WO2011093308A1 - 有機酸重合体を有効成分とするクローン病の予防又は治療剤 - Google Patents
有機酸重合体を有効成分とするクローン病の予防又は治療剤 Download PDFInfo
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- WO2011093308A1 WO2011093308A1 PCT/JP2011/051425 JP2011051425W WO2011093308A1 WO 2011093308 A1 WO2011093308 A1 WO 2011093308A1 JP 2011051425 W JP2011051425 W JP 2011051425W WO 2011093308 A1 WO2011093308 A1 WO 2011093308A1
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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
- A61K31/74—Synthetic polymeric materials
- A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
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- 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
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- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Definitions
- the present invention relates to a new pharmaceutical use of an organic acid polymer, particularly a 3-oxygermylpropionic acid polymer.
- CD Crohn's disease
- Oral drug therapy is based on 5-aminosalicylic acid (5-ASA) mesalazine and salazosulfapyridine, and corticosteroids (prednisolone) in Japan.
- Other antibacterial agents metalronidazole
- immunosuppressants azathiopurine Etc.
- corticosteroids and immunosuppressive drugs are the basis.
- corticosteroids in particular have not been shown to be effective in long-term administration for the purpose of maintaining remission, and there are many problems such as side effects, steroid dependence, and resistance.
- the 5-ASA mesalazine and salazosulfapyridine are only approved in Japan for Crohn's disease and not in the United States.
- the 5-ASA mesalazine has been reported to be ineffective for Crohn's disease. Nevertheless, the fact that it is often used for off-label use in Crohn's disease in the United States is because it is used unavoidably because there is no safe oral preparation.
- immunosuppressive drugs such as azathioprine, which are approved and used in Japan and the United States, show a certain effect, but side effects such as leukopenia and lymphoma have been reported and are not safe drugs. .
- side effects such as leukopenia and lymphoma have been reported and are not safe drugs.
- organic acid polymers especially 3-oxygermylpropionic acid polymers, have been studied for many pharmaceutical uses.
- JP-A-55-167222 Japanese Patent Laid-Open No. 2-134818 JP-A-8-059485 Japanese Patent Laid-Open No. 11-049883 JP 2000-229856 A JP 2003-81843 A JP 2000-136139 A JP 54-115324 A JP 54-116100 A JP-A-52-51327
- An object of the present invention is to provide a therapeutic agent for Crohn's disease.
- the present inventors conducted pharmacological evaluation of organic acid polymers, especially 3-oxygermylpropionic acid polymer, in a mouse 2,4,6-trinitrobenzenesulfonic acid (TNBS) -induced Crohn's disease model. It was.
- the mouse TNBS-induced Crohn's disease model is a general experimental animal model that is said to be similar to human Crohn's disease. As a result, it was found that the compound has a remarkable pharmacological effect, and the present invention has been completed.
- the present invention relates to the following formula [(O 1/2 ) 3 Ge—A—CO 2 H] n (Where n is 100 to 1000, and A is a lower alkyl group)
- a prophylactic or therapeutic agent for Crohn's disease comprising an organic acid polymer represented by the formula:
- A is preferably a lower alkyl group having 1 to 3 carbon atoms.
- an organic acid polymer a 3-oxygermylpropionic acid polymer in which A is an ethylene group is preferable.
- the polymerization degree n is preferably 200 to 900.
- Such 3-oxygermylpropionic acid polymer can be specified by the following physical properties. That is, the powder diffraction X-ray diffraction spectrum is characterized by a large diffraction peak around 6.5 ° and relatively large diffraction peaks around 11.6 °, 13.8 °, 18.4 °, 21.2 °, and 22.4 °, respectively. Oxygermylpropionic acid polymer.
- the 3-oxygermylpropionic acid showing a characteristic chart in DSC that the peak start point is around 237 ° C., the peak apex is around 256 ° C., the peak end point is around 276 ° C., and the calorific value ⁇ H is about 59 mcal / mg.
- the organic acid polymer of the present invention is effective as a therapeutic agent for Crohn's disease.
- the powder X-ray diffraction spectrum of propagermanium is shown.
- the IR spectrum of propagermanium is shown.
- 2 shows the DSC of propagermanium.
- the pathological score by the administration of propage germanium, salazosulfapyridine, and prednisolone in a mouse TNBS-induced Crohn's disease model is shown (effect on the first day of TNBS induction).
- the pathological score by the administration of propage germanium, salazosulfapyridine, and prednisolone in a mouse TNBS-induced Crohn's disease model is shown (effect on the second day of TNBS induction).
- the pathological score by the administration of propage germanium, salazosulfapyridine, and prednisolone in a mouse TNBS-induced Crohn's disease model is shown (effect on the third day of TNBS induction).
- the intestinal lesion score by administration of propagermanium, salazosulfapyridine, and prednisolone in a mouse TNBS-induced Crohn's disease model is shown.
- the organic acid polymer used in the present invention is a known compound and is represented by the following chemical formula. [(O 1/2 ) 3 Ge-A-CO 2 H] n (Where n is 100 to 1000, and A is a lower alkyl group)
- the lower alkyl group for A is preferably a lower alkyl group having 1 to 3 carbon atoms.
- Particularly preferred is a 3-oxygermylpropionic acid polymer in which A is an ethylene group.
- As the 3-oxygermylpropionic acid polymer propagermanium having a polymerization degree n of 200 to 900 is well known. Its three-dimensional structure is
- R is —CH 2 CH 2 COOH
- m is a weight average degree of polymerization converted from the weight average molecular weight of propagermanium propyl ester, and indicates 137 ⁇ 84 (average value ⁇ standard error 3 ⁇ ). It is presumed that it is an 8-membered ring structure represented by the minimum constitutional unit: (O 1/2 ) 3 GeCH 2 CH 2 COOH empirical formula: C 6 H 10 Ge 2 O 7 ].
- Propagermanium can be produced by the method described in JP-A No. 2003-81843. Moreover, the said document etc. are described as a propage germanium showing the physical-property value of following Table 1, 2.
- Table 1 shows the results of molecular weight measurement by the light scattering method
- Table 2 shows the lattice constants determined by powder X-ray analysis.
- Propagermanium can be identified from FIGS. 1 to 3 (cited from JP-A-54-115324) as a compound having the following physical property values.
- the characteristic powder X-ray diffraction spectrum shows a large diffraction peak around 6.5 ° and relatively large diffraction peaks around 11.6 °, 13.8 °, 18.4 °, 21.2 °, and 22.4 °.
- a large absorption band 800 cm -1, 900 cm -1, and the vicinity of 1700 cm -1 a relatively large absorption band, 560cm -1, 705cm -1, 760cm -1, 780cm -1, 1250cm -1 , 1350 cm ⁇ 1 , and 1400 cm ⁇ 1 (where the absorption band near 1400 cm ⁇ 1 is a doublet).
- DSC shows a characteristic chart where the peak start point is around 237 ° C., the peak apex is around 256 ° C., the peak end point is around 276 ° C., and the heat quantity ⁇ H is about 59 mcal / mg.
- the excipient is added in an amount of 0.005 parts by mass to 0.005 parts by mass to 5 parts by mass of the compound. It is preferably used as a composition prepared to contain 50 parts by weight.
- saccharides such as lactose, sucrose, and dextran
- cellulose-based polymeric substances such as hydroxypropylcellulose
- natural polymeric substances such as albumin are used.
- the said compound is normally used as an oral formulation, it can be utilized also as a suppository, a nasal formulation, an injection formulation, etc.
- the dosage when the compound is administered to humans depends on the dosage form and the age of the patient, etc., but is in the range of 1 mg to 1500 mg per day, and 10 mg per day for oral administration to adults weighing 50 kg. ⁇ 120 mg is preferred.
- the compound can be formulated according to the description of formulation examples such as JP-A No. 2003-81843.
- Crohn's disease is an idiopathic chronic disease of unknown cause, in which nonspecific lesions appear discontinuously throughout the digestive tract, mainly from the oral cavity to the anus.
- Clinical symptoms include abdominal pain, general malaise, diarrhea, diarrhea, fever, weight loss, anemia, ileus symptoms, abdominal mass, nausea, vomiting, and peritoneal inflammation.
- Crohn's disease simultaneously causes various digestive and extra-intestinal symptoms such as intestinal stenosis, intestinal obstruction, internal hemorrhoids, external hemorrhoids, intestinal perforation, abdominal mass, major bleeding, etc. in addition to malnutrition. In addition, it may be accompanied by extraintestinal complications such as arthritis, ulceris, gangrenous pyoderma and erythema nodosum.
- nutritional therapy or drug therapy is mainly employed, but radical surgical therapy cannot be expected.
- Germanium dioxide and 50% hypophosphorous acid were reacted in the presence of concentrated hydrochloric acid (5.0-fold mol) at 60-80 ° C for 4 hours. After adding concentrated hydrochloric acid (5.0-fold mol), acrylic acid (1.1 times mole) is added dropwise at 40 ° C or lower. The precipitated crystals were collected by filtration and washed with concentrated hydrochloric acid to obtain 3-trichlorogermylpropionic acid (yield 98%). Next, the obtained 3-trichlorogermylpropionic acid was dissolved in acetone (17-fold mol), filtered, and water (70-fold mol) was added dropwise at 0 ° C. with stirring, and the mixture was further stirred for 6 hours. Let stand for hours. The precipitated crystals were collected by filtration and washed with acetone to obtain a 3-oxygermylpropionic acid polymer (yield 92%).
- the results were as shown in Table 1 and Table 2, respectively.
- propagemanium was evaluated in a mouse TNBS-induced Crohn's disease model.
- This model is a general animal model that is said to be similar to human Crohn's disease because it causes weight loss, diarrheal bloody stool, and intestinal lesions.
- Prednisolone is one of the core drugs for the treatment of Crohn's disease as a corticosteroid.
- Salazosulfapyridine is a prodrug form of 5-ASA preparation and is converted to 5-ASA in the large intestine. Therefore, in animal studies, it is a positive control drug that is preferable to 5-ASA preparation in terms of drug concentration in the intestinal tract, which is the site of action. It is. In this medicinal efficacy pharmacology test, the propagermanium produced in Production Example 1 was used.
- Pharmacological test example 1 Male BALB / c Cr Slc mice were purchased from Japan SLC at the age of 7 weeks. After acclimation breeding for 5 days, each mouse was divided into 5 groups so that there was no difference in body weight, and it was subjected to the experiment. The abdomen of the mouse was shaved 2 cm square and 1% TNBS was applied to the skin. Seven days after application of TNBS, the mouse was fixed under halothane inhalation anesthesia, and 100 ⁇ L of 2.0% TNBS was injected from the rectum to induce Crohn's disease intestinal lesion.
- mouse standard feed CRF-1 (Oriental Yeast Co., Ltd.) was mixed with propagermanium 0.015% and administered by free feeding from immediately after TNBS injection until 3 days after induction.
- the average dose during the propagemanium administration period was calculated to be about 7.5 mg / kg / day as the propagemanium dose per day based on body weight and food intake.
- prednisolone was administered as a 0.5% CMC suspension at a dose of 10 mL / kg once a day from immediately after TNBS injection to 3 days after the TNBS injection using an oral sonde for mice.
- the dose was set so that the maximum clinical dose (30-40 mg / day / person) was 1 mg / kg / day.
- Pathological score One, two and three days after TNBS induction, the pathological score (weight loss, total of diarrhea / soft stool and occult blood / bleeding score) was evaluated according to the following criteria.
- A Weight loss (100% before TNBS is induced) Score 0: No decrease 1: Reduction within 5% 2: 5-10% decrease 3: 10-20% decrease 4: Reduction exceeding 20%
- B Diarrhea / loose stool score 0: Normal. Keep solid. 2: Soft stool semi-solid. It is easily broken when touched. 4: Diarrhea and fluidity.
- Occult blood / bleeding score 0: Normal. There is no blood in the stool. 2: Occult blood. Blood enters the stool. There is little dirt around the anus. 4: Lower blood. Blood enters the stool. The area around the anus is dirty with blood.
- Intestinal lesion score Evans Blue was intravenously administered 3 days after TNBS induction. Thirty minutes after administration, the cervical spine was dislocated, removed from the colon to the anus, the lumen was washed with physiological saline, the tube was opened, and the extent of the lesion was scored. The intestinal lesion score was evaluated according to the following criteria by observing the colon using a stereomicroscope. 0: No injury. 1: Hyperemia 2: Hyperemia and wall thickening. No ulcer. 3: There is an ulcer but it is not thickened. 4: There are multiple lesion sites.
- Extensive lesions total of 1cm or more
- 6 Extensive lesions (over 1.5cm in total)
- 7 Extensive lesions (total of 2cm or more)
- 8 Extensive lesions (total 2.5cm or more)
- 9 Extensive lesions (total 3cm or more)
- 10 Wide range of lesions (over 3.5cm in total)
- propagermanium was more effective than prednisolone and salazosulfapyridine, it can be expected to have an effect on both the induction and maintenance of remission of Crohn's disease.
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Abstract
Description
[(O1/2)3Ge-A-CO2H]n
(式中、nは100~1000、Aは低級アルキル基)
で表される有機酸重合体を有効成分とする、クローン病の予防又は治療剤である。
[(O1/2)3Ge-A-CO2H]n
(式中、nは100~1000、Aは低級アルキル基)
臨床症状は、腹痛、全身倦怠、下痢、下血、発熱、体重減少、貧血、イレウス症状、腹部腫瘤、悪心、嘔吐、腹膜炎症状などである。クローン病は、栄養障害の他、種々の消化器および腸管外症状、例えば、腸管狭窄、腸閉塞、内瘻、外瘻、腸穿孔、腹部腫瘤、大出血などの重篤な症状を同時に引き起こす。また他に、関節炎、虹彩炎、壊疽性膿皮症や結節性紅斑などの腸管外合併症を伴うことがある。
治療方法は、主に栄養療法又は薬物療法が採られているが、根治的手術療法が望めない。
二酸化ゲルマニウムと50%次亜リン酸(1.1倍モル)とを濃塩酸(5.0倍モル)の存在下、60~80℃で4時間反応させ、濃塩酸(5.0倍モル)を追加後、アクリル酸(1.1倍モル)を40℃以下で滴下する。析出結晶をろ取し、濃塩酸で洗浄して、3-トリクロロゲルミルプロピオン酸を得た(収率98%)。次に、得られた3-トリクロロゲルミルプロピオン酸をアセトン(17倍モル)に溶解させ、ろ過した後、撹拌下、0℃で水(70倍モル)を滴下し、更に6時間撹拌、16時間静置する。析出結晶をろ取し、アセトンで洗浄して3-オキシゲルミルプロピオン酸重合体を得た(収率92%)。
当該モデルは、体重減少、下痢性血便、腸管病変が生じるため、ヒト・クローン病に類似していると言われている一般的な病態動物モデルである。
尚、本薬効薬理試験においては、前記製造例1で製造されたプロパゲルマニウムを使用した。
1.実験方法
雄性BALB/c Cr Slcマウスを7週齢で日本エスエルシーより購入した。5日間の馴化飼育の後、各マウスを体重に差のないよう5群に群分けし、実験に供した。
マウスの腹部を2cm四方剃毛し、皮膚に1%TNBSを塗布した。TNBS塗布7日後に、マウスをハロセン吸入麻酔下で固定し、2.0%TNBS 100μLを直腸より注入しクローン病腸管病変を惹起した。
(1)病態スコア
TNBS惹起1、2及び3日後に、病態スコア(体重減少、下痢・軟便及び潜血・出血スコアの合計)を以下の基準により評価した。
(ア)体重減少(TNBS惹起前を100%とした)スコア
0:減少ない
1:5%以内の減少
2:5-10%の減少
3:10-20%の減少
4:20%を超える減少
(イ)下痢・軟便スコア
0:正常。固形を保つ。
2:軟便半固形。湿っていて触ると容易に崩れる。
4:下痢、流動性がある。
(ウ)潜血・出血スコア
0:正常。便中に血液が混入していない。
2:潜血。便中に血液が混入。肛門周囲は汚れ少。
4:下血。便中に血液が混入。肛門周囲が血液で汚れている。
TNBS惹起3日後にEvans Blueを静脈内投与した。投与30分後、頸椎脱臼し結腸から肛門まで摘出し内腔を生理食塩水で洗浄し、管を開き病変の程度をスコア化した。腸管病変スコアは実体顕微鏡を用いて結腸を観察し以下の基準に従い評価した。
0:傷害なし。
1:充血
2:充血と壁の肥厚。潰瘍なし。
3:潰瘍はあるが肥厚はしていない。
4:複数の病変部位がある。
5:広範な病変部位(合計1cm以上)
6:広範な病変部位(合計1.5cm以上)
7:広範な病変部位(合計2cm以上)
8:広範な病変部位(合計2.5cm以上)
9:広範な病変部位(合計3cm以上)
10:広範な病変部位(合計3.5cm以上)
(1)病態スコアに対する効果
プロパゲルマニウム7.5mg/kg投与群では、有意な病態スコア改善作用が惹起2日後、3日後に確認された。一方、サラゾスルファピリジン133mg/kg投与群では有意な改善効果は認められなかった。サラゾスルファピリジン400mg/kg投与群では、惹起2日、3日後に改善効果が求められたが、プロパゲルマニウム群よりも効果は弱かった。
一方、クローン病に対する寛解導入効果の点でもっとも信頼度が高いプレドニゾロン1mg/kg投与群では惹起2日後に効果はみられず、惹起3日後にのみ効果が認められたものの、プロパゲルマニウム7.5mg/kg投与群より改善効果は弱かった。
プロパゲルマニウム7.5mg/kg投与群は、サラゾスルファピリジン133mg/kg投与群、サラゾスルファピリジン400mg/kg投与群、及びプレドニゾロン1mg/kg投与群と比べ、腸管病変スコアの改善効果がもっとも優れていた。
即ち、病変コントロール群(スコア8.1)に比べ、プロパゲルマニウム群ではスコアが4.9に減少し、サラゾスルファピリジン133mg/kg群では6.1、サラゾスルファピリジン400mg/kg群では6.8と減少効果は弱く、プレドニゾロン1mg/kg群では5.2の減少効果であり、プロパゲルマニウム群がもっとも優れていた。
Claims (8)
- 以下の式
[(O1/2)3Ge-A-CO2H]n
(式中、nは100~1000、Aは低級アルキル基)
で表される有機酸重合体を有効成分とする、クローン病の予防又は治療剤。 - Aが炭素数1から3の低級アルキル基である、請求項1に記載の予防又は治療剤。
- 有機酸重合体が、Aがエチレン基である3-オキシゲルミルプロピオン酸重合体である、請求項1に記載の予防又は治療剤。
- 3-オキシゲルミルプロピオン酸重合体の重合度nが200~900である、請求項3に記載の予防又は治療剤。
- 3-オキシゲルミルプロピオン酸重合体が、以下の特徴的な粉末X線回折スペクトルを示す化合物である、請求項3に記載の予防又は治療剤。
大きい回折ピーク:6.5°付近
比較的大きい回折ピーク:11.6°、13.8°、18.4°、21.2°、および22.4°の各付近 - 3-オキシゲルミルプロピオン酸重合体が、IRスペクトルで以下の特徴的な吸収を示す化合物である、請求項3に記載の予防又は治療剤。
大きい吸収バンド:800cm-1、900cm-1、および1700cm-1の各付近
比較的大きい吸収バンド:560cm-1、705cm-1、760cm-1、780cm-1、1250cm-1、1350cm-1、および1400cm-1の各付近(但し、1400cm-1付近の吸収バンドはダブレットである) - 3-オキシゲルミルプロピオン酸重合体が、DSCで以下の特徴的なチャートを示す化合物である、請求項3に記載の予防又は治療剤。
ピーク開始点:237℃付近
ピーク頂点 :256℃付近
ピーク終了点:276℃付近
熱量ΔH=ほぼ59mcal/mg - 3-オキシゲルミルプロピオン酸重合体が、分子式:(C3H5GeO3.5)n、重量平均重合度:n=548±337、及び、重量平均分子量:平均値±標準誤差=9.29×104±5.72×104を示す化合物である、請求項3に記載の予防又は治療剤。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11737021.3A EP2529743B1 (en) | 2010-01-28 | 2011-01-26 | Prophylactic or therapeutic agent for crohn's disease comprising organic acid polymer as active ingredient |
KR1020127019936A KR20120127430A (ko) | 2010-01-28 | 2011-01-26 | 유기산 중합체를 유효 성분으로 하는 크론병의 예방 또는 치료제 |
US13/514,083 US20120244102A1 (en) | 2010-01-28 | 2011-01-26 | Agent for preventing or treating crohn's disease, comprising organic acid polymer |
AU2011211090A AU2011211090B2 (en) | 2010-01-28 | 2011-01-26 | Prophylactic or therapeutic agent for Crohn's disease comprising organic acid polymer as active ingredient |
CN201180005529.7A CN102695515B (zh) | 2010-01-28 | 2011-01-26 | 以有机酸聚合物作为有效成分的克罗恩病的预防或治疗剂 |
CA2783420A CA2783420A1 (en) | 2010-01-28 | 2011-01-26 | Prophylactic or therapeutic agent for crohn's disease comprising organic acid polymer as active ingredient |
ZA2012/04070A ZA201204070B (en) | 2010-01-28 | 2012-06-04 | Prophylactic or therapeutic agent for crohn's disease comprising organic acid polymer as active ingredient |
HK13100894.2A HK1173670A1 (en) | 2010-01-28 | 2013-01-21 | Prophylactic or therapeutic agent for crohns disease comprising organic acid polymer as active ingredient |
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JP2010-016166 | 2010-01-28 | ||
JP2010016166A JP4620169B1 (ja) | 2010-01-28 | 2010-01-28 | 有機酸重合体を有効成分とするクローン病の予防又は治療剤 |
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PCT/JP2011/051425 WO2011093308A1 (ja) | 2010-01-28 | 2011-01-26 | 有機酸重合体を有効成分とするクローン病の予防又は治療剤 |
Country Status (10)
Country | Link |
---|---|
US (1) | US20120244102A1 (ja) |
EP (1) | EP2529743B1 (ja) |
JP (1) | JP4620169B1 (ja) |
KR (1) | KR20120127430A (ja) |
CN (1) | CN102695515B (ja) |
AU (1) | AU2011211090B2 (ja) |
CA (1) | CA2783420A1 (ja) |
HK (1) | HK1173670A1 (ja) |
WO (1) | WO2011093308A1 (ja) |
ZA (1) | ZA201204070B (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015020040A1 (ja) | 2013-08-06 | 2015-02-12 | 国立大学法人九州大学 | 有機酸重合体を有効成分とする癌細胞の生着予防又は生着抑制のための医薬 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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ES2637286T3 (es) | 2011-07-08 | 2017-10-11 | Defensin Therapeutics Aps | Tratamiento oral de la enfermedad inflamatoria intestinal |
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- 2010-01-28 JP JP2010016166A patent/JP4620169B1/ja not_active Expired - Fee Related
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2011
- 2011-01-26 US US13/514,083 patent/US20120244102A1/en not_active Abandoned
- 2011-01-26 CN CN201180005529.7A patent/CN102695515B/zh not_active Expired - Fee Related
- 2011-01-26 AU AU2011211090A patent/AU2011211090B2/en not_active Ceased
- 2011-01-26 KR KR1020127019936A patent/KR20120127430A/ko not_active Application Discontinuation
- 2011-01-26 WO PCT/JP2011/051425 patent/WO2011093308A1/ja active Application Filing
- 2011-01-26 EP EP11737021.3A patent/EP2529743B1/en not_active Not-in-force
- 2011-01-26 CA CA2783420A patent/CA2783420A1/en not_active Abandoned
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2012
- 2012-06-04 ZA ZA2012/04070A patent/ZA201204070B/en unknown
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015020040A1 (ja) | 2013-08-06 | 2015-02-12 | 国立大学法人九州大学 | 有機酸重合体を有効成分とする癌細胞の生着予防又は生着抑制のための医薬 |
Also Published As
Publication number | Publication date |
---|---|
CN102695515B (zh) | 2015-03-25 |
JP4620169B1 (ja) | 2011-01-26 |
CN102695515A (zh) | 2012-09-26 |
AU2011211090A1 (en) | 2012-07-12 |
EP2529743A1 (en) | 2012-12-05 |
HK1173670A1 (en) | 2013-05-24 |
AU2011211090B2 (en) | 2014-04-24 |
EP2529743A4 (en) | 2013-09-18 |
EP2529743B1 (en) | 2015-08-12 |
US20120244102A1 (en) | 2012-09-27 |
ZA201204070B (en) | 2013-03-27 |
CA2783420A1 (en) | 2011-08-04 |
JP2011153102A (ja) | 2011-08-11 |
KR20120127430A (ko) | 2012-11-21 |
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