WO2013102437A1 - 丹参或丹参制剂在制备治疗肝纤维化相关疾病的药物中的应用 - Google Patents
丹参或丹参制剂在制备治疗肝纤维化相关疾病的药物中的应用 Download PDFInfo
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- WO2013102437A1 WO2013102437A1 PCT/CN2013/070037 CN2013070037W WO2013102437A1 WO 2013102437 A1 WO2013102437 A1 WO 2013102437A1 CN 2013070037 W CN2013070037 W CN 2013070037W WO 2013102437 A1 WO2013102437 A1 WO 2013102437A1
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- Prior art keywords
- liver
- danshen
- use according
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- fibrosis
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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
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/537—Salvia (sage)
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Definitions
- the invention belongs to the field of medicine, and specifically relates to the application of salvia miltiorrhiza or salvia miltiorrhiza preparations in treating diseases related to liver fibrosis.
- Liver fibrosis is an inevitable stage of cirrhosis, and anti-fibrosis is essential.
- anti-fibrosis is essential.
- drugs such as cytokines and antioxidants have been used for experimental research, but the clinical therapeutic effect is not satisfactory.
- the anti-fibrosis effect of traditional Chinese medicine has received increasing attention from people and has shown good application prospects.
- Salvia miltiorrhiza is bitter, slightly cold, and has the effects of promoting blood circulation, nourishing blood and soothing the nerves, cooling blood and removing phlegm and detoxifying the muscles. It is a commonly used medicine for promoting blood circulation and removing blood stasis.
- Salvia miltiorrhiza contains mainly fat-soluble diterpenoids and water-soluble phenolic acids, and contains other components such as flavonoids, triterpenoids and alcohols.
- the water-soluble phenolic acid component is a polyphenolic acid such as salvianolic acid, protocatechuic aldehyde, protocatechuic acid, caffeic acid and salviane and a derivative or dimer of caffeic acid (such as salvianolic acid A).
- Tanshinone is one of the representative components of Salvia miltiorrhiza Bunge. Modern pharmacological studies have demonstrated that Danshen has the effects of dilating coronary artery, anti-myocardial ischemia, anticoagulation, antithrombotic, sedative pain, and lowering blood fat and anti-atherosclerosis.
- the invention uses the CC compound factor method to induce the liver fibrosis model, and gives the high, medium and low doses of the test drug danshen preparation with the ⁇ ig, and the experiment is carried out for 7 weeks, and the serum alanine aminotransferase (ALT) and the Tianmen are measured.
- Aspartate aminotransferase (AST), N-acetyl- ⁇ -D-glucosaminidase (NAG) activity and total protein (TP), albumin (ALB), type IV collagen determination of liver tissue super Oxide dismutase (SOD) activity, malonic acid
- results show that Salvia miltiorrhiza
- the preparation can significantly inhibit the activity of ALT, AST and NAG in serum, reduce the amount of type IV collagen in serum, increase the amount of TP and ALB in serum, reduce the level of Hyp and MDA in liver tissue, and increase liver tissue.
- the activity of SOD; inhibiting the increase of collagen fibers in liver tissue can also reduce the expression of ⁇ -SMA in liver tissue.
- the salvia miltiorrhiza according to the present invention comprises a fresh salvia miltiorrhiza medicinal material or a processed salvia miltiorrhiza medicinal material, and a product prepared by processing the salvia miltiorrhiza medicinal material, for example, a product obtained by pulverizing or extracting the salvia miltiorrhiza medicinal material, and the extraction of the salvia miltiorrhiza medicinal material can be carried out by water extraction.
- the method of alcohol extraction, water extraction and alcohol precipitation may further include a purification step, such as resin purification.
- the Danshen preparation of the invention is a medicine prepared by using Danshen as a raw material medicine, and the Danshen preparations which have been marketed at present include Danshen tablets, Danshen capsules, Danshen dropping pills and the like.
- the salvia miltiorrhiza preparation of the present invention is prepared by the following method: First, the raw material medicine is processed into a pharmaceutical active ingredient, and further prepared into a pharmaceutical preparation.
- the preparation method of the Danshen preparation of the present invention belongs to the prior art, can be obtained from the existing patent publications, or can be prepared according to the disclosed pharmaceutical standards.
- the Danshen preparation of the present invention is preferably Danshen dropping pills.
- the salvia miltiorrhiza preparation according to the present invention is a pharmaceutical composition prepared from salvia miltiorrhiza, and the composition may contain a pharmaceutically acceptable carrier as needed, and the pharmaceutically acceptable carrier may be 0.1-99.9% by weight in the preparation. .
- the pharmaceutical composition of the present invention is present in unit dosage form, which refers to a unit of the preparation, such as each tablet of the tablet, each capsule of the capsule, each bottle of the oral solution, the granules per bag, and each of the injections. Branch and so on.
- the Salvia miltiorrhiza preparation of the present invention may be in any pharmaceutically acceptable dosage form, and the dosage forms include: tablets, such as sugar-coated tablets, film-coated tablets, enteric coated tablets; capsules, such as hard capsules, soft capsules; Liquid; granules; granules; granules; granules; powders; ointments; for example, ointments, plasters; medicinal preparations; suspensions; powders; solutions; for example, injections; suppositories; creams; Pills; patch.
- tablets such as sugar-coated tablets, film-coated tablets, enteric coated tablets
- capsules such as hard capsules, soft capsules
- Liquid granules; granules; granules; granules; powders; ointments; for example, ointments, plasters
- medicinal preparations suspensions; powders; solutions; for example, injections; supposito
- the orally administered preparation may contain usual excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent, and a moisturizing agent.
- a binder such as a polyethylene glycol dimethacrylate, polymethyl methacrylate, polymethyl methacrylate, polymethyl methacrylate, polymethyl methacrylate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium sulfate, sodium
- Suitable fillers include cellulose, mannitol, lactose and other similar fillers.
- Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives (e.g., sodium starch glycolate).
- Suitable lubricants include magnesium stearate.
- Suitable pharmaceutically acceptable wetting agents include sodium decyl sulfate.
- Solid oral compositions can be prepared by conventional methods such as mixing, filling, tableting, and the like.
- the active substance can be distributed throughout the composition using a large amount of the filler by repeated mixing.
- the oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be a dry product which may be formulated with water or other suitable carrier before use.
- Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate or hydrogenated edible fats.
- Emulsifiers such as egg yolk, sorbitan monooleate or gum arabic; non-aqueous vehicles which may include edible oils, such as almond oil, fractionated coconut oil, oily esters such as glycerides, propylene glycol or ethanol: A preservative such as p-hydroxybenzyl or propylparaben or sorbic acid; if desired, may contain conventional flavoring or coloring agents.
- edible oils such as almond oil, fractionated coconut oil, oily esters such as glycerides, propylene glycol or ethanol
- a preservative such as p-hydroxybenzyl or propylparaben or sorbic acid; if desired, may contain conventional flavoring or coloring agents.
- the liquid unit dosage form prepared contains the active substance of the invention and a sterile vehicle.
- This compound may be suspended or dissolved depending on the carrier and concentration.
- the solution is usually prepared by dissolving the active substance in a carrier, sterilizing it by filtration, filling it into a suitable vial or ampoule, and then sealing. Excipients such as local anesthetics, preservatives, and buffers can also be dissolved in such carriers.
- the composition can be frozen after filling the vial and the water removed under vacuum.
- the salvia miltiorrhiza preparation of the present invention may optionally be added to a suitable pharmaceutically acceptable carrier when prepared as a medicament
- the pharmaceutically acceptable carrier includes, but is not limited to, the following: from a sugar alcohol such as mannitol or sorbitol Alcohol, xylitol; amino acids, such as cysteine hydrochloride, methionine, glycine; vitamin C; disodium EDTA, sodium EDTA; inorganic salts, such as monobasic alkali metal carbonates, acetates, phosphates or Aqueous solution; sodium chloride, potassium chloride; sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate; calcium carbonate, calcium hydrogencarbonate; stearate, such as calcium stearate, magnesium stearate; For example, hydrochloric acid, sulfuric acid, phosphoric acid; organic or organic acid salts such as acetic acid, thioglycolic acid, sodium lactate;
- the Danshen preparation of the present invention determines the usage amount according to the condition of the patient at the time of use.
- a Danshen dropping pill prepared according to the method of Example 1 can be administered 20 times a day, 3 times a day, and a course of 24-32 weeks.
- Figure 1 Effect of Danshen Dripping Pills on the expression of ⁇ -SMA in liver tissue of rats with liver fibrosis induced by CC1 4 (10 X 20).
- Figure 2 Effect of Danshen Dripping Pills on the pathological morphology of liver tissue in rats with CC1 4 induced hepatic fibrosis (HE staining, 10 X 10).
- Figure 3 Effect of Danshen dripping pills on liver histopathology in rats with CC-induced hepatic fibrosis (Masson staining, 10 X 10).
- Salvia miltiorrhiza is pulverized into medium powder, extracted with 95% ethanol as solvent, extracted 3 times, each time 2 hours, ethanol is recovered and concentrated into thick paste, and the dregs are boiled twice with water for 1 hour each time. After that, the filtrate was concentrated to an appropriate amount, and combined with the above thick paste to obtain a salvia miltiorrhiza extract.
- the above-mentioned salvia miltiorrhiza extract is pulverized and passed through a 80 mesh sieve; the 10% starch slurry is separately made into a soft material, and then granulated by a 14 mesh nylon sieve, and dried at 70 ° C to a moisture content of 3% or less: after the above particles are uniformly mixed, Fill in the empty capsule No. 1 and you will get it.
- hepatic fibrosis The key to the occurrence of hepatic fibrosis is the activation of hepatic stellate cells (HSC) and the excessive deposition of extracellular matrix (ECM).
- HSC hepatic stellate cells
- ECM extracellular matrix
- the activated HSC proliferates in a large amount and is transformed into myofibroblasts, which in turn produces a large amount of ECM.
- the principle of using the CC model to induce liver fibrosis in this experiment is: direct dissolution of the liver cell membrane, resulting in degeneration and necrosis of hepatocytes, but the toxicity of CC is mainly related to its active metabolites, and ec is metabolized by mixed functional oxidase in hepatocytes.
- ALT and AST activity are sensitive indicators of hepatocyte injury.
- Serum total protein determination (TP), albumin (ALB) reduction is positively correlated with the degree of liver synthesis.
- the other groups were injected subcutaneously (sc) with pure CC 5 ml/kg for the first time, and sc 40% CCU-olive oil 3 ml/kg every 3 days for 7 weeks.
- the corn flour feed of 20% lard plus 0.5% cholesterol was fed for the first 2 weeks, and the corn flour feed was fed for 3-6 weeks.
- Fuzheng Huayu 1500 mg/kg
- Each drug-administered group received ig corresponding drugs every day from the day of modeling, and the control group and the model group were given distilled water (10 mL/kg) for 7 weeks.
- the rats were anesthetized with sodium pentobarbital, blood was taken from the abdominal aorta, and serum was collected by centrifugation.
- Sections were routinely dewaxed, hydrated, washed with PBS for 15 min, 3% 3 ⁇ 40 2 blocked endogenous peroxidase, incubated at room temperature for 10 min, washed with PBS for 15 min ; placed in a 0.01 mol/L sodium citrate buffer solution After 15 min, rinse with natural PBS for 15 min, remove excess fluid; add a-SMA (1:100) monoclonal antibody, incubate at 37 °C for 1 h, wash with PBS for 15 min; add Polymer Helper, 37 ° (incubation) 20 1 ⁇ 11, wash in PBS for 15 min; add poly-HRP anti-Mouse IgG antibody, incubate at 37 °C for 20 min, wash in PBS for 15 min, DAB color, rinse with tap water for 10 min.
- a-SMA (1:100) monoclonal antibody incubate at 37 °C for 1 h, wash with PBS for 15 min
- Polymer Helper 37 ° (incuba
- Hematoxylin counterstaining, dehydration, transparent, A-SMA staining was brownish yellow.
- Image analysis was performed using Image-Proplus 6.0 image analysis software. Five fields were randomly taken from each slice, and the integrated optical density (IOD) of each field of view was recorded. The IOD value was more. Large, indicating that the positive expression product is stronger.
- liver fibrosis was examined microscopically and semi-quantitatively analyzed.
- the standard of hepatic fibrosis was: "one" normal liver, only a small amount of fibrous connective tissue in the portal area, which is a normal structural component; " Collagen fibrosis around the central canal and lobular central vein, a small number of fiber bundles in the central vein and portal vein are scattered and extended, but no fibrous septa is formed, and the lobular structure is still preserved; " + + "collagen fibrosis, central venous and portal vein fiber bundles Peripheral extension, incompletely spaced, lobular structure mostly retained; "+ + +” collagen fibers proliferate, with a small amount of thin, completely separated, lobular structure disrupted; " + + + + “completely thickened, pseudolobule formation .
- the results are shown in Table 5, Figure 2, and Figure 3.
- the liver lobules of the rats were intact in structure and clear in structure.
- the liver cells were normal in shape and arranged in a cord-like shape centered on the central vein.
- the hepatic sinus was clear, and a small amount of fibrous tissue in the larger portal area was present as a normal structure.
- the hepatic lobules of the model group had different degrees of destruction, and the liver cells were disorderly arranged.
- the portal area, central vein, and portal vein had different degrees of fibrous tissue proliferation, suggesting that the model was successful.
- the above lesions were also present in each of the drug-administered groups, but the degree of lesion was significantly lighter than that of the model group.
- liver fibrosis degree of rats was graded, and the results were tested for significance of grade data.
- the liver fibrosis degree of rats was significantly improved in each dose group of Danshen Dripping Pill (P ⁇ 0.05, P ⁇ 0.01). The results showed that Danshen Dripping Pill had obvious protective effect on liver fibrosis rats.
- the experiment showed that Danshen Dropping Pill can inhibit the expression of a-SMA, and the effect of medium and low dose is obvious, which indicates that Danshen Dropping Pill can inhibit the proliferation of HSC, and its anti-fibrotic mechanism is closely related to the inhibition of HSC expression of a-SMA.
- the results of pathological examination showed that the Danshen Dripping Pills group can significantly improve the degree of liver fibrosis damage, and the effect of medium and low dose is obvious, indicating that Danshen Dripping Pill has protective effect on liver fibrosis rats.
- Prud home GJ Paleobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic consideration [J]. Lab Invest, 2007, 87(11): 1077- 1091.
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Abstract
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13733640.0A EP2801365A4 (en) | 2012-01-04 | 2013-01-04 | USE OF DANSHEN OR A DANSHENE PREPARATION IN THE MANUFACTURE OF MEDICAMENTS FOR THE TREATMENT OF DISEASES ASSOCIATED WITH LIVER FIBROSIS |
JP2014550629A JP2015503572A (ja) | 2012-01-04 | 2013-01-04 | 肝線維症に関連する疾患の治療用薬剤の調製におけるラディックス・サルビアエ・ミルチオルヒザエ(タンジン)又はその製剤の使用 |
US14/370,711 US9895405B2 (en) | 2012-01-04 | 2013-01-04 | Use of radix salviae miltiorrhizae (danshen) or its preparations in preparation of drugs for treating diseases related to hepatic fibrosis |
RU2014130412A RU2623147C2 (ru) | 2012-01-04 | 2013-01-04 | Использование корня шалфея многокорневищного (radix salviae miltiorrhizae) (дань шэнь) или препаратов из него в приготовлении лекарственных средств для лечения заболеваний, связанных с фиброзом печени |
KR1020147020997A KR20140114398A (ko) | 2012-01-04 | 2013-01-04 | 간 섬유증 관련 질환 치료를 위한 약물의 제조에서 단삼 및 이의 제제의 용도 |
AU2013207295A AU2013207295B2 (en) | 2012-01-04 | 2013-01-04 | Use of radix salviae miltiorrhizae (danshen) or its preparations in preparation of drugs for treating diseases related to hepatic fibrosis |
CA2862442A CA2862442A1 (en) | 2012-01-04 | 2013-01-04 | Uses of danshen or danshen preparation in preparation of drugs for treating diseases related to hepatic fibrosis |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210000557.6 | 2012-01-04 | ||
CN2012100005576A CN103191186A (zh) | 2012-01-04 | 2012-01-04 | 丹参制剂在制备抗肝纤维化药物中的应用 |
Publications (1)
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WO2013102437A1 true WO2013102437A1 (zh) | 2013-07-11 |
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PCT/CN2013/070037 WO2013102437A1 (zh) | 2012-01-04 | 2013-01-04 | 丹参或丹参制剂在制备治疗肝纤维化相关疾病的药物中的应用 |
Country Status (9)
Country | Link |
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US (1) | US9895405B2 (zh) |
EP (1) | EP2801365A4 (zh) |
JP (1) | JP2015503572A (zh) |
KR (1) | KR20140114398A (zh) |
CN (1) | CN103191186A (zh) |
AU (1) | AU2013207295B2 (zh) |
CA (1) | CA2862442A1 (zh) |
RU (1) | RU2623147C2 (zh) |
WO (1) | WO2013102437A1 (zh) |
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CN108949677B (zh) * | 2018-07-05 | 2021-11-30 | 浙江大学 | 地黄苷c和丹酚酸a在促进体外培养骨髓间充质干细胞增殖和抑制复制性衰老中的应用 |
CN115192585B (zh) * | 2022-06-02 | 2023-09-15 | 上海中医药大学附属曙光医院 | 一种包含丹酚酸a、二氢丹参酮i和隐丹参酮的组合物及其用途 |
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CN1759855A (zh) * | 2004-10-15 | 2006-04-19 | 合肥恒星药物研究所 | 一种治疗慢性肝炎的药物 |
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2012
- 2012-01-04 CN CN2012100005576A patent/CN103191186A/zh active Pending
-
2013
- 2013-01-04 RU RU2014130412A patent/RU2623147C2/ru not_active IP Right Cessation
- 2013-01-04 CA CA2862442A patent/CA2862442A1/en not_active Abandoned
- 2013-01-04 AU AU2013207295A patent/AU2013207295B2/en not_active Ceased
- 2013-01-04 EP EP13733640.0A patent/EP2801365A4/en not_active Withdrawn
- 2013-01-04 US US14/370,711 patent/US9895405B2/en not_active Expired - Fee Related
- 2013-01-04 KR KR1020147020997A patent/KR20140114398A/ko not_active Application Discontinuation
- 2013-01-04 WO PCT/CN2013/070037 patent/WO2013102437A1/zh active Application Filing
- 2013-01-04 JP JP2014550629A patent/JP2015503572A/ja active Pending
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Also Published As
Publication number | Publication date |
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EP2801365A4 (en) | 2016-03-02 |
JP2015503572A (ja) | 2015-02-02 |
KR20140114398A (ko) | 2014-09-26 |
RU2623147C2 (ru) | 2017-06-22 |
AU2013207295B2 (en) | 2017-10-19 |
CA2862442A1 (en) | 2013-07-11 |
RU2014130412A (ru) | 2016-02-20 |
US20150044310A1 (en) | 2015-02-12 |
US9895405B2 (en) | 2018-02-20 |
EP2801365A1 (en) | 2014-11-12 |
AU2013207295A1 (en) | 2014-07-24 |
CN103191186A (zh) | 2013-07-10 |
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