WO2006003907A1 - 血管内膜過増殖疾患の予防または治療剤 - Google Patents
血管内膜過増殖疾患の予防または治療剤 Download PDFInfo
- Publication number
- WO2006003907A1 WO2006003907A1 PCT/JP2005/011896 JP2005011896W WO2006003907A1 WO 2006003907 A1 WO2006003907 A1 WO 2006003907A1 JP 2005011896 W JP2005011896 W JP 2005011896W WO 2006003907 A1 WO2006003907 A1 WO 2006003907A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drugs
- mitiglinide
- coronary artery
- hydrate
- pharmaceutical composition
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a chemical structural formula
- Mitiglinide represented by the following formula: (2S) _ 2_ benzyl 1 3 _ (cis 1 hexahydro 1 2
- the present invention relates to a pharmaceutical composition for preventing or treating coronary artery bypass surgery and postoperative restenosis of coronary intervention in the treatment of ischemic heart disease.
- Heart disease is one of the most common causes of death along with malignant neoplasms. About half of these are due to ischemic heart diseases such as angina pectoris and myocardial infarction. The importance of prevention and treatment is increasing. In the treatment of ischemic heart disease, coronary artery bypass surgery (Coronary Artery Bypass Graft Surgery, hereinafter referred to as CABG), and coronary artery intervention (Percutaneous Coronary Intervention, less invasive treatment). As appropriate, the PCI and the reconnaissance are directly responsible. [J plays a role.] CABG is a method of revascularization of an obstructed blood vessel, and forms a side tube that bypasses the obstructed portion.
- PTCA percutaneous transluminal coronary angioplasty
- PTCA is currently a new type of coronary stent, directional intracoronary atherectomy (Directional Coronary Artherectomy, hereinafter referred to as DCA) and rotational atherectomy (hereinafter referred to as rotablator). It is sometimes called P0BA (Plain Old Balloon Angioplasty) to distinguish it from treatment devices.
- DCA Directional Coronary Artherectomy
- rotablator rotational atherectomy
- Drug therapy for diseases caused by intimal hyperproliferation such as postoperative restenosis of CABG or PCI includes, for example, antiallergic drugs (such as tranilast), antiplatelet drugs (such as cilostazol), angio Tensin II receptor blockers, angiotensin converting enzyme inhibitors, chymase inhibitors, probucol, travidinole, etc. have been studied.
- antiallergic drugs such as tranilast
- antiplatelet drugs such as cilostazol
- angio Tensin II receptor blockers such as angiotensin converting enzyme inhibitors, chymase inhibitors, probucol, travidinole, etc.
- angio Tensin II receptor blockers such as angiotensin II receptor blockers
- angiotensin converting enzyme inhibitors such as chymase inhibitors
- probucol such as travidinole
- travidinole etc.
- Mitiglinide calcium hydrate (scientific name: bis ⁇ (2S) _ 2_ benzolinole 3_ (cis-hexahydro _ 2_isoindolinylcarbonyl) propionic acid ⁇ calcium dihydrate) is It is a commercially available fast-acting non-SU anti-diabetic drug represented by formula (II) and is known to be effective in controlling blood glucose in patients with type 2 diabetes by correcting postprandial and fasting hyperglycemia. (Patent Document 1, Patent Document 2). In addition, it is reported that it is useful for preventing or preventing the progression of diabetic complications by controlling blood glucose (Patent Document 3). However, mitiglinide or a pharmacologically acceptable salt thereof, or a hydrate thereof, It has not been reported to be useful for the prevention or treatment of diseases caused by intimal hyperproliferation.
- mitiglinide or a pharmacologically acceptable salt thereof, or a hydrate thereof is used for the treatment of diseases caused by intimal hyperproliferation such as CABG and PCI after surgery. It is not known at all to be effective for prevention or treatment, nor is it suggested in the above literature.
- Patent Document 1 Japanese Patent Laid-Open No. 356459
- Patent Document 2 International Publication No. 2004Z002473 Pamphlet
- Patent Document 3 International Publication No. 2004Z002474 Pamphlet
- Patent Document 4 JP-A-6_340622
- Patent Document 5 Japanese Patent Laid-Open No. 6_340623
- Non-Patent Document 1 Shigeru Saito, Internal Medicine, 2004, No. 93, No. 5, p. 805 -811
- Non-Patent Document 2 Toshihiro Tamura et al., Internal Medicine, 2004, No. 93, No. 5, p. 890-896 Disclosure of Invention
- An object of the present invention is to provide a pharmaceutical composition for prevention or treatment of diseases caused by intimal hyperproliferation such as postoperative restenosis such as CABG and PCI.
- mitiglinide calcium hydrate represented by the above formula (II) is a stimulus for rubbing the usagi common carotid artery endothelium.
- the present invention provides:
- composition according to (1) or (2) above which contains, as an active ingredient, a calcium salt of mitiglinide represented by the formula (I) or a hydrate thereof;
- the inventors of the present invention have used the model of intimal thickening caused by the common carotid artery endothelium abrasion of a rabbit rabbit diabetes model to suppress the intimal thickening action of mitiglinide calcium hydrate represented by the above formula (II). investigated.
- the compound showed a significant effect of suppressing intimal thickening compared with the control group even at a dose that did not affect the fasting blood glucose level.
- the compound has a potent inhibitory effect on intimal thickening and is extremely useful for the prevention or treatment of diseases caused by intimal hyperproliferation.
- Examples of diseases caused by intimal hyperproliferation include coronary artery bypass grafting (CABG) and postoperative restenosis of coronary artery interpension (PCI).
- CABG coronary artery bypass surgery under heartbeat
- low-invasion coronary artery bypass surgery such as coronary artery bypass surgery without using cardiopulmonary bypass
- bypass surgery performed by stopping the heart using cardiopulmonary bypass Blood vessels such as the radial artery or gastroepiploic artery are used.
- PCI includes balloon dilatation (PTCA, cutting balloon, etc.), coronary stents (including drug-eluting stents coated with sirolimus, paclitaxel, etc.), plaque excision (DCA, rotablator, etc.), Examples include trans-radial coronary intervention (TRI).
- PTCA balloon dilatation
- coronary stents including drug-eluting stents coated with sirolimus, paclitaxel, etc.
- DCA plaque excision
- TRI trans-radial coronary intervention
- the compound represented by the formula (I) or a pharmacologically acceptable salt thereof, or a hydrate thereof hereinafter referred to as the compound of the present invention, which is an active ingredient of the present invention, It can be easily produced by a method described in the literature or a method analogous thereto (for example, see Patent Documents 1, 4, and 5).
- Examples of the pharmacologically acceptable salt of the compound represented by the formula (I) include salts with inorganic bases such as sodium salt, potassium salt, calcium salt, monoreforin, piperidine, Examples thereof include salts with organic amines such as phenylalanol or amino acids, preferably calcium salts.
- inorganic bases such as sodium salt, potassium salt, calcium salt, monoreforin, piperidine
- organic amines such as phenylalanol or amino acids, preferably calcium salts.
- mitiglinide calcium hydrate represented by the above formula (II) which is more preferably a calcium salt of mitiglinide represented by the above formula (I) or a hydrate thereof, is preferable. The most preferred.
- dosage forms are used depending on the usage.
- dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, and the like. It is administered parenterally.
- the pharmaceutical composition of the present invention comprises an appropriate excipient, a disintegrant, a binder, a lubricant, a diluent, a buffer, an isotonic agent according to the method used in pharmacology depending on the dosage form.
- it can be prepared by mixing or diluting and dissolving appropriately with pharmaceutical additives such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, solubilizing agents, etc., and preparing them according to conventional methods.
- pharmaceutical additives such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, solubilizing agents, etc.
- the powder is mixed with the compound of the present invention by adding an appropriate excipient, lubricant, etc. as necessary to obtain a powder.
- a tablet can be easily produced by a method described in the literature or a method analogous thereto (see Patent Documents 2 and 3). If necessary, the tablets can be coated to form film-coated tablets, sugar-coated tablets, enteric-coated skin tablets, and the like.
- a capsule is prepared by adding an appropriate excipient, lubricant, etc. to the compound of the present invention and mixing well, if necessary, and then filling the capsule into an appropriate capsule. Further, it may be filled after being granulated or finely granulated by a conventional method.
- the pharmaceutical composition of the present invention can also be used in appropriate combination with other drugs having an intimal hyperproliferative inhibitory effect.
- antiallergic drugs tranilast, pemirolast, etc.
- antiplatelet drugs atto oral pins, cilostazol, ticlopidine, clopidogrel, nafadarel, abciximab, eptifibatide, tirofiban, gantofiban, etc.
- Angiotensin converting enzyme inhibitors imidapril hydrochloride, lisinopril, etc.
- angiotensin II receptor antagonists vanolesartan, oral sultan potassium, ilbesartan, etc.
- chymase inhibitors cytostatic drugs (sirolimus, paclitaxel) , Rapamycin, etc.), probucol, travidil, BO-653 and the like.
- the present invention is based on the same or different routes of administration as a single preparation, simultaneous administration as a single preparation Both forms of administration, including simultaneous administration and spaced administration by the same or different routes of administration as separate formulations, are included.
- the dose of the compound of the present invention depends on the patient's weight, age, sex, presence of complications, disease and degree of treatment.
- oral administration it can be administered in a range of approximately:! To 60 mg as a single adult dose.
- the administration method may be oral or parenteral administration 1 to 3 times a day.
- the dosage amount of the said compound of this invention can be reduced suitably according to the dosage amount of another chemical
- the compound of the present invention has an excellent effect of suppressing intimal thickening. Therefore, it is possible to provide a pharmaceutical composition useful for the prevention and treatment of diseases caused by intimal hyperproliferation.
- FIG. 1 is a graph showing the effect on intimal thickening after vascular endothelial abrasion in alumoxane-induced diabetic rabbits.
- the vertical axis represents the intima area Z ratio of the vascular media (%)
- the horizontal axis represents the normal group, the control group, and the mitiglinide administration group (M group) from the left.
- FIG.2 Blood glucose level 2 weeks after administration of aroxane in aroxan-induced diabetic rabbits It shows the action.
- the vertical axis indicates plasma glucose level (mg / dL)
- the horizontal axis indicates the normal group, the control group, and the mitiglinide administration group (M group) from the left.
- FIG. 3 shows the effect on blood glucose level 6 weeks after administration of aroxane in aroxan-induced diabetic rabbits.
- the vertical axis indicates plasma glucose level (mg / dL)
- the horizontal axis indicates from the left, the normal group, the control group, and the mitiglinide administration group (M group).
- the bilateral common carotid arteries were removed, and the intima, media and lumen area of the vascular tissue section were measured with an image analyzer.
- the fasting plasma glucose concentration was measured 2 weeks after the administration of aroxane (day of vascular endothelial abrasion) and 6 weeks after (day of angioplasty).
- the mitiglinide-administered group showed a significant inhibitory effect on the intimal thickening compared to the control group against the intimal hyperplasia due to the rubbing of the common rabbit carotid artery endothelium (Fig. 1). ).
- the intima / media area ratio on the side not subjected to the rubbing treatment was all 0%.
- Neither the mitiglinide-administered group nor the control group had an effect on fasting glucose levels at 2 weeks and 6 weeks after the administration of aroxane ( Figures 2 and 3).
- the pharmaceutical composition of the present invention significantly improves the thickness of the rabbit carotid artery intima. It has an excellent inhibitory effect and has been shown to be extremely useful for the prevention and treatment of restenosis after coronary artery inter-pension such as percutaneous transluminal coronary angioplasty (PTCA) in ischemic heart disease.
- PTCA percutaneous transluminal coronary angioplasty
- the pharmaceutical composition of the present invention is extremely useful as a prophylactic and therapeutic agent for diseases caused by intimal hyperproliferation such as postoperative restenosis such as coronary artery bypass grafting and coronary artery inter-pension in the treatment of ischemic heart disease. is there.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002571822A CA2571822A1 (en) | 2004-07-01 | 2005-06-29 | Preventive or therapeutic agent for vascular intimal proliferative disease |
JP2006528726A JP4955392B2 (ja) | 2004-07-01 | 2005-06-29 | 血管内膜過増殖疾患の予防または治療剤 |
US11/630,874 US20070254938A1 (en) | 2004-07-01 | 2005-06-29 | Preventive or Therapeutic Agent for Vascular Intimal Proliferative Disease |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004-195421 | 2004-07-01 | ||
JP2004195421 | 2004-07-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006003907A1 true WO2006003907A1 (ja) | 2006-01-12 |
Family
ID=35782715
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/011896 WO2006003907A1 (ja) | 2004-07-01 | 2005-06-29 | 血管内膜過増殖疾患の予防または治療剤 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20070254938A1 (ja) |
JP (1) | JP4955392B2 (ja) |
CA (1) | CA2571822A1 (ja) |
TW (1) | TW200607498A (ja) |
WO (1) | WO2006003907A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114246905A (zh) * | 2020-09-21 | 2022-03-29 | 山东新时代药业有限公司 | 一种中药组合物在制备防治冠心病pci术后再狭窄药物中的用途 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH10306092A (ja) * | 1997-03-07 | 1998-11-17 | Takeda Chem Ind Ltd | 2−ピペラジノン−1−酢酸誘導体及びその用途 |
WO2004002474A1 (ja) * | 2002-06-28 | 2004-01-08 | Kissei Pharmaceutical Co., Ltd. | 糖尿病性合併症の予防又は進展阻止用医薬組成物 |
WO2004002473A1 (ja) * | 2002-06-28 | 2004-01-08 | Kissei Pharmaceutical Co., Ltd. | 血糖コントロール用医薬組成物 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU654331B2 (en) * | 1991-03-30 | 1994-11-03 | Kissei Pharmaceutical Co. Ltd. | Succinic acid compounds |
US5441947A (en) * | 1993-08-25 | 1995-08-15 | Eli Lilly And Company | Methods of inhibiting vascular restenosis |
US6242600B1 (en) * | 1997-03-07 | 2001-06-05 | Takeda Chemical Industries, Ltd. | 2-piperazinone-1-acetic acid derivatives and their use |
PE20020323A1 (es) * | 2000-08-22 | 2002-06-13 | Novartis Ag | COMPOSICION FARMACEUTICA QUE COMPRENDE UN POTENCIADOR DE LA SECRESION DE INSULINA E INHIBIDORES DE HMG-Co-A-REDUCTASA O INHIBIDORES DE LA ENZIMA CONVERTIDORA DE ANGIOTENSINA (ACE) |
-
2005
- 2005-06-29 WO PCT/JP2005/011896 patent/WO2006003907A1/ja active Application Filing
- 2005-06-29 JP JP2006528726A patent/JP4955392B2/ja not_active Expired - Fee Related
- 2005-06-29 US US11/630,874 patent/US20070254938A1/en not_active Abandoned
- 2005-06-29 CA CA002571822A patent/CA2571822A1/en not_active Abandoned
- 2005-07-01 TW TW094122300A patent/TW200607498A/zh unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH10306092A (ja) * | 1997-03-07 | 1998-11-17 | Takeda Chem Ind Ltd | 2−ピペラジノン−1−酢酸誘導体及びその用途 |
WO2004002474A1 (ja) * | 2002-06-28 | 2004-01-08 | Kissei Pharmaceutical Co., Ltd. | 糖尿病性合併症の予防又は進展阻止用医薬組成物 |
WO2004002473A1 (ja) * | 2002-06-28 | 2004-01-08 | Kissei Pharmaceutical Co., Ltd. | 血糖コントロール用医薬組成物 |
Non-Patent Citations (3)
Title |
---|
FUJITA Z.: "PTCA-go Saikyosaku ni Oyobosu Tonyobyo Chiryoho no Kento", THE JOURNALOF THE JAPANESE SOCIETY OF INTERNAL MEDICINE, vol. 89, 2000, pages 228, XP002997705 * |
NAKAJIMA K.: "PCI-go no Saikyosaku to Tonyobyo Chiryo tono Kanren", CIRC.J., vol. 66, 2002, pages 923, XP002997704 * |
OKAZAKI H.: "Rotablator-go no Saikyosaku to Tonyobyo Chiryo tono Kankei", JPN.CIRC.J., vol. 64, no. 1, 2000, pages 664, XP002997703 * |
Also Published As
Publication number | Publication date |
---|---|
US20070254938A1 (en) | 2007-11-01 |
TW200607498A (en) | 2006-03-01 |
CA2571822A1 (en) | 2006-01-12 |
JPWO2006003907A1 (ja) | 2008-04-17 |
JP4955392B2 (ja) | 2012-06-20 |
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