age, sex, and body weight of the patient. In general, 0.1 mg to 100 mg, preferably 0.5 mg to 10 mg per kg of body weight is administered daily or every other day Or one to three times a day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.
The present invention also provides a health food for promoting bone regeneration comprising asialic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
The asialic acid may be separated from Centella asiatica and used in combination.
The abovementioned acidic acid is a compound represented by the following formula (1).
[Chemical Formula 1]
The asialic acid induces differentiation of osteoblast-derived mesenchymal stem cells into osteoblasts, increases alkaline phosphatase (APL) activity in the process of differentiating into osteoblasts, It is desirable to increase expression of ColI alpha (collagen type I alpha), ALP, osteocalcin, and bone sialoprotein (BSP), which are known as cell differentiation markers.
It is preferable that the bone regeneration has bone regeneration effect on bone defect due to various bone tissue damage, fracture, bone damage, bone necrosis, osteoarthritis, osteoarthritis or osteoporosis as well as bone tissue and bone damage destroyed by periodontal disease.
In a specific example of the present invention, the inventors of the present invention conducted a study to determine the effect of inducing the proliferation of hAD-BMSC of the asialic acid into osteoblasts, from alveolar bone marrow aspirates (0.5-1.0 cc) As a result of treatment with asialic acid after obtaining leaf stem cells (hAD-BMSC), it was confirmed that asialic acid significantly induces osteoblast proliferation in a culture-dependent manner (see Fig. 1).
Furthermore, the present inventors have confirmed the effect of accelerating the bone differentiation ability of hAD-BMSC of asialic acid. As a result, the acidic acid increases the activity of basic alkaline phosphatase (APL) known as an indicator enzyme of bone cell activity (see FIG. 2 ), Increased calcium accumulation (see FIG. 3), increased expression of ColIα (Collagen type I α), ALP, OCN (osteocalcin) and BSP (bone sialoprotein) known as osteoblast differentiation markers It was confirmed that bone marrow differentiation ability of human alveolar bone marrow derived mesenchymal stem cells was significantly promoted.
Therefore, the asialic acid of the present invention can be used as a prophylactic or therapeutic agent for the treatment of osteoarthritis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, , And bone sialoprotein (BSP), the bone marrow-derived mesenchymal stem cells can be effectively used as an effective ingredient for bone regeneration health food.
There is no particular limitation on the type of food to which the acidic acid of the present invention is added. Examples of the foods to which the above substances can be added include dairy products including dairy products, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen and other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, all of which include health functional foods in a conventional sense.
The asialic acid of the present invention can be added intact to the food or can be used together with other food or food ingredients, and can be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health functional food may be 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
When the health food composition according to the present invention is a beverage composition, there are no particular restrictions on other components other than those containing the above-mentioned compounds as essential components in the indicated ratios, and various flavors or natural carbohydrates, ≪ / RTI > Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 10 g per 100 of the composition of the present invention.
In addition, the health food composition according to the present invention can be used as a nutritional supplement, a vitamin, a mineral (electrolyte), a flavoring agent such as a synthetic flavor agent and a natural flavor agent, a coloring agent and a thickening agent (cheese, chocolate etc.) Alginic acid and its salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like. In addition, it may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.
These components may be used independently or in combination. The proportion of such additives is not limited, but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the asialic acid of the present invention.
In addition, the present invention provides a bone grafting aid comprising asialic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
The asialic acid may be separated from Centella asiatica and used in combination.
The abovementioned acidic acid is a compound represented by the following formula (1).
[Chemical Formula 1]
The asialic acid induces differentiation of osteoblast-derived mesenchymal stem cells into osteoblasts, increases alkaline phosphatase (APL) activity in the process of differentiating into osteoblasts, It is desirable to increase expression of ColI alpha (collagen type I alpha), ALP, osteocalcin, and bone sialoprotein (BSP), which are known as cell differentiation markers.
The bone grafting aid is preferably used in combination with a bone grafting agent. The bone grafting agent may be an autograft obtained from the inside or outside of the patient's mouth, an allograft derived from the bone of another, Xenografts derived from other species such as calves, and synthetic plastiploids synthesized using synthetic materials.
In a specific example of the present invention, the present inventors found that when the deproteinized bovine bone (0CS-B), which is a bone graft material, was used together with the asialic acid of the present invention, the amount of bone regeneration was larger than that of the bone graft material alone, A large amount of bone was formed along the surface, and the new bone around the bone graft material was confirmed to be compatible with the graft material while being in close contact with the graft material.
Therefore, the asialic acid of the present invention shows an effect of increasing bone regeneration through bone grafting treatment, and thus can be used as a bone grafting aid.
Hereinafter, the present invention will be described in detail with reference to Examples, Experimental Examples and Preparation Examples.
However, the following Examples, Experimental Examples and Preparation Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples, Experimental Examples and Production Examples.
< Example 1> Origin of human alveolar bone marrow Intermediate lobe Human alveolar bone marrow mesenchymal stem cells; hAD - BMSC ) ≪ / RTI > Osteoblast Induction of differentiation
To obtain human alveolar bone marrow-derived mesenchymal stem cells (hAD-BMSC), alveolar bone marrow aspirates (0.5-1.0 cc) were injected into an osteotomy site during dental implant surgery using an 18-gauge needle syringe (Four patients aged 50 to 60 years). All patients were approved by the Clinical Research Ethics Committee at Wonkwang University School of Dentistry. hAD-BMSC was isolated and proliferated according to the method reported previously (Matsubara T, SK, Ishii M, Sugiyama M, Igarashi A, Oda R, Nishimura M, Saito M, Nakagawa K, Yamanaka K, Miyazaki K, Shimizu M , Bhawal UK, Tsuji K, Nakamura K, Kato Y., Alveolar bone marrow as a cell source for regenerative medicine: differences between alveolar and iliac bone marrow stromal cells. J Bone Miner Res, 2005. 20 (3): 399-409 .). The characteristics of the hAD-BMSC such as the morphology, surface markers and the ability to differentiate into osteoblasts have already been known, and the present inventors used 3-6 lineage cells. Specifically, in order to induce osteoblast differentiation, cells (about 90% confluence) were supplemented with 10 mM? -Glycerophosphate, 50 占 퐂 / mL ascorbic acid and 100 mM dexamethasone ) (Sigma Aldrich, St. Louis, Mo., USA). The culture medium and OS were also replaced every 2 days after the initial plating.
< Example 2> Statistical analysis
The experimental results are shown as mean ± mean error. Multiple comparisons were made using one-way analysis variance (ANOVA) followed by Dunnett's test. P values <0.05 and <0.01 were considered statistically significant.
< Experimental Example 1> Asiatic acid Confirming cell proliferation inducing effect
To confirm the effect of asiatic acid (Sigma Aldrich) on inducing proliferation of hAD-BMSC into osteoblasts, MTT assay was performed.
Specifically, hAD-BMSC was cultured in a 96-well culture medium at a concentration of 5 × 10 3 / well, cultured with an asialic acid treatment, and cultured for 1, 2, 3, 4 and 5 days And 20 μl of the MTT solution prepared at a concentration of 5 mg / ml was added to the cell culture medium to measure the absorbance. Then, light was blocked with foil, and the mixture was incubated for 4 hours at 37 ° C in a CO 2 incubator. After removing the culture solution, 200 μl of DMSO was added and dissolved, and the absorbance was measured at 590 nm.
As a result, as shown in Fig. 1, asiatic acid (1 and 10 占 퐂 / mL) was cultured more than the OS treated group of Example 1, which was a negative control and a positive control, (Fig. 1). As shown in Fig.
< Experimental Example 2> Asian acid hAD - BMSC Confirming the effect of promoting bone differentiation
<2-1> Asian acid APL (Alkaline 포스화제 ) And activity of calcium accumulation
In order to measure the differentiation effect of asialic acid from hAD-BMSC to osteoblast, activity and staining of intracellular ALP, known as an indicator enzyme of bone cell activity, were performed.
Specifically, ALP activity was measured by a conventionally reported method using p-nitrophenyl phosphate as a substrate 5 days after the OS treatment in Example 1 above. In addition, the asialic acid of the present invention (1 and 10 占 퐂 / mL) was also treated at the time of OS treatment. ALP activity was normalized to total protein content as measured by BCA protein assay (Pierce, Rockford, USA). The results were expressed as nmol / 30 min / mg (protein) and the experiment was repeated 4 times. In order to investigate ALP activity through histochemical analysis, cells were incubated with 0.1 mg / mL naphthol AS-MX phosphate (Sigma Aldrich) and 0.6 mg / mL fasteless Violet Elbitate (Sigma Aldrich) Fast Red Violet LB Salt) (Sigma Aldrich) and photographed with a digital camera (Nikon D80).
Calcium accumulation was also measured using Alizarin Red sulfate (AR-S) (Sigma Aldrich).
Specifically, hAD-BMSCs were continuously cultured in 24-well plates for 21 days with treatment with asialic acid (1 and 10 / / mL). Cells were then fixed with ice-cold 70% ethanol for 1 hour at 4 ° C, and ethanol was removed. Cells were then stained with 40 mM AR-S staining solution for 1 minute at room temperature. The stained cells were photographed with a digital camera (Nikon D80).
As a result, as shown in FIG. 2 and FIG. 3, the OS-treated cells showed strong ALP staining and showed strong ALP staining even in the cells treated with the asialic acid (1 and 10 / / mL) Respectively. In addition, it was confirmed that the ALP activity was significantly increased in the OS and the asialic acid (1 and 10 ㎍ / mL) -treated group compared to the non-treated control group (Fig. 2B). It was also found that the calcium accumulation was increased in the AR-S staining group treated with asialic acid (1 and 10 / / mL) as compared to the untreated control group (Fig. 3).
<2-2> Asian acid Osteoblast differentiation On the marker Check the effect on
After incubation of hAD-BMSC cells for 5 days in the presence or absence of OS and asiatic acid, the cells were incubated for 5 days with coli alpha (Collagen type I alpha), ALP, OCN (osteocalcin) and BSP (bone sialoprotein) The effect was confirmed.
Specifically, the asialic acid and the OS-treated hAD-BMSC were collected and homogenized in Trizol reagent, and then the organic layer and the aqueous solution layer were separated using chloroform. RNA was then recovered via isopropyl alcohol precipitation. The pellet was washed with ice-cold 70% ethanol and RNA concentration was calculated with Nano-drop 2000. Semi-quantitative PCR (RT-PCR) was performed using HiPi ™ one-step 5 × RT-PCR Premix (ELPIS, Korea) with GAPDH as a control. A primer set for each gene was designed and the annealing temperature for semi-quantitative PCR was determined. After amplification, the PCR products were separated by electrophoresis on a 1% (w / v) agarose gel stained with 0.5 μL / mL EtBr and images were obtained with a gel imaging system (red TM, Alpha Innotech, , And JPG file format. Then, the signal intensity of the captured image was quantified using Image J software (http://rsbweb.nih.gov/ij/). Relative density was determined by the signal intensities of ColI, ALP, OCN and BSP for GAPDH, and GAPDH was used to standardize the variation of all RNA amplification efficiencies. The primers used for the amplification are shown in Table 1 below.
As a result, as shown in Fig. 4, it was confirmed that the asialic acid of the present invention increased expression of ColI alpha, ALP, OCN and BSP, which are known as osteoblast differentiation markers (Fig. 4).
Therefore, it was confirmed that the asialic acid of the present invention promotes the bone differentiation ability of hAD-BMSC by increasing ALP activity and calcium accumulation and increasing expression of ColI alpha, ALP, OCN and BSP, which are known as osteoblast differentiation markers.
<
A total of two bone defects were formed in the skull of New Zealand white rabbits (n = 3) using a 5 mm diameter trephine burr.
As a result, as shown in Fig. 5, a dense connective tissue was formed in a group of only bone graft materials (Fig. 5A), and new bone was formed to some extent around the bone graft material (Fig. 5A) The use of asianic acid with bone graft material resulted in more bone regeneration than that of bone graft material alone. Large amount of bone graft was formed along the surface of bone graft material, and new bone around bone graft material was in close contact with the graft material (Fig. 5 (b)). In addition, Osteoblastic lining cells appeared not only around the bone graft material but also around the new bone, and it was confirmed that the bone marrow regeneration activity was significantly higher in the group using the Asian acid with the bone graft material (Fig. 5).
Hereinafter, production examples of each preparation according to the present invention will be illustrated. The following Preparation Examples are intended to aid the understanding of the practice of the present invention and do not imply that the process for preparing a formulation according to the present invention is limited to the following Preparation Examples.
< Manufacturing example 1> Manufacture of Pharmaceuticals
<1-1> Sanje Produce
Asiatic acid 10 mg
Sucrose 100 mg
Talc 10 mg
The above components are powdered and mixed, and filled in an airtight container to prepare a powder.
<1-2> Preparation of tablets
Asiatic acid 10 mg
Starch 100 mg
Sucrose 100 mg
The tablets are prepared by mixing the above components according to a conventional method for producing tablets and then tableting them.
≪ 1-3 > Preparation of capsules
Asiatic acid 10 mg
Lactose 15 mg
1 mg of magnesium stearate
The above components are mixed according to a conventional method for preparing a capsule, and then filled in a gelatin capsule to prepare a capsule.
<1-4> Preparation of Granules
Asiatic acid 10 mg
Soybean extract 50 mg
Glucose 200 mg
Starch 500 mg
After mixing the above components, 100 ml of 30% ethanol is added and the mixture is dried at 60 to form granules, and the granules are filled by filling the granules.
<1-5> Pennant Produce
Asiatic acid 10 mg
Lactose 1,500 mg
Glycerin 1,500 mg
Starch 980 mg
After mixing the above components, the mixture is prepared to be 4 g per one ring according to a conventional method for producing a pellet.
<1-6> Preparation of injections
Asiatic acid 10 mg
180 mg mannitol
Sterile sterilized water for injection 2,870 mg
Na 2 HPO 4 12 H 2 O 30 mg
(2 mL) per 1 ampoule according to a conventional injection preparation method.
<1-7> Liquid Produce
Asiatic acid 10 mg
10,000 mg per isomerization
Mannitol 5,000 mg
Purified water quantity
Dissolving the above components in purified water according to a usual liquid preparation method, adding an appropriate fragrance, filling the bottle and sterilizing it.
< Manufacturing example 2> Manufacturing of food
<2-1> Production of flour food
0.5 to 5.0 parts by weight of the asialic acid of the present invention was added to wheat flour, and the mixture was used to prepare bread, cake, cookies, crackers and noodles.
<2-2> soup And gravies
0.1 to 5.0 parts by weight of the asialic acid of the present invention was added to the soup and the juice to prepare a health improvement meat product, noodle soup and juice.
<2-3> Ground Beef Produce
10 parts by weight of the asialic acid of the present invention was added to ground beef to prepare ground beef for health promotion.
<2-4> Dairy products ( dairyproducts )
5 to 10 parts by weight of the asialic acid of the present invention was added to milk, and various dairy products such as butter and ice cream were prepared using the milk.
<2-5> Solar Produce
Brown rice, barley, glutinous rice, and yulmu were dried by a known method and dried, and the mixture was granulated to a powder having a particle size of 60 mesh.
Black soybeans, black sesame seeds, and perilla seeds were steamed and dried by a known method, and then they were prepared into powders having a particle size of 60 mesh by a grinder.
The asialic acid of the present invention was concentrated under reduced pressure in a vacuum concentrator, dried by spraying, and dried with a hot-air drier, and the dried product was pulverized to a size of 60 mesh with a pulverizer to obtain a dry powder.
The grains, seeds and the asialic acid of the present invention prepared above were blended in the following proportions.
(30 parts by weight of brown rice, 15 parts by weight of yulmu, 20 parts by weight of barley)
Seeds (7 parts by weight of perilla, 8 parts by weight of black beans, 7 parts by weight of black sesame seeds)
The asialic acid (3 parts by weight) of the present invention,
(0.5 part by weight),
(0.5 parts by weight)
< Manufacturing example 3> Manufacturing of beverage
<3-1> Health drink Produce
(5 g) of the present invention was homogeneously blended with a sub ingredient such as liquid fructose (0.5%), oligosaccharide (2%), sugar (2%), salt (0.5% And then packed in small containers such as glass bottles and plastic bottles.
<3-2> Preparation of vegetable juice
5 g of the asialic acid of the present invention was added to 1,000 ml of tomato or carrot juice to prepare vegetable juice.
<3-3> Production of fruit juice
1 g of the asialic acid of the present invention was added to 1,000 ml of apple or grape juice to prepare fruit juice.
<110> cooperation foundation wonkwang university <120> Pharmaceutical composition for increasing bone regeneration containing Acidic acid or pharmaceutically acceptable salts thereof as an active ingredient <130> p2015-149 <160> 10 <170> Kopatentin 1.71 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Collagen type I alpha sense primer <400> 1 ggacacaatg gattgcaagg 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Collagen type I alpha antisense primer <400> 2 taaccactgc tccactctgg 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ALP sense primer <400> 3 acgtggctaa gaatgtcatc 20 <210> 4 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> ALP antisense primer <400> 4 ctgctaggcg atgtcctta 19 <210> 5 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> OCN sense primer <400> 5 catgagagcc ctcaca 16 <210> 6 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> OCN antisense primer <400> 6 agagcgacac cctagac 17 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> BSP sense primer <400> 7 tggagatgac agttcagaag 20 <210> 8 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> BSP antisense primer <400> 8 gtactggtgc cgtttagc 18 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH sense primer <400> 9 gtcagtggtg gacctgacct 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH antisense primer <400> 10 aggggagatt cagtgtggtg 20
Claims (11)
[Chemical Formula 1]
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Citations (2)
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| JP5539224B2 (en) * | 2008-01-11 | 2014-07-02 | シャンハイ・インスティチュート・オブ・ファーマシューティカル・インダストリー（エスアイピーアイ） | Therapeutic formulations based on asiatic acid and selected salts thereof |
| KR101534395B1 (en) * | 2013-08-01 | 2015-07-09 | 서울대학교산학협력단 | A composition for preventing or treating bone disorders, comprising trapidil |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5539224B2 (en) * | 2008-01-11 | 2014-07-02 | シャンハイ・インスティチュート・オブ・ファーマシューティカル・インダストリー（エスアイピーアイ） | Therapeutic formulations based on asiatic acid and selected salts thereof |
| KR101534395B1 (en) * | 2013-08-01 | 2015-07-09 | 서울대학교산학협력단 | A composition for preventing or treating bone disorders, comprising trapidil |
Non-Patent Citations (1)
| Title |
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| Asiatic Acid Inhibits Adipogenic Differentiation of Bone Marrow Stromal Cells, Cell Biochem Biophys., 68(2), 437-442(2014.03.)* |
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