EP2405899A2 - Valsartan-formulierungen - Google Patents
Valsartan-formulierungenInfo
- Publication number
- EP2405899A2 EP2405899A2 EP10726655A EP10726655A EP2405899A2 EP 2405899 A2 EP2405899 A2 EP 2405899A2 EP 10726655 A EP10726655 A EP 10726655A EP 10726655 A EP10726655 A EP 10726655A EP 2405899 A2 EP2405899 A2 EP 2405899A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- valsartan
- microcrystalline cellulose
- pregelatinized starch
- tablet
- silicon dioxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 42
- 229960004699 valsartan Drugs 0.000 title claims abstract description 41
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 title claims abstract 6
- 239000000203 mixture Substances 0.000 title description 21
- 238000009472 formulation Methods 0.000 title description 12
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 40
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 40
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 40
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 40
- 229920000881 Modified starch Polymers 0.000 claims abstract description 29
- 239000013543 active substance Substances 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 9
- 239000004615 ingredient Substances 0.000 claims description 2
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000002245 particle Substances 0.000 description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 5
- 239000006186 oral dosage form Substances 0.000 description 5
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229960000913 crospovidone Drugs 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 150000005846 sugar alcohols Polymers 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 229960004977 anhydrous lactose Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229940102034 valsartan 80 mg Drugs 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- PDRNJKDODQMLSW-HZVMSULOSA-N N[C@@H](CCCNC(N)=N)C(O)=O.N[C@@H](CCCNC(N)=N)C(O)=O.Nc1nc2[nH]cc(CCc3ccc(cc3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)c2c(=O)[nH]1 Chemical compound N[C@@H](CCCNC(N)=N)C(O)=O.N[C@@H](CCCNC(N)=N)C(O)=O.Nc1nc2[nH]cc(CCc3ccc(cc3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)c2c(=O)[nH]1 PDRNJKDODQMLSW-HZVMSULOSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000008358 core component Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Definitions
- the present invention relates to a new pharmaceutical formulation in the form of a tablet consisting of valsartan as an active agent, pregelatinized starch, microcrystalline cellulose.
- Valsartan a compound having the chemical name N-(1-oxopentyl)-N-[[2'-(1h-tetrazol-5- yl)[1 ,1 '-biphenyl]-4-yl]methyl]-L-valine, of formula I
- Valsartan belongs to the group of drugs that block receptors of angiotensin Il and thus cause a decrease of blood pressure.
- Presently valsartan tablets are marketed by Novartis as DIOVAN® in doses of 40, 80, 160 and 320 mg and it is used to treat hypertension.
- WO 9524901 A1 (CIBA-GEIGY AG) 07.03.1995, page 6 is directed to the use of valsartan for the treatment of diabetic nephropathy.
- a hard gelatine capsule comprising valsartan is disclosed.
- the described capsule dosage form above is prepared by below method. Valsartan and microcrystalline cellulose are granulated via wet granulation with solution of polyvidone and sodium lauryl sulphate in water. The granules are dried. Crospovidone and magnesium stearate are added to the dry granulate and the mixture is filled into capsules.
- the first fifth components above formulation are mixed and compacted at pressures 25 to 65 kN.
- the compacted material is further forced through a sieve.
- Granulate produced in this way is mixed with magnesium stearate and the mixture is compressed into tablets.
- WO 9749394 A2 discloses compressed solid oral dosage forms, e.g., by compaction of valsartan (optionally in salt form) optionally combined with HCTZ.
- the preferred range of cellulose is given 10 to 30%, e.g., 21%, for valsartan/HCTZ compositions and 5% valsartan alone.
- the preferred range of crospovidone is given as 10 to 20%, e.g., 13%.
- WO 0038676 A1 (NOVARTIS AG) 22.12.1999, page 24, lines 23-30 the application relates to a solid oral dosage form comprising valsartan as the active agent and microcrystalline cellulose wherein the weight ratio of valsartan to microcrystalline cellulose is from 2.5:1 to 0.3:1 , e.g., 2:1 to 1 :1 , e.g., 1.4:1.
- This application relates to a solid oral dosage form comprising valsartan as the active agent and more than 30% of microcrystalline cellulose by weight based on the total weight of the core components of said solid oral dosage form e.g., 31 to 65%, e.g., 50%.
- this application relates to a solid oral dosage form comprising valsartan as the active agent and microcrystalline cellulose wherein the weight ratio of valsartan to microcrystalline cellulose is from 2.5:1 to 0.3:1 , e.g., 2:1 to 1 :1 , e.g., 1.4:1
- the tablet material described in this application includes, apart from the valsartan active substance, optionally valsartan in combination with HCTZ, other additives, of which the most important one is suitably selected filler, which has a decisive importance for quality of the produced tablets.
- filler having a defined particle size and in defined amount.
- a preferable composition of the filler according to the invention WO 2005041941 A2 is microcrystalline cellulose having a particle size of 10 to 1000 ⁇ m, preferably 50 to 190 ⁇ m, especially preferably 90 ⁇ m, in amounts above 40 to 60% by weight, spray-dried anhydrous lactose having a particle size of 10 to 250 ⁇ m, preferably 150 to 250 ⁇ m, in amounts of 30 to 60%, compact lactose hydrate having particle size of 10 to 250 ⁇ m, in amounts 40 to 60% by weight, a polyalcohol selected from mannitol or sorbitol, which is compacted and has a particle size of 100 to 850 ⁇ m, preferably 200 to 400 ⁇ m, in amounts of 40 to 60% by weight, calcium hydrogen phosphate having particle size of 10 to 200 ⁇ m in amounts of 40 to 60% by weight, a combination of microcrystalline cellulose with lactose, preferably spray-dried anhydrous lactose, in a weight ratio of 1 :2 to 2:1 in amounts of 20 to 55%, and
- Summary of the Invention Objective of the present invention is to create a tablet containing valsartan as active ingredient, which has high powder flowability and easily divided into two or more pieces while being stable enough for transport and commercial use and that resists humidity for several days without taking up moisture or breaking apart if unblistered.
- Valsartan is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly soluble in water. In state of the art valsartan is micronized to obtain better dissolution. This process causes flowability problem in manufacturing. While in the state of the art tablets are known, said tablets have several disadvantages. Normally those tablets are very porous and thus not very hard. As a consequence they cannot be broken into two or more pieces, which renders them useless for regiments wherein only one half of a tablet shall be taken at a time. Additionally these porous tablets tend to be very sensitive to humidity. As a consequence they can not be stored for some days once the blister is opened.
- the present invention relates a pharmaceutical formulation in the form of a tablet consisting of
- the tabletting mixture includes substances that improve its flow properties.
- Microcrystalline cellulose and pregelatinized starch are the most advantageous substance for the described mixture in this invention; preferably in a weight ratio of microcrystalline cellulose to pregelatinized starch is greater than 0.1 and less than 1.0. This ratio is calculated by dividing the weight of microcrystalline cellulose to the weight of pregelatinized starch. Ratio of these substances is important for avoiding fluctuations of the tablet weight, caused by inappropriate flow of the solid mixture through the hopper into the high performance tabletting machine.
- the tablet has 80 mg to 320 mg valsartan.
- the tablet contains one or more filling and/or disintegrating agents. These agents are useful to produce tablets of a certain size and to support flowability step.
- the filling and/or disintegrating agents are microcrystalline cellulose and pregelatinized starch.
- the tablet also contains one or more lubricant or glidant. Lubricants and glidants are well known in the state of the art. Among them, the lubricant(s) are selected from the group of stearate, preferably magnesium stearate.
- the glidant(s) are selected from the group of silicon dioxide, preferably colloidal silicon dioxide.
- invention in the form of a tablet consisting of 20 to 34% of valsartan
- magnesium stearate 0.5 to 4.5% of magnesium stearate.
- the tablets that described in examples are produced by direct compression techniques.
- valsartan, microcrystalline cellulose, pregelatinized starch are mixed. Colloidal silicon dioxide are added to this powder and mixed. Then magnesium stearate are added to this powder and mixed. Finally, mixture is compressed by tablet compression machine.
- the present invention relates to tablet comprising valsartan as the active agent, microcrystalline cellulose and pregelatinized starch wherein the weight ratio of microcrystalline cellulose to pregelatinized starch is greater than 0.1 and less than 1.0.
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR200901901 | 2009-03-11 | ||
| PCT/TR2010/000046 WO2010104485A2 (en) | 2009-03-11 | 2010-03-10 | Valsartan formulations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2405899A2 true EP2405899A2 (de) | 2012-01-18 |
Family
ID=41226269
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP10726655A Ceased EP2405899A2 (de) | 2009-03-11 | 2010-03-10 | Valsartan-formulierungen |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP2405899A2 (de) |
| WO (1) | WO2010104485A2 (de) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013191668A1 (en) * | 2012-06-22 | 2013-12-27 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Compositions preventing hypertension comprising soluplus |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1994926A1 (de) * | 2007-05-24 | 2008-11-26 | Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi | Valsartanformulierungen |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9507086A (pt) | 1994-03-17 | 1997-09-16 | Ciba Geigy Ag | Tratamento de nefroterapia diabética com valsartan |
| GB9613470D0 (en) | 1996-06-27 | 1996-08-28 | Ciba Geigy Ag | Small solid oral dosage form |
| ES2373556T3 (es) | 1998-12-23 | 2012-02-06 | Novartis Ag | Comprimidos de valsartán. |
| WO2005041941A2 (en) | 2003-11-03 | 2005-05-12 | Zentiva, A.S. | Valsartan containing formulation |
| AU2005318365B2 (en) * | 2004-12-24 | 2011-02-03 | Krka, D.D., Novo Mesto | Solid pharmaceutical composition comprising valsartan |
| EP1906936A2 (de) * | 2005-05-18 | 2008-04-09 | Combino Pharm, S.L. | Formulierungen mit losartan und/oder dessen salzen |
| GT200600371A (es) * | 2005-08-17 | 2007-03-21 | Formas de dosis sólidas de valsartan y amlodipina y método para hacer las mismas | |
| WO2007049291A1 (en) * | 2005-10-27 | 2007-05-03 | Lupin Limited | Novel solid dosage forms of valsartan and rochlorothiazide |
| WO2007049292A1 (en) * | 2005-10-27 | 2007-05-03 | Lupin Limited | Pharmaceutical formulation of losartan |
| US20080227836A1 (en) * | 2005-10-31 | 2008-09-18 | Lupin Ltd | Stable Solid Oral Dosage Forms of Valsartan |
-
2010
- 2010-03-10 WO PCT/TR2010/000046 patent/WO2010104485A2/en not_active Ceased
- 2010-03-10 EP EP10726655A patent/EP2405899A2/de not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1994926A1 (de) * | 2007-05-24 | 2008-11-26 | Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi | Valsartanformulierungen |
Non-Patent Citations (1)
| Title |
|---|
| See also references of WO2010104485A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010104485A3 (en) | 2010-11-25 |
| WO2010104485A2 (en) | 2010-09-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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