WO2005094793A1 - Process for preparing a solid pharmaceutical composition - Google Patents
Process for preparing a solid pharmaceutical composition Download PDFInfo
- Publication number
- WO2005094793A1 WO2005094793A1 PCT/EP2005/003277 EP2005003277W WO2005094793A1 WO 2005094793 A1 WO2005094793 A1 WO 2005094793A1 EP 2005003277 W EP2005003277 W EP 2005003277W WO 2005094793 A1 WO2005094793 A1 WO 2005094793A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- perindopril
- process according
- salt
- carbonate
- hydrate
- Prior art date
Links
Classifications
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the invention relates to a process for preparing a solid pharmaceutical composition of perindopril or a salt thereof as well as a solid pharmaceutical composition.
- ACE inhibitors such as Perindopril
- Perindopril are a prodrug for perindo- prilat which is in vivo the actually active substance.
- Especially solid formulations like tablets suffer from substantial degradation and thereby reduce the effective amount of perindopril.
- the main degradation routes are 1) the hydrolysis of the ester group and 2) intramolecular cyclization resulting in diketopiperazine (DKP) , especially in an acidic environment .
- DKP diketopiperazine
- WO 03/075842 disclose formulations of moexipril hydro- chloride which have been stabilized by addition of alkali or alkaline earth metal carbonates.
- a mixture including moexipril hydrochloride as well as the alkaline reacting carbonate is processed by wet granulation so that the stabilizing effect is likely due to the in-situ forming of the sodium salt of moexi- _ pril.
- the_ amount_ of the carbonate should be greater than the stoichiometric amount of the moexipril hydrochloride.
- US 5,350,582 discloses the use of stabilizing the ACE inhibitor enalapril maleate by addition of alkaline reacting substances which results in formation of the corresponding more stable sodium salt of enalapril.
- This in- situ reaction may be accomplished by using sodium hydrogen carbonate and use of a wet granulation process which allows the neutralization between the alkaline stabilizer and the enalapril maleate to occur.
- a wet granulation process which allows the neutralization between the alkaline stabilizer and the enalapril maleate to occur.
- For 1 mole of enalapril maleate a total of 3 moles of sodium hydrogen carbonate are used.
- the process according to the invention for preparing a solid pharmaceutical composition of perindopril or a salt thereof comprises
- step (i) dry mixing of perindopril or a salt thereof with at least one inorganic carbonate, at least one carrier, and optionally other components, and (ii) dry processing of the mixture obtained in step (i) to the desired solid form.
- perindopril or a salt thereof is dry mixed with at least one inorganic carbonate, at least one carrier and optionally other components.
- dry mixing means that to none of the ingredients to be mixed a liquid, like water, ethanol or combinations thereof, is added and additionally that the mixing is effected without adding such a liquid.
- perindopril is preferably used in form of its tert . -butylamine salt, which is also referred to as perindopril erbumine, as this leads to particularly stable compositions.
- Perindopril erbumine can exist in various polymorphic forms, for example form ⁇ disclosed in WO 01/87835, form ⁇ disclosed in WO 01/87836 and form ⁇ disclosed in WO 01/83439. It is an advantage of the present commposition that an undesired transformation of a polymorph is prevented or at least strongly reduced.
- the inorganic carbonate is preferably sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, calcium hydrogen carbonate or a mixture thereof. It has further been shown that particularly stable compositions can be obtained when the molar ratio of perindopril or a salt thereof to inorganic carbonate is 1 to 0.1-0.9 and more preferably 1 to 0.05-0.83.
- the carrier can be an inorganic or organic substance.
- Preferred examples of such carriers are dibasic calcium phosphate, triba- sic calcium phosphate, magnesium oxide, microcrystalline cellulose, powdered cellulose, lactose and starch.
- the carrier is microcrystalline cellulose, lactose or a mixture thereof.
- microcrystalline cellulose which has a low moisture content of 0.3 to 5.0 % by weight, preferably 0.3 to 1.5 % by weight.
- the moisture content is determined as loss upon drying of a sample in a furnace at 100- 150°C until a constant mass is reached.
- lactose is particularly preferably anhydrous lactose.
- compositions which have been obtained by using microcrystalline cellulose of the afore-mentioned low moisture content and/or anhydrous lactose show a very low level of degradation and are therefore highly stable products.
- lubricants may be selected from the group consisting of magnesium stearate, calcium stearate, castor oil, glycerol monostearate, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
- the composition also comprises indapamide or a hydrate thereof.
- the water content of such a hydrate can vary depending on the humi- dity level of the atmosphere and can be up to 3 % in case of the hemihydrate .
- a preferred hydrate is the hemihydrate .
- compositions are preferred which comprise indapamide or a hydrate thereof in form of particles having specific sizes. It is preferred that 90 % by volume of the particles of indapamide or a hydrate thereof have a size of less than 80 ⁇ m, in particular of less than 70 ⁇ m.
- step (ii) the obtained mixture is dry processed to the desired solid form.
- dry processing means that no liquid is added to the mixture and that the processing is also effected without addition of any liquid. It is preferred that the mixture obtained in step (i) is processed by means of direct compression using a suitable apparatus, like a punch tableting machine.
- the process according to the invention avoids the use of any liquids, including water or aqueous liquids, which on their own may lead to undesired degradation reactions . It is surprising that despite the avoiding of for example a wet granulation step it is possible by means of the process according to the invention to produce very stable compositions of perindopril or a salt thereof. In particular, it was found that tablets prepared according to the present process, after storage, form only small amounts of diketopiperazine (DKP) . It is furthermore surprising that the use of small amounts of inorganic carbonate, i.e. below the stoichiometric amount, provide an additional stabilizing effect even though according to the prior art at least stoichiometric amounts need to be used.
- DKP diketopiperazine
- the process according to the invention preferably results in tablets, minitablets or granules.
- the invention also relates to a solid pharmaceutical composition of perindopril or salt thereof, comprising
- perindopril or a salt thereof at least one of microcrystalline cellulose having a moisture content of 0.3 to 5.0 % by weight and anhydrous lactose, (c) optionally at least one inorganic carbonate, and (d) optionally other components.
- the preferred embodiments of these composition have already been described above with respect to the process according to the invention.
- at least one inorganic carbonate is present in the composition according to the invention.
- the molar ratio of perindopril or a salt thereof to inorganic carbonate is 1 to 0.1-0.9 and preferably 1 to 0.50-0.83.
- composition further comprises indapamide or a hydrate thereof. It is also preferred that 90 % by volume of the particles of indapamide or a hydrate thereof have a size of less than 80 ⁇ m, in particular of less than 70 ⁇ m.
- microcrystalline cellulose preferably has a moisture content of 0.3 to 1.5 % weight.
- the present process does not lead to a substantial transformation of polymorphs of perindopril or a salt thereof which is a further benefit in relation to conventional processes.
- Example 1 (comparison) and Examples 2 to 7 (invention)
- lactose anhydrous is lactose having a water content of less than 1% by weight, determined by Karl-Fischer method according to Ph.Eur. 2.5.12.
- the tablets prepared according to example 1 and according to examples 2, 3 and 4 were stored for 3 weeks at 50°C in closed containers.
- the results given below show the amount of diketopiperazine after 3 weeks .
- example 1 shows that even without alkaline reacting carbonate there is a decrease of the quantity of diketopiperazine in case of example 4 using micro- crystalline cellulose of a low moisture content.
- examples 2 and 3 even more decreased amounts of diketopiperazine were determined and these examples include as a stabilizer sodium hydrogen carbonate.
- the amount of diketopiperazine was determined with a HPLC method using a Hypersil ODS column, 250mm x 4.6mm i.d., packed with 5 ⁇ m particles, and a detector operating at a wavelength of 215mm.
- a gradient elution was effected using the following mobile phase A: buffer solution of pH 2.0 prepared by adding into a 1000ml volumetric flask, 0.92g sodium heptansulfonate, and 1ml Triethylamin (TEA) and filling with water to volume, and adjusting pH value of solution to 2.0 with perchloric acid B: acetonitrile
- the flow rate of the mobile phase was set to 1.0 ml/min and the column temperature was set at 70 °C. 20 ⁇ l of a standard solution and of the sample solution at a working concentration of about 3.0 mg/ml of perindopril erbumine in the buffer solution of pH 2.0 were injected. Diketopiperazine was detected on basis the of the retention time of the DKP peak on the chromatogram of the standard solution. The percentage of diketopiperazine was calculated as area %.
- Tablets according to examples 2, 3 and 4 were additionally stored for 4 weeks at 40 °C in 75% relative humidity in closed containers. Again, the amounts of the degradation product diketopiperazine were determined as mentioned above and the results are given in the table below.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
- Indole Compounds (AREA)
Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/599,154 US20070172524A1 (en) | 2004-03-29 | 2005-03-29 | Process for preparing a solid pharmaceutical composition |
LTEP05730288.7T LT1729739T (en) | 2004-03-29 | 2005-03-29 | Process for preparing a solid pharmaceutical composition |
ES05730288.7T ES2603856T3 (en) | 2004-03-29 | 2005-03-29 | Procedure for preparing a solid pharmaceutical composition |
EP05730288.7A EP1729739B1 (en) | 2004-03-29 | 2005-03-29 | Process for preparing a solid pharmaceutical composition |
JP2007505484A JP4948392B2 (en) | 2004-03-29 | 2005-03-29 | Process for preparing a solid pharmaceutical composition |
DK05730288.7T DK1729739T3 (en) | 2004-03-29 | 2005-03-29 | PROCESS FOR THE PREPARATION OF A solid pharmaceutical composition. |
EA200601608A EA011712B1 (en) | 2004-03-29 | 2005-03-29 | Process for preparing a solid pharmaceutical composition |
NO20064934A NO20064934L (en) | 2004-03-29 | 2006-10-27 | Process for the preparation of a solid pharmaceutical composition |
US12/477,727 US20100172995A1 (en) | 2004-03-29 | 2009-06-03 | Process For Preparing A Solid Pharmaceutical Composition |
CY20161101118T CY1118180T1 (en) | 2004-03-29 | 2016-11-03 | METHOD FOR PRODUCTION OF SOLID PHARMACEUTICAL COMPOSITION |
HRP20161602TT HRP20161602T1 (en) | 2004-03-29 | 2016-11-30 | Process for preparing a solid pharmaceutical composition |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE200410019845 DE102004019845A1 (en) | 2004-03-29 | 2004-03-29 | Solid composition used as acetyl cholinesterase inhibitor comprises perindopril, microcrystalline cellulose, inorganic carbonate and other components |
DE102004019845.4 | 2004-03-29 | ||
DE102004059521.6 | 2004-12-09 | ||
DE102004059521A DE102004059521A1 (en) | 2004-12-09 | 2004-12-09 | Solid composition used as acetyl cholinesterase inhibitor comprises perindopril, microcrystalline cellulose, inorganic carbonate and other components |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/477,727 Division US20100172995A1 (en) | 2004-03-29 | 2009-06-03 | Process For Preparing A Solid Pharmaceutical Composition |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005094793A1 true WO2005094793A1 (en) | 2005-10-13 |
Family
ID=34963866
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/003277 WO2005094793A1 (en) | 2004-03-29 | 2005-03-29 | Process for preparing a solid pharmaceutical composition |
Country Status (14)
Country | Link |
---|---|
US (2) | US20070172524A1 (en) |
EP (1) | EP1729739B1 (en) |
JP (1) | JP4948392B2 (en) |
CY (1) | CY1118180T1 (en) |
DK (1) | DK1729739T3 (en) |
EA (1) | EA011712B1 (en) |
ES (1) | ES2603856T3 (en) |
HR (1) | HRP20161602T1 (en) |
HU (1) | HUE031058T2 (en) |
LT (1) | LT1729739T (en) |
NO (1) | NO20064934L (en) |
PL (1) | PL1729739T3 (en) |
PT (1) | PT1729739T (en) |
WO (1) | WO2005094793A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007025695A1 (en) * | 2005-08-30 | 2007-03-08 | Lek Pharmaceuticals D.D. | Pharmaceutical composition comprising perindopril or its salts |
WO2007058634A1 (en) * | 2005-11-17 | 2007-05-24 | Diagen Smartno Pri Ljubljani, D.O.O. | Stable formulation of amorphous perindopril salts, a process for their preparation, especially industrial preparation, and their use in the therapy of hypertension |
EP1815857A1 (en) | 2006-02-02 | 2007-08-08 | LEK Pharmaceuticals D.D. | A pharmaceutical composition comprising perindopril |
WO2007120930A2 (en) * | 2006-04-19 | 2007-10-25 | Teva Pharmaceutical Industries Ltd. | Stable pharmaceutical compositions of 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivatives |
WO2008068577A2 (en) * | 2006-12-01 | 2008-06-12 | Glenmark Pharmaceuticals Limited | Pharmaceutical compositions |
JP2009537538A (en) * | 2006-05-15 | 2009-10-29 | アカドイア プハルマセウチカルス インコーポレーテッド | Pimavanserin pharmaceutical formulation |
JP2010516699A (en) * | 2007-01-18 | 2010-05-20 | エヴォルヴァ エスアー | Substituted 1,3-dioxanes useful as PPAR modulators |
US8470869B2 (en) | 2007-06-27 | 2013-06-25 | Krka, Tovarna Zdravil D.D. Novo Mesto | Salts of perindopril |
WO2014076632A1 (en) | 2012-11-15 | 2014-05-22 | Adamed Sp. Z O.O. | A pharmaceutical composition containing an ace inhibitor and a calcium channel blocker |
EP1729739B1 (en) | 2004-03-29 | 2016-09-28 | Les Laboratoires Servier | Process for preparing a solid pharmaceutical composition |
CN109700774A (en) * | 2019-03-05 | 2019-05-03 | 上药东英(江苏)药业有限公司 | A kind of perindopril tert-butylamine piece and its powder vertical compression technique |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI21800A (en) * | 2004-05-14 | 2005-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | New procedure of synthesis of perindopril |
TWI435917B (en) | 2006-12-27 | 2014-05-01 | Fujifilm Corp | Pigment-dispersed composition, curable composition, color filter and production method thereof |
WO2011087629A2 (en) * | 2009-12-22 | 2011-07-21 | Fmc Corporation | Microcrystalline cellulose and calcium carbonate compositions useful as recompactible pharmaceutical excipients |
WO2016178591A2 (en) | 2015-05-05 | 2016-11-10 | Gene Predit, Sa | Genetic markers and treatment of male obesity |
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-
2005
- 2005-03-29 PL PL05730288T patent/PL1729739T3/en unknown
- 2005-03-29 HU HUE05730288A patent/HUE031058T2/en unknown
- 2005-03-29 JP JP2007505484A patent/JP4948392B2/en not_active Expired - Fee Related
- 2005-03-29 PT PT57302887T patent/PT1729739T/en unknown
- 2005-03-29 LT LTEP05730288.7T patent/LT1729739T/en unknown
- 2005-03-29 EA EA200601608A patent/EA011712B1/en not_active IP Right Cessation
- 2005-03-29 DK DK05730288.7T patent/DK1729739T3/en active
- 2005-03-29 ES ES05730288.7T patent/ES2603856T3/en active Active
- 2005-03-29 US US10/599,154 patent/US20070172524A1/en not_active Abandoned
- 2005-03-29 EP EP05730288.7A patent/EP1729739B1/en not_active Revoked
- 2005-03-29 WO PCT/EP2005/003277 patent/WO2005094793A1/en active Application Filing
-
2006
- 2006-10-27 NO NO20064934A patent/NO20064934L/en not_active Application Discontinuation
-
2009
- 2009-06-03 US US12/477,727 patent/US20100172995A1/en not_active Abandoned
-
2016
- 2016-11-03 CY CY20161101118T patent/CY1118180T1/en unknown
- 2016-11-30 HR HRP20161602TT patent/HRP20161602T1/en unknown
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WO2003059388A1 (en) * | 2002-01-15 | 2003-07-24 | Delta Hf. | Formulations of quinapril and related ace inhibitors |
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Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1729739B1 (en) | 2004-03-29 | 2016-09-28 | Les Laboratoires Servier | Process for preparing a solid pharmaceutical composition |
WO2007025695A1 (en) * | 2005-08-30 | 2007-03-08 | Lek Pharmaceuticals D.D. | Pharmaceutical composition comprising perindopril or its salts |
EP1948224A1 (en) | 2005-11-17 | 2008-07-30 | Diagen Smartno pri Ljubljani, d.o.o. | Stable formulation of amorphous perindopril salts, a process for their preparation, especially industrial preparation, and their use in the therapy of hypertension |
WO2007058634A1 (en) * | 2005-11-17 | 2007-05-24 | Diagen Smartno Pri Ljubljani, D.O.O. | Stable formulation of amorphous perindopril salts, a process for their preparation, especially industrial preparation, and their use in the therapy of hypertension |
EP1815857A1 (en) | 2006-02-02 | 2007-08-08 | LEK Pharmaceuticals D.D. | A pharmaceutical composition comprising perindopril |
WO2007120930A2 (en) * | 2006-04-19 | 2007-10-25 | Teva Pharmaceutical Industries Ltd. | Stable pharmaceutical compositions of 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivatives |
JP2009533461A (en) * | 2006-04-19 | 2009-09-17 | テバ ファーマシューティカル インダストリーズ リミティド | Stable pharmaceutical composition of 2-aza-bicyclo [3.3.0] -octane-3-carboxylic acid derivative |
WO2007120930A3 (en) * | 2006-04-19 | 2008-02-07 | Teva Pharma | Stable pharmaceutical compositions of 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivatives |
JP2009537538A (en) * | 2006-05-15 | 2009-10-29 | アカドイア プハルマセウチカルス インコーポレーテッド | Pimavanserin pharmaceutical formulation |
WO2008068577A2 (en) * | 2006-12-01 | 2008-06-12 | Glenmark Pharmaceuticals Limited | Pharmaceutical compositions |
WO2008068577A3 (en) * | 2006-12-01 | 2009-04-23 | Glenmark Pharmaceuticals Ltd | Pharmaceutical compositions |
JP2010516699A (en) * | 2007-01-18 | 2010-05-20 | エヴォルヴァ エスアー | Substituted 1,3-dioxanes useful as PPAR modulators |
US8470869B2 (en) | 2007-06-27 | 2013-06-25 | Krka, Tovarna Zdravil D.D. Novo Mesto | Salts of perindopril |
WO2014076632A1 (en) | 2012-11-15 | 2014-05-22 | Adamed Sp. Z O.O. | A pharmaceutical composition containing an ace inhibitor and a calcium channel blocker |
CN109700774A (en) * | 2019-03-05 | 2019-05-03 | 上药东英(江苏)药业有限公司 | A kind of perindopril tert-butylamine piece and its powder vertical compression technique |
Also Published As
Publication number | Publication date |
---|---|
LT1729739T (en) | 2016-11-10 |
JP2007530623A (en) | 2007-11-01 |
ES2603856T3 (en) | 2017-03-01 |
PL1729739T3 (en) | 2017-04-28 |
EA200601608A1 (en) | 2007-02-27 |
US20070172524A1 (en) | 2007-07-26 |
JP4948392B2 (en) | 2012-06-06 |
EA011712B1 (en) | 2009-04-28 |
HRP20161602T1 (en) | 2016-12-30 |
NO20064934L (en) | 2006-10-27 |
EP1729739B1 (en) | 2016-09-28 |
DK1729739T3 (en) | 2016-10-31 |
CY1118180T1 (en) | 2017-06-28 |
EP1729739A1 (en) | 2006-12-13 |
PT1729739T (en) | 2016-12-01 |
US20100172995A1 (en) | 2010-07-08 |
HUE031058T2 (en) | 2017-06-28 |
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