WO2010005123A1 - Composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic acid, a salt thereof, or a derivative thereof - Google Patents
Composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic acid, a salt thereof, or a derivative thereof Download PDFInfo
- Publication number
- WO2010005123A1 WO2010005123A1 PCT/KR2008/003985 KR2008003985W WO2010005123A1 WO 2010005123 A1 WO2010005123 A1 WO 2010005123A1 KR 2008003985 W KR2008003985 W KR 2008003985W WO 2010005123 A1 WO2010005123 A1 WO 2010005123A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- orotate
- composition
- acid
- composition according
- hyaluronic acid
- Prior art date
Links
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 title claims abstract description 100
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 53
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 53
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 53
- 229960005010 orotic acid Drugs 0.000 title claims abstract description 46
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 13
- 230000002708 enhancing effect Effects 0.000 title claims abstract description 7
- 229920002683 Glycosaminoglycan Polymers 0.000 title abstract description 29
- 150000003839 salts Chemical class 0.000 title abstract description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
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- 206010021198 ichthyosis Diseases 0.000 claims abstract description 9
- 231100000241 scar Toxicity 0.000 claims abstract description 9
- 230000009759 skin aging Effects 0.000 claims abstract description 9
- IMAGLCGCHKGGLR-UHFFFAOYSA-M Choline orotate Chemical compound C[N+](C)(C)CCO.[O-]C(=O)C1=CC(=O)NC(=O)N1 IMAGLCGCHKGGLR-UHFFFAOYSA-M 0.000 claims description 40
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- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
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- KYOBSHFOBAOFBF-XVFCMESISA-N orotidine 5'-phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1C(O)=O KYOBSHFOBAOFBF-XVFCMESISA-N 0.000 claims description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- KXWFMGMEXVNZFJ-VWMHFEHESA-N (2s)-2,5-diaminopentanoic acid;2,4-dioxo-1h-pyrimidine-6-carboxylic acid Chemical compound NCCC[C@H](N)C(O)=O.OC(=O)C1=CC(=O)NC(=O)N1 KXWFMGMEXVNZFJ-VWMHFEHESA-N 0.000 claims description 2
- FVGJURXBWORGKL-JEDNCBNOSA-N (2s)-2,6-diaminohexanoic acid;2,4-dioxo-1h-pyrimidine-6-carboxylic acid Chemical compound NCCCC[C@H](N)C(O)=O.OC(=O)C1=CC(=O)NC(=O)N1 FVGJURXBWORGKL-JEDNCBNOSA-N 0.000 claims description 2
- QXWPJYVLNHANJZ-LJTMIZJLSA-N 2,4-dioxo-1h-pyrimidine-6-carboxylic acid;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound OC(=O)C1=CC(=O)NC(=O)N1.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO QXWPJYVLNHANJZ-LJTMIZJLSA-N 0.000 claims description 2
- ROOICMQQLCQCBE-UHFFFAOYSA-N 2-[carbamimidoyl(methyl)amino]acetic acid;2,4-dioxo-1h-pyrimidine-6-carboxylic acid Chemical compound NC(=N)N(C)CC(O)=O.OC(=O)C1=CC(=O)NC(=O)N1 ROOICMQQLCQCBE-UHFFFAOYSA-N 0.000 claims description 2
- VOTPLFCPIRIALF-UHFFFAOYSA-N 3-(2,4-dioxo-1h-pyrimidine-6-carbonyl)oxy-4-(trimethylazaniumyl)butanoate Chemical compound C[N+](C)(C)CC(CC([O-])=O)OC(=O)C1=CC(=O)NC(=O)N1 VOTPLFCPIRIALF-UHFFFAOYSA-N 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
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- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
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- 229910017052 cobalt Inorganic materials 0.000 claims description 2
- 239000010941 cobalt Substances 0.000 claims description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- UFIVEPVSAGBUSI-UHFFFAOYSA-N dihydroorotic acid Chemical compound OC(=O)C1CC(=O)NC(=O)N1 UFIVEPVSAGBUSI-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
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- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
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- FKCRAVPPBFWEJD-UHFFFAOYSA-N orotidine Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1C(O)=O FKCRAVPPBFWEJD-UHFFFAOYSA-N 0.000 claims description 2
- FKCRAVPPBFWEJD-XVFCMESISA-N orotidine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1C(O)=O FKCRAVPPBFWEJD-XVFCMESISA-N 0.000 claims description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
Definitions
- HYALURONIC ACID OR GLYCOSAMINOGLYCAN COMPRISING OROTIC ACID, A SALT THEREOF, OR A
- the present invention relates to a composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic acid, a salt thereof, or a derivative thereof. More specifically, the present invention relates to a composition for preventing, treating or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis, xeroderma, etc. comprising orotic acid, a salt thereof, or a derivative thereof.
- Glycosaminoglycan is a polysaccharide containing amino sugars, of which examples include hyaluronic acid, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate and dermatan sulfate.
- Hyaluronic acid and glycosaminoglycan are biopolymers naturally occurring in all organisms, and a human body includes 56% of them in the skin, 35% in the muscular tissue, and 9% in the joint fluid and spinal fluid, etc. They play an important role in maintaining the phenomena of life.
- one molecule of hyaluronic acid binds to 218 molecules of water to exhibit viscosity and elasticity at the same time, which performs various functions such as cushioning and lubricating in the skin muscle and joint.
- hyaluronic acid binds to various cell receptors such as CD44 and RHAMM to regulate the phenomena of life via cell differentiation, proliferation, and intercellular communication.
- a human body maintains a certain amount of hyaluronic acid and glycosaminoglycan by rapid metabolism that more than 3g per day are degraded in the process of removing reactive oxygen species produced by UV, inflammation, etc. and biosynthesized again, but their production rates are gradually decreased with aging. As the production rate becomes less than the degradation rate, the skin loses its elasticity and forms wrinkles, and the cushioning and lubricating do not function properly in the joint, etc., so that degenerative diseases that the cartilage is gradually destructed and abrased are continuously aggravated.
- Hyaluronic acid and glycosaminoglycan are being safely used using their phys- iochemical properties in various medical applications such as a juvantia for maintaining eyeball shape during cataract surgery, an anti-adhesion barrier after surgery, an injection for removing wrinkles, a wound healing agent, a carrier for sustained release formulations or cellular therapeutic agents, an ophthalmic agent for treating scheroma or ophthalmic diseases, a treating agent for interstitial cystitis or gum diseases, and a cell proliferation scaffold in tissue engineering, as well as cosmetic applications such as a skin moisturizing agent.
- hyaluronic acid is being recently used in functional food applications for skin moisturizing or preventing hyaluronic acid related diseases.
- injected hyaluronic acid has a half-life of 12 hours in the body and does not exhibit its medicinal effects directly.
- Hyaluronic acid is injected into the joint cavity once a week for 5 weeks to stimulate type B synovial cells of joint synovium and increase the biosynthesis of hyaluronic acid, so that the amount of hyaluronic acid in the joint returns to the healthy state, but within 1 year after the treatment the production of hyaluronic acid is slowly decreased and the symptoms of arthritis recur.
- orotic acid was used in a drug for alleviating orotic aciduria since it is converted into orotic acid 5 '-phosphate in the body by catalytic action of orotic acid kinase, which is useful for deficiency of enzyme, pyrimidine nucleotide or nucleic acid[MATINDALE, 1989, 1627].
- orotic acid, a salt thereof, or a derivative thereof has an effect of promoting biosynthesis of hyaluronic acid or glycosaminoglycan in chondrocyte cells, fibroblast cells, synovial cells, corneal epithelial cells, keratocyte cells, etc., to complete the present invention.
- An object of the present invention is, therefore, to provide a composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic acid, a salt thereof, or a derivative thereof.
- Another object of the present invention is to provide a composition for preventing, treating or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis or xeroderma comprising orotic acid, a salt thereof, or a derivative thereof.
- the present invention relates to a composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic acid, a salt thereof, or a derivative thereof represented by the following formula (I).
- R is hydrogen, metal ion, ammonium ion, protonated basic amino acid, nontoxic water soluble positive ion having molecular weight of less than 1,000 daltons, C -C
- (I) includes orotic acid, metal ion(sodium, potassium, calcium, magnesium, zinc, manganese, selenium, chromium, lithium, copper, cobalt or iron ion) of orotic acid, ammonium ion of orotic acid, choline orotate, creatine orotate, carnitine orotate, arginine orotate, methylglucamine orotate, ornithine orotate, lysine orotate, chitosan orotate, chitosan oligo orotate, polylysine orotate, orotidylate(orotidine monophosphate), orotidine, dihydroorotic acid, etc., preferably orotic acid and choline orotate, but is not lmited thereto.
- (I) can be obtained by extraction from natural products or chemical synthesis using well known processes in the art.
- the present invention uses orotic acid, a salt thereof, or a derivative thereof which has good cellular uptake property to provide a new composition for promoting biosynthesis of hyaluronic acid or glycosaminoglycan.
- the present invention is based on the facts that since there is a rate-determing step in the cellular biosynthesis mechanism of hyaluronic acid or glycosaminoglycan, and activity of an enzyme associated with the biosynthesis step determines production amount of hyaluronic acid or glycosaminoglycan, the amount of hyaluronic acid or glycosaminoglycan in the body can be promptly increased using a material to facilitate the enzyme activity.
- composition comprising orotic acid, a salt thereof, or a derivative thereof according to the present invention can be used for preventing, treating or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis or xeroderma, etc. which can be caused by decline of production and hypofunction of hyaluronic acid or glycosaminoglycan.
- arthritis includes degenerative arthritis, osteoarthritis and rheumatoid arthritis caused by aging, and means inflammatory disease of joint caused by production deficiency or degradation of hyaluronic acid or glycosaminoglycan in the joint cavity.
- gingivitis includes gingivitis, gum wound, etc. It was reported that hyaluronic acid was effective in the treatment of periodontium and gum diseases[J. Clin. Periodontal. 2003, 30(2): 159-64].
- interstitial cystitis means disease involving lesion or inflammation on epithelial cells in the bladder and resulting in dysuria or pain. It was reported that hyaluronic acid or glycosaminoglycan was applied to the lesions to exhibit a significant treating effect[Scan. J. Urol. Nephrol. 2005, 39(2), 143-147)].
- Hyaluronic acid directly used shows its activities locally, while the present composition has various administration routes and can increase hyaluronic acid or glycosaminoglycan systemically as a safe treatment showing rapid effects.
- the present composition can be used in a variety of fields such as medicines, functional foods, cosmetics, toothpastes and gargles.
- the pharmaceutical composition according to the present invention can be administered orally, e.g., ingestion or inhalation; or parenterally, e.g., injection, deposition, implantation or suppositories.
- the injection can be, for example, intravenous, intradermal, subcutaneous, intramuscular or intraperitoneal.
- the pharmaceutical composition of the present invention may be formulated as tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injection solutions, emulsions, suspensions, syrups, aerosols, etc.
- composition of the present invention can be prepared in a manner well known in the art using a pharmaceutically acceptable carrier(s) which are usually used for each form.
- pharmaceutically acceptable carriers include excipient, filler, expander, binder, disintegrator, lubricant, preservative, antioxidant, isotonic agent, buffer, coating agent, sweetening agent, dissolvent, base, dispersing agent, wetting agent, suspending agent, stabilizer, colorant, aromatic, etc.
- the pharmaceutical composition of the present invention contains 0.01 to 100 wt% of orotic acid, a salt thereof, or a derivative thereof depending on the form thereof.
- the specific dosage of the present pharmaceutical composition can be varied with species of mammals including a human-being, route of administration, body weight, gender, age, severity of disease, judgment of doctor, etc. It is preferable that 0.01 to 50 mg of the active ingredient is administered per kg of body weight a day for oral use, while 0.01 to 10 mg of the active ingredient is administered per kg of body weight a day for parenteral use.
- the total daily dosage can be administered once or over several times depending on the severity of disease, judgment of doctor, etc.
- the functional food according to the present invention can be used for preventing or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis or xeroderma, etc.
- the term "functional food” as used herein means food which an active ingredient(s) is added to improve functionality of ordinary food, and can be prepared by adding an active ingredient(s) to ordinary food or in a form of capsule, powder, suspension, etc.
- orotic acid, a salt thereof, or a derivative thereof is used as a food additive according to the present invention, it can be added as it is or together with other food ingredients in a manner well known in the art.
- the mixed amount of the active ingredient can be determined depending on the purpose of use(preventing or improving).
- Orotic acid, a salt thereof, or a derivative thereof is generally added in an amount of 0.0001 to 10 wt%, preferably 0.1 to 5 wt% based on the total amount of raw materials. However, the amount can be decreased below the above- specified range if prolonged intake is desired.
- the functional food according to the present invention includes meats, sausages, breads, chocolates, candies, snacks, cakes, pizzas, ramens, noodles, gums, dairy products including ice creams, soups, beverages, teas, drinks, alcoholic beverages, vitamin complexes, etc.
- the functional food according to the present invention includes extracts, teas, juices, jellys, etc. comprising orotic acid, a salt thereof, or a derivative thereof as a main ingredient.
- the functional food according to the present invention in the form of capsule, powder, suspension, etc. can be prepared in a manner well known in the art using a sitologically acceptable carrier(s) which are usually used for each form.
- the functional food of the present invention in the form of capsule, powder, suspension, etc. contains 0.001 to 100 wt% of orotic acid, a salt thereof, or a derivative thereof depending on the form thereof.
- orotic acid, a salt thereof, or a derivative thereof is used as a cosmetic ingredient according to the present invention, it can be added as it is or together with other cosmetic ingredients in a manner well known in the art.
- the mixed amount of the active ingredient can be determined depending on the purpose of use.
- Orotic acid, a salt thereof, or a derivative thereof is generally added in an amount of 0.0001 to 10 wt%, preferably 0.1 to 5 wt% based on the total amount of raw materials.
- the examples of cosmetics include toners, lotions, creams, packs and makeups, etc.
- Orotic acid, a salt thereof, or a derivative thereof is used as an oral cleaner such as toothpaste or gargle according to the present invention, it can be added as it is or together with other ingredients in a manner well known in the art.
- the mixed amount of the active ingredient can be determined depending on the purpose of use.
- Orotic acid, a salt thereof, or a derivative thereof is generally added in an amount of 0.0001 to 10 wt%, preferably 0.1 to 5 wt% based on the total amount of raw materials.
- orotic acid, a salt thereof, or a derivative thereof has a superior effect of promoting biosynthesis of hyaluronic acid or gly- cosaminoglycan in chondrocyte cells, fibroblast cells, synovial cells, corneal epithelial cells, keratocyte cells, etc.
- Orotic acid, a salt thereof, or a derivative thereof therefore, can be used for preventing, treating or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis, xeroderma, etc. which can be caused by decline of production and hypofunction of hyaluronic acid or glycosaminoglycan.
- Figure 1 is a graph illustrating increase of hyarulonic acid production by orotic acid in chondrocyte cells, synovial cells and fibroblast cells(NIH3T3).
- Figure 2 is a graph showing restoration of goblet cells after treating choline orotate in an animal model with scheroma, as compared to a positive control group.
- Figure 3 is a tissue staining photograph illustrating restoration of goblet cells after treating choline orotate in an animal model with scheroma, as compared to before treating choline orotate.
- Figure 4 is a graph showing change of tear secretion amount after dropping choline orotate in the eyes of an animal model with scheroma, as compared to a control group.
- Figure 5 is a graph showing change of tear secretion amount after orally administering choline orotate to an animal model with scheroma, as compared to a control group. Best Mode for Carrying out the Invention
- Example 1 Effect of orotic acid on production of hyaluronic acid in chondrocyte cells
- Cartilage tissues were isolated from a 3-4 week old rabbit in an aseptic condition, treated with 0.2% collagenase type II at 37 0 C for 4 hours, and filtered with a lOOum filter to give chondrocyte cells.
- the obtained cells were replaced with a chondrocyte medium(DMEM/F12, 10% FBS, insulin, nonessential amino acid, ascorbic acid, penicillin, Gibco BRL product) every other day at 37 0 C in 5% CO .
- chondrocyte cells were mixed with 1.5% alginate solution in 2x10 cells/ml, and the resulting mixture was dropped into 102mM CaCl solution(pH7.4) using a syringe to give chondrocyte-beads, which were washed with 0.15M NaCl.
- the beads were replaced with a chondrocyte medium(DMEM/F12, nonessential amino acid, ascorbic acid, penicillin, Gibco BRL product) adding orotic acid every other day at 37 0 C in 5% CO 2.
- the beads were cultured in a chondrocyte medium with the addition of orotic acid for 2 weeks, they were washed with phosphate buffer saline(PBS). The beads were recovered, treated with a solution of 55mM sodium citrate, 3OmM EDTA and 15OmM sodium chloride(pH6.8) at 4 0 C for 10 ⁇ 15min, and then reacted overnight with 20ug/ml of papain dissolved in a solution of 0.1 M sodium acetate, 5OmM sodium EDTA and 5mM L-cysteine hydrochloride(pH5.53) at 56 ⁇ 60°C. The beads were heated for lOmin for enzyme inhibition, and the resulting samples were kept at -2O 0 C until the assay.
- PBS phosphate buffer saline
- HA binding protein(HABP) was coated on a 96-well plate at 4 0 C overnight and blocked with 1% bovine serum albumin(BSA). The samples were bound at 37 0 C for 60min and washed with 0.5% phosphate buffer saline. Biotin-HABP was bound at room temperature for 60min and extra-avidin alkaline phosphatase was added. Then, the samples were colored with p-nitrophenyl-phosphate(PNPP), and the color reaction was inhibited by 3N-NaOH. The absorbance was measured at 405nm and the obtained results are given in Fig. 1.
- BSA bovine serum albumin
- Example 2 Effect of orotic acid on production of hyaluronic acid in synovial cells
- Example 3 Effect of orotic acid on production of hyaluronic acid in fibroblast cells(NIH3T3)
- fibroblast cells were cultured in Dulbecco's modified Eagle's medium(DMEM) containing 10% fetal bovine serum(FBS), added to a 24-well plate in 2x10 cells/well, and subcultured. Next day, the cells were replaced with DMEM containing 5% FBS and orotic acid was added. Afterwards, the cells were cultured at 37 0 C for 3 days and then total amount of hyaluronic acid in the medium was measured at 405nm by sandwich ELIZA method using HA binding protein(HABP) and HA binding protein-biotin. Hyaluronic acid(SIGMA H) was used as a standard. The obtained results are illustrated in Fig. 1.
- DMEM Dulbecco's modified Eagle's medium
- FBS fetal bovine serum
- Example 4 Isolation of keratocyte cells and corneal epithelial cells
- Corneal tissues were cleared by removing blood vessels, etc. The cleared tissues were washed with 5% antibiotic-PBS, added to 3ml of IX trypsin(0.05%)/EDTA(0.01%), and subjected to shaking incubation at 37 0 C for 80min.
- the collected suspension was washed with a SHEM medium(10% FBS in DMEM/ F12(l:l) + 0.5% PS(penicillin and streptomycin) + 4mM L-glutamine + 10ng/ml EGF (epidermal growth factor) + 5ug/ml insulin + 30ng/ml choleratoxin + 0.18mM adenine + 2nM 3,3',5-triiodo-L-thyromine sodium salt + 0.4ug/ml hydrocortisone) and centrifuged at l,200rpm for 5min. The separated cells were used as epithelium, and the remaining tissues were incubated at 37 0 C for 2 hours after adding 1.2U/ml dispase II.
- SHEM medium 10% FBS in DMEM/ F12(l:l) + 0.5% PS(penicillin and streptomycin) + 4mM L-glutamine + 10ng/ml EGF (epidermal growth factor) + 5ug
- the tissues were treated with 5ml of 200U/ml type I collagenase and subjected to shaking incubation at 37 0 C.
- the collected suspension was washed with a culture medium(10% FBS in DMEM/F12(1:1) + 1% PS), centrifuged at l,200rpm for 5min, and plated on a dish.
- Example 5 Effect of choline orotate on production of hyaluronic acid in keratocyte cells
- Keratocyte cells were treated with choline orotate(0uM ⁇ 10uM) and stimulated for 48 hours. Then, lOOul of the cell culture was reacted with lOOul of b- HABP(biotin-hyaluonic acid binding protein, 50ng/ml) at room temperature for 1 hour.
- 96-well plate which was kept in a refrigerator for 24 hours and washed with a standard assay buffer(SAB) three times. Then, 1% BSA was added to the 96-well plate, reacted at room temperature for 90min, and washed with SAB three times to give a HA coated plate.
- SAB standard assay buffer
- Keratocyte cells were treated with choline orotate(0uM ⁇ 10uM) and stimulated for 48 hours. Then, the cell culture was taken and the amount of glycosaminoglycan was measured at 550nm using a Biocolor assay kit. As shown in the following Table 2, it was verified that the keratocyte cells treated with choline orotate promoted production of glycosaminoglycan in a concentration-dependent manner.
- Example 7 Effect of choline orotate on production of hyaluronic acid in corneal epithelial cells
- Corneal epithelial cells were treated with choline orotate(0uM ⁇ 10uM) and stimulated for 48 hours. Then, lOOul of the cell culture was reacted with lOOul of b- HABP(biotin-hyaluonic acid binding protein, 50ng/ml) at room temperature for 1 hour.
- HA 20ug/ml, 2OmM Na CO solution was added to a 96-well plate, which was kept in a refrigerator for 24 hours and washed with a standard assay buffer(SAB) three times. Then, 1% BSA was added to the 96-well plate, reacted at room temperature for 90min, and washed with SAB three times to give a HA coated plate.
- SAB standard assay buffer
- Example 8 Effect of choline orotate on production of glycosaminoglycan in corneal epithelial cells
- Corneal epithelial cells were treated with choline orotate(0uM ⁇ 10uM) and stimulated for 48 hours. Then, the cell culture was taken and the amount of glycosaminoglycan was measured at 550nm using a Biocolor assay kit. As shown in the following Table 4, it was verified that the corneal epithelial cells treated with choline orotate promoted production of glycosaminoglycan in a concentration-dependent manner.
- Example 9 Effect of choline orotate on healing wounds
- Human keratinocyte cells(HaCaT) were sufficiently cultured in Dulbecco's Modified Eagle's Medium(DMEM) containing 10% fetal bovine serum(FBS) in a 6-well plate. Wounds 50um wide were made with 25 G7/8 injection needle. The separated parts formed around the wounds were photographed with a camera attached to a microscope. The wounds were separated to a control group and a trial group, and the trial group was treated with lOuM of choline orotate. Then, the movement of cells in the wounded parts was observed for 72 hours. Closure rates of the wounds were represented in percentage compared to the control group. It was confirmed that the group treated with choline orotate has significant wound healing effects over 30%.
- Example 10 Effect of choline orotate on improving scheroma and ophthalmic diseases
- impression cytology was performed to evaluate improvement of scheroma and ophthalmic diseases.
- Fig. 2 it was confirmed that the eye drops using choline orotate significantly restored goblet cells over 80% of the initial value in the impression cytology, as compared to the positive control group and the control group.
- impression cytology tissue staining illustrated restoration of impression cytology cells after treating choline orotate, as compared to before treating choline orotate.
- Example 11 Effect of instillation of choline orotate on tear secretion amount in mouse model with scheroma induced by Botox
- phenol red thread test (30sec) was performed on 26 B6 mice to measure their tear secretion amount. Then, the mice were anesthetized and 2OmU(O. ImI) of botulinum toxin(Botox) was injected to their both eyes. On the third day, Botox boosting was performed. On the 7 day, the decrease of the tear secretion amount was confirmed, and then eye drops comprising 5% choline orotate were dropped into the right eye four times a day and a saline solution was dropped into the left eye two times a day. On 0 , 8 , 14 , 23 and 30 days phenol red thread test was carried out without anesthesia.
- Fig. 4 shows change of the tear secretion amount of the choline orotate instillation group, as compared to the control group. As shown in Fig. 4, it was confirmed that the tear secretion amount was increased by choline orotate.
- Example 12 Effect of oral administration of choline orotate on tear secretion amount in mouse model with scheroma induced by Botox
- phenol red thread test (30sec) was performed on 26 B6 mice to measure their tear secretion amount. Then, the mice were anesthetized and 2OmU(O. ImI) of botulinum toxin(Botox) was injected to their both eyes. On the third day, Botox boosting was performed. On the 7 day, the decrease of the tear secretion amount was confirmed, and then 800mg/kg of choline orotate was orally administered to a trial group and a saline solution was administered to a control group. On 0 , 8 , 19 ' , 22 and 28 days phenol red thread test was carried out without anesthesia.
- Fig. 5 shows change of the tear secretion amount of the choline orotate oral administration group, as compared to the control group. As shown in Fig. 5, it was confirmed that the tear secretion amount was increased by choline orotate.
Abstract
The present invention relates to a composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic acid, a salt thereof, or a derivative thereof. The composition comprising orotic acid, a salt thereof, or a derivative thereof according to the present invention can be used for preventing, treating or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis or xeroderma, etc. which can be caused by decline of production and hypofunction of hyaluronic acid or glycosaminoglycan.
Description
Description COMPOSITION FOR ENHANCING BIOSYNTHESIS OF
HYALURONIC ACID OR GLYCOSAMINOGLYCAN COMPRISING OROTIC ACID, A SALT THEREOF, OR A
DERIVATIVE THEREOF Technical Field
[1] The present invention relates to a composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic acid, a salt thereof, or a derivative thereof. More specifically, the present invention relates to a composition for preventing, treating or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis, xeroderma, etc. comprising orotic acid, a salt thereof, or a derivative thereof. Background Art
[2] Glycosaminoglycan is a polysaccharide containing amino sugars, of which examples include hyaluronic acid, chondroitin sulfate, keratan sulfate, heparin, heparan sulfate and dermatan sulfate.
[3] Hyaluronic acid and glycosaminoglycan are biopolymers naturally occurring in all organisms, and a human body includes 56% of them in the skin, 35% in the muscular tissue, and 9% in the joint fluid and spinal fluid, etc. They play an important role in maintaining the phenomena of life. In particular, one molecule of hyaluronic acid binds to 218 molecules of water to exhibit viscosity and elasticity at the same time, which performs various functions such as cushioning and lubricating in the skin muscle and joint. Also, hyaluronic acid binds to various cell receptors such as CD44 and RHAMM to regulate the phenomena of life via cell differentiation, proliferation, and intercellular communication.
[4] A human body maintains a certain amount of hyaluronic acid and glycosaminoglycan by rapid metabolism that more than 3g per day are degraded in the process of removing reactive oxygen species produced by UV, inflammation, etc. and biosynthesized again, but their production rates are gradually decreased with aging. As the production rate becomes less than the degradation rate, the skin loses its elasticity and forms wrinkles, and the cushioning and lubricating do not function properly in the joint, etc., so that degenerative diseases that the cartilage is gradually destructed and abrased are continuously aggravated.
[5] Hyaluronic acid and glycosaminoglycan are being safely used using their phys-
iochemical properties in various medical applications such as a juvantia for maintaining eyeball shape during cataract surgery, an anti-adhesion barrier after surgery, an injection for removing wrinkles, a wound healing agent, a carrier for sustained release formulations or cellular therapeutic agents, an ophthalmic agent for treating scheroma or ophthalmic diseases, a treating agent for interstitial cystitis or gum diseases, and a cell proliferation scaffold in tissue engineering, as well as cosmetic applications such as a skin moisturizing agent. Also, hyaluronic acid is being recently used in functional food applications for skin moisturizing or preventing hyaluronic acid related diseases.
[6] Moreover, effects of hyaluronic acid on arthritis, which alleviate pain, eliminate inflammation, prevent destruction of cartilage tissues, or increase activity through a lubricating function, were clinically proved. Furthermore, it was recently reported that if hyaluronic acid is administered for a long time cartilage is regenerated through proliferation of chondrocytes and enhanced synthesis of cartilage matrix.
[7] However, injected hyaluronic acid has a half-life of 12 hours in the body and does not exhibit its medicinal effects directly. Hyaluronic acid is injected into the joint cavity once a week for 5 weeks to stimulate type B synovial cells of joint synovium and increase the biosynthesis of hyaluronic acid, so that the amount of hyaluronic acid in the joint returns to the healthy state, but within 1 year after the treatment the production of hyaluronic acid is slowly decreased and the symptoms of arthritis recur.
[8] Furthermore, since long-term treatment is necessary for diseases due to decline of production and hypofunction of hyaluronic acid and glycosaminoglycan, there is a need in the art for the development of an effective drug which has no side effect and can be administered for a long time.
[9] With regard to pharmacological effects of orotic acid, it was reported that orotic acid was used in a drug for alleviating orotic aciduria since it is converted into orotic acid 5 '-phosphate in the body by catalytic action of orotic acid kinase, which is useful for deficiency of enzyme, pyrimidine nucleotide or nucleic acid[MATINDALE, 1989, 1627].
Disclosure of Invention Technical Problem
[10] The present inventors discovered that orotic acid, a salt thereof, or a derivative thereof has an effect of promoting biosynthesis of hyaluronic acid or glycosaminoglycan in chondrocyte cells, fibroblast cells, synovial cells, corneal epithelial cells, keratocyte cells, etc., to complete the present invention.
[11] An object of the present invention is, therefore, to provide a composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic
acid, a salt thereof, or a derivative thereof. [12] Another object of the present invention is to provide a composition for preventing, treating or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis or xeroderma comprising orotic acid, a salt thereof, or a derivative thereof.
Technical Solution [13] The present invention relates to a composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic acid, a salt thereof, or a derivative thereof represented by the following formula (I).
(I)
[15] wherein,
[16] R is hydrogen, metal ion, ammonium ion, protonated basic amino acid, nontoxic water soluble positive ion having molecular weight of less than 1,000 daltons, C -C
20 alkyl, C 1-C 20 alkenyl, or C 1 -C 20 alkoxy.
[17] Orotic acid, a salt thereof, or a derivative thereof represented by the above formula
(I) includes orotic acid, metal ion(sodium, potassium, calcium, magnesium, zinc, manganese, selenium, chromium, lithium, copper, cobalt or iron ion) of orotic acid, ammonium ion of orotic acid, choline orotate, creatine orotate, carnitine orotate, arginine orotate, methylglucamine orotate, ornithine orotate, lysine orotate, chitosan orotate, chitosan oligo orotate, polylysine orotate, orotidylate(orotidine monophosphate), orotidine, dihydroorotic acid, etc., preferably orotic acid and choline orotate, but is not lmited thereto.
[18] Orotic acid, a salt thereof, or a derivative thereof represented by the above formula
(I) can be obtained by extraction from natural products or chemical synthesis using well known processes in the art.
[19]
[20] Based on the facts that cells can restore decline of production capability of hyaluronic acid or glycosaminoglycan with aging for themselves for a certain period by injection of exogenous hyaluronic acid, the present invention uses orotic acid, a salt thereof, or a derivative thereof which has good cellular uptake property to provide a new composition for promoting biosynthesis of hyaluronic acid or glycosaminoglycan. The present invention is based on the facts that since there is a rate-determing step in
the cellular biosynthesis mechanism of hyaluronic acid or glycosaminoglycan, and activity of an enzyme associated with the biosynthesis step determines production amount of hyaluronic acid or glycosaminoglycan, the amount of hyaluronic acid or glycosaminoglycan in the body can be promptly increased using a material to facilitate the enzyme activity.
[21]
[22] Therefore, the composition comprising orotic acid, a salt thereof, or a derivative thereof according to the present invention can be used for preventing, treating or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis or xeroderma, etc. which can be caused by decline of production and hypofunction of hyaluronic acid or glycosaminoglycan.
[23] The term "arthritis" as used herein includes degenerative arthritis, osteoarthritis and rheumatoid arthritis caused by aging, and means inflammatory disease of joint caused by production deficiency or degradation of hyaluronic acid or glycosaminoglycan in the joint cavity.
[24] The term "gum diseases" as used herein includes periodontitis, gingivitis, gum wound, etc. It was reported that hyaluronic acid was effective in the treatment of periodontium and gum diseases[J. Clin. Periodontal. 2003, 30(2): 159-64].
[25] The terms "scheroma" and "ophthalmic diseases" as used herein include diseases caused by lack of tear, hormonal disorder, aging etc., diseases due to injury by LASIK surgery, cataract surgery or glaucoma surgery, and diseases such as conjunctivitis and keratitis.
[26] The term "interstitial cystitis" as used herein means disease involving lesion or inflammation on epithelial cells in the bladder and resulting in dysuria or pain. It was reported that hyaluronic acid or glycosaminoglycan was applied to the lesions to exhibit a significant treating effect[Scan. J. Urol. Nephrol. 2005, 39(2), 143-147)].
[27] Hyaluronic acid directly used shows its activities locally, while the present composition has various administration routes and can increase hyaluronic acid or glycosaminoglycan systemically as a safe treatment showing rapid effects.
[28] Therefore, the present composition can be used in a variety of fields such as medicines, functional foods, cosmetics, toothpastes and gargles.
[29]
[30] The pharmaceutical composition according to the present invention can be administered orally, e.g., ingestion or inhalation; or parenterally, e.g., injection, deposition, implantation or suppositories. The injection can be, for example, intravenous, intradermal, subcutaneous, intramuscular or intraperitoneal. Depending on the route of administration, the pharmaceutical composition of the present invention
may be formulated as tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injection solutions, emulsions, suspensions, syrups, aerosols, etc. The above various forms of the pharmaceutical composition of the present invention can be prepared in a manner well known in the art using a pharmaceutically acceptable carrier(s) which are usually used for each form. Examples of the pharmaceutically acceptable carriers include excipient, filler, expander, binder, disintegrator, lubricant, preservative, antioxidant, isotonic agent, buffer, coating agent, sweetening agent, dissolvent, base, dispersing agent, wetting agent, suspending agent, stabilizer, colorant, aromatic, etc.
[31] The pharmaceutical composition of the present invention contains 0.01 to 100 wt% of orotic acid, a salt thereof, or a derivative thereof depending on the form thereof.
[32] The specific dosage of the present pharmaceutical composition can be varied with species of mammals including a human-being, route of administration, body weight, gender, age, severity of disease, judgment of doctor, etc. It is preferable that 0.01 to 50 mg of the active ingredient is administered per kg of body weight a day for oral use, while 0.01 to 10 mg of the active ingredient is administered per kg of body weight a day for parenteral use. The total daily dosage can be administered once or over several times depending on the severity of disease, judgment of doctor, etc.
[33]
[34] On the other hand, the functional food according to the present invention can be used for preventing or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis or xeroderma, etc.
[35] The term "functional food" as used herein means food which an active ingredient(s) is added to improve functionality of ordinary food, and can be prepared by adding an active ingredient(s) to ordinary food or in a form of capsule, powder, suspension, etc.
[36] Where orotic acid, a salt thereof, or a derivative thereof is used as a food additive according to the present invention, it can be added as it is or together with other food ingredients in a manner well known in the art. The mixed amount of the active ingredient can be determined depending on the purpose of use(preventing or improving). Orotic acid, a salt thereof, or a derivative thereof is generally added in an amount of 0.0001 to 10 wt%, preferably 0.1 to 5 wt% based on the total amount of raw materials. However, the amount can be decreased below the above- specified range if prolonged intake is desired.
[37] There is no particular limit to the kinds of the functional food according to the present invention. The examples of food to which orotic acid, a salt thereof, or a derivative thereof can be added include meats, sausages, breads, chocolates, candies, snacks, cakes, pizzas, ramens, noodles, gums, dairy products including ice creams,
soups, beverages, teas, drinks, alcoholic beverages, vitamin complexes, etc. Specifically, the functional food according to the present invention includes extracts, teas, juices, jellys, etc. comprising orotic acid, a salt thereof, or a derivative thereof as a main ingredient.
[38] The functional food according to the present invention in the form of capsule, powder, suspension, etc. can be prepared in a manner well known in the art using a sitologically acceptable carrier(s) which are usually used for each form. The functional food of the present invention in the form of capsule, powder, suspension, etc. contains 0.001 to 100 wt% of orotic acid, a salt thereof, or a derivative thereof depending on the form thereof.
[39]
[40] Where orotic acid, a salt thereof, or a derivative thereof is used as a cosmetic ingredient according to the present invention, it can be added as it is or together with other cosmetic ingredients in a manner well known in the art. The mixed amount of the active ingredient can be determined depending on the purpose of use. Orotic acid, a salt thereof, or a derivative thereof is generally added in an amount of 0.0001 to 10 wt%, preferably 0.1 to 5 wt% based on the total amount of raw materials. The examples of cosmetics include toners, lotions, creams, packs and makeups, etc.
[41]
[42] Where orotic acid, a salt thereof, or a derivative thereof is used as an oral cleaner such as toothpaste or gargle according to the present invention, it can be added as it is or together with other ingredients in a manner well known in the art. The mixed amount of the active ingredient can be determined depending on the purpose of use. Orotic acid, a salt thereof, or a derivative thereof is generally added in an amount of 0.0001 to 10 wt%, preferably 0.1 to 5 wt% based on the total amount of raw materials.
Advantageous Effects
[43] According to the present invention, orotic acid, a salt thereof, or a derivative thereof has a superior effect of promoting biosynthesis of hyaluronic acid or gly- cosaminoglycan in chondrocyte cells, fibroblast cells, synovial cells, corneal epithelial cells, keratocyte cells, etc. Orotic acid, a salt thereof, or a derivative thereof, therefore, can be used for preventing, treating or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis, xeroderma, etc. which can be caused by decline of production and hypofunction of hyaluronic acid or glycosaminoglycan. Brief Description of Drawings
[44] Figure 1 is a graph illustrating increase of hyarulonic acid production by orotic acid in chondrocyte cells, synovial cells and fibroblast cells(NIH3T3).
[45] Figure 2 is a graph showing restoration of goblet cells after treating choline orotate in an animal model with scheroma, as compared to a positive control group.
[46] Figure 3 is a tissue staining photograph illustrating restoration of goblet cells after treating choline orotate in an animal model with scheroma, as compared to before treating choline orotate.
[47] Figure 4 is a graph showing change of tear secretion amount after dropping choline orotate in the eyes of an animal model with scheroma, as compared to a control group.
[48] Figure 5 is a graph showing change of tear secretion amount after orally administering choline orotate to an animal model with scheroma, as compared to a control group. Best Mode for Carrying out the Invention
[49] The present invention is further illustrated by the following examples, which are not to be construed to limit the scope of the invention.
[50]
[51] Example 1: Effect of orotic acid on production of hyaluronic acid in chondrocyte cells
[52] 1. Isolation of chondrocyte cells
[53] Cartilage tissues were isolated from a 3-4 week old rabbit in an aseptic condition, treated with 0.2% collagenase type II at 370C for 4 hours, and filtered with a lOOum filter to give chondrocyte cells. The obtained cells were replaced with a chondrocyte medium(DMEM/F12, 10% FBS, insulin, nonessential amino acid, ascorbic acid, penicillin, Gibco BRL product) every other day at 370C in 5% CO .
[54] 2. Preparation of beads
[55] The chondrocyte cells were mixed with 1.5% alginate solution in 2x10 cells/ml, and the resulting mixture was dropped into 102mM CaCl solution(pH7.4) using a syringe to give chondrocyte-beads, which were washed with 0.15M NaCl. The beads were replaced with a chondrocyte medium(DMEM/F12, nonessential amino acid, ascorbic acid, penicillin, Gibco BRL product) adding orotic acid every other day at 370C in 5% CO 2.
[56] 3. Content of hyaluronic acid in the beads
[57] 3-1. Obtaining beads
[58] After the beads were cultured in a chondrocyte medium with the addition of orotic acid for 2 weeks, they were washed with phosphate buffer saline(PBS). The beads were recovered, treated with a solution of 55mM sodium citrate, 3OmM EDTA and 15OmM sodium chloride(pH6.8) at 40C for 10~15min, and then reacted overnight with 20ug/ml of papain dissolved in a solution of 0.1 M sodium acetate, 5OmM sodium EDTA and 5mM L-cysteine hydrochloride(pH5.53) at 56~60°C. The beads were
heated for lOmin for enzyme inhibition, and the resulting samples were kept at -2O0C until the assay.
[59] 3-2. HA assay
[60] One day before the assay, HA binding protein(HABP) was coated on a 96-well plate at 40C overnight and blocked with 1% bovine serum albumin(BSA). The samples were bound at 370C for 60min and washed with 0.5% phosphate buffer saline. Biotin-HABP was bound at room temperature for 60min and extra-avidin alkaline phosphatase was added. Then, the samples were colored with p-nitrophenyl-phosphate(PNPP), and the color reaction was inhibited by 3N-NaOH. The absorbance was measured at 405nm and the obtained results are given in Fig. 1.
[61]
[62] Example 2: Effect of orotic acid on production of hyaluronic acid in synovial cells
[63] Human synovial cells were cultured in Dulbecco's modified Eagle's medium(DMEM) containing 10% fetal bovine serum(FBS), added to a 24-well plate in 2x10 cells/well, and subcultured. Next day, the cells were replaced with DMEM containing 5% FBS and orotic acid was added. Afterwards, the cells were cultured at 370C for 3 days and then total amount of hyaluronic acid in the medium was measured at 405nm by sandwich ELIZA method using HA binding protein(HABP) and HA binding protein-biotin. Hyaluronic acid(SIGMA H) was used as a standard. The obtained results are shown in Fig. 1.
[64]
[65] Example 3: Effect of orotic acid on production of hyaluronic acid in fibroblast cells(NIH3T3)
[66] Rabbit fibroblast cells were cultured in Dulbecco's modified Eagle's medium(DMEM) containing 10% fetal bovine serum(FBS), added to a 24-well plate in 2x10 cells/well, and subcultured. Next day, the cells were replaced with DMEM containing 5% FBS and orotic acid was added. Afterwards, the cells were cultured at 370C for 3 days and then total amount of hyaluronic acid in the medium was measured at 405nm by sandwich ELIZA method using HA binding protein(HABP) and HA binding protein-biotin. Hyaluronic acid(SIGMA H) was used as a standard. The obtained results are illustrated in Fig. 1.
[67]
[68] Example 4: Isolation of keratocyte cells and corneal epithelial cells
[69] Corneal tissues were cleared by removing blood vessels, etc. The cleared tissues were washed with 5% antibiotic-PBS, added to 3ml of IX trypsin(0.05%)/EDTA(0.01%), and subjected to shaking incubation at 370C for 80min. The collected suspension was washed with a SHEM medium(10% FBS in DMEM/
F12(l:l) + 0.5% PS(penicillin and streptomycin) + 4mM L-glutamine + 10ng/ml EGF (epidermal growth factor) + 5ug/ml insulin + 30ng/ml choleratoxin + 0.18mM adenine + 2nM 3,3',5-triiodo-L-thyromine sodium salt + 0.4ug/ml hydrocortisone) and centrifuged at l,200rpm for 5min. The separated cells were used as epithelium, and the remaining tissues were incubated at 370C for 2 hours after adding 1.2U/ml dispase II. After removing 1.2U/ml dispase II, the tissues were treated with 5ml of 200U/ml type I collagenase and subjected to shaking incubation at 370C. The collected suspension was washed with a culture medium(10% FBS in DMEM/F12(1:1) + 1% PS), centrifuged at l,200rpm for 5min, and plated on a dish.
[70]
[71] Example 5: Effect of choline orotate on production of hyaluronic acid in keratocyte cells
[72] Keratocyte cells were treated with choline orotate(0uM~10uM) and stimulated for 48 hours. Then, lOOul of the cell culture was reacted with lOOul of b- HABP(biotin-hyaluonic acid binding protein, 50ng/ml) at room temperature for 1 hour.
[73] One day before the experiment, HA 20ug/ml, 2OmM Na CO solution was added to a
96-well plate, which was kept in a refrigerator for 24 hours and washed with a standard assay buffer(SAB) three times. Then, 1% BSA was added to the 96-well plate, reacted at room temperature for 90min, and washed with SAB three times to give a HA coated plate.
[74] To the coated plate was added the above-prepared cell culture, which was reacted with stirring at room temperature for 1 hour and washed with SAB three times. Then, extra- avidin alkaline phosphatase( 1:80000) was added, reacted at room temperature for 30min, and washed with SAB three times, lmg/ml disodium p-nitrophenyl phosphate dissolved in 10OmM NaCl and 5mM MgCl solution was added and reacted for 20~60min. 3N NaOH was added to terminate the reaction and the absorbance was measured at 405nm. As shown in the following Table 1, it was confirmed that the keratocyte cells treated with choline orotate promoted production of hyaluronic acid in a concentration-dependent manner.
[75] Table 1
[Table 1] [Table ]
[76] [77] Example 6: Effect of choline orotate on production of glycosaminoglycan in keratocyte cells
[78] Keratocyte cells were treated with choline orotate(0uM~10uM) and stimulated for 48 hours. Then, the cell culture was taken and the amount of glycosaminoglycan was measured at 550nm using a Biocolor assay kit. As shown in the following Table 2, it was verified that the keratocyte cells treated with choline orotate promoted production of glycosaminoglycan in a concentration-dependent manner.
[79] Table 2 [Table 2] [Table ]
[80] [81] Example 7: Effect of choline orotate on production of hyaluronic acid in corneal epithelial cells
[82] Corneal epithelial cells were treated with choline orotate(0uM~10uM) and stimulated for 48 hours. Then, lOOul of the cell culture was reacted with lOOul of b- HABP(biotin-hyaluonic acid binding protein, 50ng/ml) at room temperature for 1 hour.
[83] One day before the experiment, HA 20ug/ml, 2OmM Na CO solution was added to a 96-well plate, which was kept in a refrigerator for 24 hours and washed with a standard assay buffer(SAB) three times. Then, 1% BSA was added to the 96-well plate, reacted
at room temperature for 90min, and washed with SAB three times to give a HA coated plate.
[84] To the coated plate was added the above-prepared cell culture, which was reacted with stirring at room temperature for 1 hour and washed with SAB three times. Then, extra- avidin alkaline phosphatase( 1:80000) was added, reacted at room temperature for 30min, and washed with SAB three times, lmg/ml disodium p-nitrophenyl phosphate dissolved in 10OmM NaCl and 5mM MgCl solution was added and reacted for 20~60min. 3N NaOH was added to terminate the reaction and the absorbance was measured at 405nm. As shown in the following Table 3, it was confirmed that the corneal epithelial cells treated with choline orotate promoted production of hyaluronic acid in a concentration-dependent manner.
[85] Table 3 [Table 3] [Table ]
[86] [87] Example 8: Effect of choline orotate on production of glycosaminoglycan in corneal epithelial cells
[88] Corneal epithelial cells were treated with choline orotate(0uM~10uM) and stimulated for 48 hours. Then, the cell culture was taken and the amount of glycosaminoglycan was measured at 550nm using a Biocolor assay kit. As shown in the following Table 4, it was verified that the corneal epithelial cells treated with choline orotate promoted production of glycosaminoglycan in a concentration-dependent manner.
[89] Table 4
[Table 4] [Table ]
[90] [91] Example 9: Effect of choline orotate on healing wounds [92] Human keratinocyte cells(HaCaT) were sufficiently cultured in Dulbecco's Modified Eagle's Medium(DMEM) containing 10% fetal bovine serum(FBS) in a 6-well plate. Wounds 50um wide were made with 25 G7/8 injection needle. The separated parts formed around the wounds were photographed with a camera attached to a microscope. The wounds were separated to a control group and a trial group, and the trial group was treated with lOuM of choline orotate. Then, the movement of cells in the wounded parts was observed for 72 hours. Closure rates of the wounds were represented in percentage compared to the control group. It was confirmed that the group treated with choline orotate has significant wound healing effects over 30%.
[93] [94] Example 10: Effect of choline orotate on improving scheroma and ophthalmic diseases
[95] In vivo animal test was performed using the method inducing scheroma and ophthalmic diseases by causing inflammation via injection of concanavalin A into the lacrimal gland of rabbits [Journal of ocular pharmacology & therapeutics 21(2), 139-148, 2005]. Choline orotate was dissolved to a concentration of 5% in a phosphate-buffered saline solution, which was used as eye drops. A commercially available 0.1% hyaluronic acid preparation(Hyalein) was used as a positive control, and a phosphate-buffered saline solution was used as a control. The choline orotate preparation, hyaluronic acid preparation and phosphate-buffered saline solution were respectively dropped into the eyes of the scheroma and ophthalmic diseases-induced rabbits, and impression cytology was performed to evaluate improvement of scheroma and ophthalmic diseases. As shown in Fig. 2, it was confirmed that the eye drops using choline orotate significantly restored goblet cells over 80% of the initial value in the impression cytology, as compared to the positive control group and the control group. Also, as shown in Fig. 3, impression cytology tissue staining illustrated restoration of
impression cytology cells after treating choline orotate, as compared to before treating choline orotate.
[96]
[97] Example 11: Effect of instillation of choline orotate on tear secretion amount in mouse model with scheroma induced by Botox
[98] Prior to anesthesia, phenol red thread test(30sec) was performed on 26 B6 mice to measure their tear secretion amount. Then, the mice were anesthetized and 2OmU(O. ImI) of botulinum toxin(Botox) was injected to their both eyes. On the third day, Botox boosting was performed. On the 7 day, the decrease of the tear secretion amount was confirmed, and then eye drops comprising 5% choline orotate were dropped into the right eye four times a day and a saline solution was dropped into the left eye two times a day. On 0 , 8 , 14 , 23 and 30 days phenol red thread test was carried out without anesthesia. Fig. 4 shows change of the tear secretion amount of the choline orotate instillation group, as compared to the control group. As shown in Fig. 4, it was confirmed that the tear secretion amount was increased by choline orotate.
[99]
[100] Example 12: Effect of oral administration of choline orotate on tear secretion amount in mouse model with scheroma induced by Botox
[101] Prior to anesthesia, phenol red thread test(30sec) was performed on 26 B6 mice to measure their tear secretion amount. Then, the mice were anesthetized and 2OmU(O. ImI) of botulinum toxin(Botox) was injected to their both eyes. On the third day, Botox boosting was performed. On the 7 day, the decrease of the tear secretion amount was confirmed, and then 800mg/kg of choline orotate was orally administered to a trial group and a saline solution was administered to a control group. On 0 , 8 , 19 ' , 22 and 28 days phenol red thread test was carried out without anesthesia. Fig. 5 shows change of the tear secretion amount of the choline orotate oral administration group, as compared to the control group. As shown in Fig. 5, it was confirmed that the tear secretion amount was increased by choline orotate.
Claims
[1] A composition for enhancing biosynthesis of hyaluronic acid or gly- cosaminoglycan comprising a compound of formula (I).
1
(I) wherein,
R is hydrogen, metal ion, ammonium ion, protonated basic amino acid, nontoxic water soluble positive ion having molecular weight of less than 1,000 daltons, C
-C alkyl, C -C alkenyl, or C -C alkoxy.
20 1 20 1 20
[2] The composition according to claim 1, wherein the compound is selected from the group consisting of orotic acid, metal ion of orotic acid, ammonium ion of orotic acid, choline orotate, creatine orotate, carnitine orotate, arginine orotate, methylglucamine orotate, ornithine orotate, lysine orotate, chitosan orotate, chitosan oligo orotate, polylysine orotate, orotidylate(orotidine monophosphate), orotidine and dihydroorotic acid.
[3] The composition according to claim 1, wherein the metal ion is sodium, potassium, calcium, magnesium, zinc, manganese, selenium, chromium, lithium, copper, cobalt or iron ion.
[4] The composition according to claim 1, wherein the compound is choline orotate.
[5] The composition according to claim 1, wherein the compound is orotic acid.
[6] The composition according to any one of claims 1 to 5, wherein the composition is used for preventing, treating or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis or xeroderma.
[7] The composition according to claim 6, wherein the composition is used for preventing, treating or improving scheroma or ophthalmic diseases.
[8] The composition according to claim 6, wherein the composition is used for preventing, treating or improving arthritis.
[9] The composition according to claim 6, wherein the composition is used for treating wound.
[10] The composition according to claim 6, wherein the composition is used as a medicine, functional food, cosmetic, toothpaste or gargle.
[11] A pharmaceutical composition for preventing or treating arthritis, disk, skin
aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis or xeroderma comprising choline orotate together with a pharmaceutically acceptable carrier.
[12] A functional food for preventing or improving arthritis, disk, skin aging, wrinkle, scheroma, ophthalmic diseases, wound, scar, colpoxerosis, gum diseases, interstitial cystitis, atopic dermatitis or xeroderma comprising choline orotate together with a sitologically acceptable carrier.
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| PCT/KR2008/003985 WO2010005123A1 (en) | 2008-07-07 | 2008-07-07 | Composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic acid, a salt thereof, or a derivative thereof |
| KR1020117000310A KR20110031947A (en) | 2008-07-07 | 2008-07-07 | Composition for enhancing biosynthesis of hyaluronic acid or glycosaminoglycan comprising orotic acid, a salt thereof, or a derivative thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018012157A1 (en) | 2016-07-14 | 2018-01-18 | 昭和電工株式会社 | Melanin production inhibitor, skin-lightening agent, fibroblast cell activator, collagen and/or elastin production promotor, and wrinkle-improving agent |
| US11357805B2 (en) | 2018-07-27 | 2022-06-14 | Johnson & Johnson Surgical Vision, Inc. | Compositions and methods for treating the eye |
| RU2792627C2 (en) * | 2018-07-27 | 2023-03-22 | Джонсон Энд Джонсон Серджикал Вижион, Инк. | Compositions and methods for treating eye disorders |
| US11878041B2 (en) | 2018-07-27 | 2024-01-23 | Johnson & Johnson Surgical Vision, Inc. | Compositions and methods for treating the eye |
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| KR102051693B1 (en) * | 2012-05-29 | 2019-12-03 | 가부시키가이샤 미토콘도리아 겐큐쇼 | Dihydroorotic acid dehydrogenase inhibitor |
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| US20060209253A1 (en) * | 2004-10-20 | 2006-09-21 | Giles Brian C | Method and composition for eliminating ocular hypoxic acidosis |
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| US20080025949A1 (en) * | 2006-07-31 | 2008-01-31 | Karmali Rashida A | Compositions and methods of reducing tissue levels of drugs when given as orotate derivatives |
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| US5013656A (en) * | 1987-10-19 | 1991-05-07 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing orotic acid by fermentation |
| US20060209253A1 (en) * | 2004-10-20 | 2006-09-21 | Giles Brian C | Method and composition for eliminating ocular hypoxic acidosis |
| US20070179145A1 (en) * | 2005-02-22 | 2007-08-02 | Karmali Rashida A | Compositions and methods of reducing side effects and toxicity of methotrexate when given as orotate derivatives |
| US20080025949A1 (en) * | 2006-07-31 | 2008-01-31 | Karmali Rashida A | Compositions and methods of reducing tissue levels of drugs when given as orotate derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018012157A1 (en) | 2016-07-14 | 2018-01-18 | 昭和電工株式会社 | Melanin production inhibitor, skin-lightening agent, fibroblast cell activator, collagen and/or elastin production promotor, and wrinkle-improving agent |
| CN109414388A (en) * | 2016-07-14 | 2019-03-01 | 昭和电工株式会社 | Melanin production inhibitor, whitening agent, fibroblast activator, collagen and/or elastin laminin generate promotor and Wrinkle-diminishing agent |
| JPWO2018012157A1 (en) * | 2016-07-14 | 2019-04-25 | 昭和電工株式会社 | Melanin production inhibitor, skin lightening agent, fibroblast activating agent, collagen and / or elastin production promoter, and wrinkle improver |
| US10646487B2 (en) | 2016-07-14 | 2020-05-12 | Showa Denko K.K. | Melanin production inhibitor, whitening agent, fibroblast activator, collagen and/or elastin production promotor and wrinkle ameliorant |
| US11045471B2 (en) | 2016-07-14 | 2021-06-29 | Showa Denko K.K. | Melanin production inhibitor, whitening agent, fibroblast activator, collagen and/or elastin production promotor and wrinkle ameliorant |
| US11357805B2 (en) | 2018-07-27 | 2022-06-14 | Johnson & Johnson Surgical Vision, Inc. | Compositions and methods for treating the eye |
| RU2792627C2 (en) * | 2018-07-27 | 2023-03-22 | Джонсон Энд Джонсон Серджикал Вижион, Инк. | Compositions and methods for treating eye disorders |
| US11878041B2 (en) | 2018-07-27 | 2024-01-23 | Johnson & Johnson Surgical Vision, Inc. | Compositions and methods for treating the eye |
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| US11969451B2 (en) | 2020-11-16 | 2024-04-30 | Johnson & Johnson Surgical Vision, Inc. | Compositions and methods for treating the eye |
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