WO2011112160A1 - Extended release trimetazidine tablets - Google Patents
Extended release trimetazidine tablets Download PDFInfo
- Publication number
- WO2011112160A1 WO2011112160A1 PCT/TR2010/000173 TR2010000173W WO2011112160A1 WO 2011112160 A1 WO2011112160 A1 WO 2011112160A1 TR 2010000173 W TR2010000173 W TR 2010000173W WO 2011112160 A1 WO2011112160 A1 WO 2011112160A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- extended release
- trimetazidine
- composition according
- release tablet
- tablet
- 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
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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Definitions
- Present invention is related to the controlled release form containing 1 -(2,3,4- trimethoxybenzyl) piperazine dihydrochloride and prepared by direct compressing using polyethylene oxide.
- the formulation presents a stable release profile in the pH limit of gastrointestinal system and stabilized in terms of impurities.
- Trimetazidine is a 1-(2,3,4-trimethoxybenzyl) piperazine compound, molecular formula of which is Ci 4 H 2 2 2 0 3 (Formula I). Its molecular weight is 266.34 and freely soluble in water, it has two pKa values at 4.32 and 8.95.
- Trimetazidine prevents the reduction of intracellular ATP (Adenosintriphosphate) by protecting the energy metabolism of the cell exposed to hypoxia or ischemia.
- intracellular ATP Adosintriphosphate
- mechanism of ion pumps and intracellular entrance-exit of Na/K ions are arranged and cellular homeostasis is established. It is indicated in treatment of 'Angina pectoris'.
- trimetazidine dihydrochloride 20 mg immediate release tablets and controlled release tablets containing 35 mg Trimetazidine. It is quickly absorbed and reaches maximum blood concentration in 1.8+0.7 h. Plasma elimination half life is about 6+1.4 hours. As it has a short plasma elimination half life, 20 mg preparation is applied 2 or 3 times daily to practically get relatively stable plasma levels. As the active substance is absorbed quickly, maximum plasma concentration is reached shortly after the dose application. On the other hand, when next dose is taken, plasma level is quite low.
- EP 0673649 describes the extended release form prepared with a coat made of a polymer insoluble in water and a plastifiying agent.
- JP61212517 describes trimetazidine matrix tablet in which hydroxypropyl methylcellulosephytalate, cellulose acetate phytalate as polymeric matrix.
- EP 1108424 describes the extended release trimetazidine tablets prepared by wet granulation in which cellulose derivatives were used as matrix.
- the characteristic of the patent is the controlling of extended release by a cellulose derivative polymer chosen among cellulose ethers, hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethy!cellulose, methyl cellulose, hydroxypropyl methyl cellulose. Hydroxy propyl methyl cellulose was preferentially used as a cellulose derivative.
- EP1195160 describes the extended release form, generated with trimetazidine and at least one or more hydrocolloidal material, one or more hydrophobic polymer and at least one or more other hydrophobic materials.
- EP1448173 describes the spheres of trimetazide, extended release of which were provided by coating with polymers insoluble in water.
- WO2009034541 describes the matrix tablets prepared by polymers insoluble or swelling in water or a mix of these two. Xanthane gum was used as polymer swelling in water.
- Y-145 is not present in pharmacopeia (Computer Assisted Optimization and Validation of LC Analysis of Trimetazidine dihydrochloride and its Impurities, J. Chrom.ScL.Vol 46 May/June 2008).
- This compound is chemically 4-(2,3,4-trimethoxybenzyl)- 1-piperazinecarbaldehyde hydrochloride compound. Relative retension time of this compound was found to be 0.31 in HPLC test performed in conformity with European Pharmacopeia.
- Polyethylene oxide used in the formulation, is a water soluble resin and is also known by the trade name Polyox WSR 303. Viscosity of 1% solution is 7500-10000. It is used in 15-40%, preferably 28-32% concentration in the formulation.
- pH buffer agent calcium phosphate dibasic dihydrate Due to pH buffer agent calcium phosphate dibasic dihydrate in the formulation, similar release was observed in all pH levels of the digestive system. It is used in 45-70%, preferably 50-54%) concentration in the formulation.
- Formula 1-3 was prepared by wet granulation and 4-5 by direct compressing.
- Figure 2 Dissolution profile of formulation 4 in pH:1.2. 5.4 and 6.8 environment.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Related to the controlled release form prepared by direct compressing using polyethylene oxide. The formulation presents a stable release profile in the pH limit of gastrointestinal system and stabilized in terms of impurities.
Description
EXTENDED RELEASE TRIMETAZIDINE TABLETS DESCRIPTION Technical Field:
Present invention is related to the controlled release form containing 1 -(2,3,4- trimethoxybenzyl) piperazine dihydrochloride and prepared by direct compressing using polyethylene oxide. The formulation presents a stable release profile in the pH limit of gastrointestinal system and stabilized in terms of impurities.
Previous Technique:
Trimetazidine is a 1-(2,3,4-trimethoxybenzyl) piperazine compound, molecular formula of which is Ci4H22 203 (Formula I). Its molecular weight is 266.34 and freely soluble in water, it has two pKa values at 4.32 and 8.95.
Trimetazidine prevents the reduction of intracellular ATP (Adenosintriphosphate) by protecting the energy metabolism of the cell exposed to hypoxia or ischemia. Thus mechanism of ion pumps and intracellular entrance-exit of Na/K ions are arranged and cellular homeostasis is established. It is indicated in treatment of 'Angina pectoris'.
There are trimetazidine dihydrochloride 20 mg immediate release tablets and controlled release tablets containing 35 mg Trimetazidine. It is quickly absorbed and reaches maximum blood concentration in 1.8+0.7 h. Plasma elimination half life is about 6+1.4 hours. As it has a short plasma elimination half life, 20 mg preparation is applied 2 or 3 times daily to practically get relatively stable plasma levels. As the active substance is absorbed quickly, maximum plasma concentration is reached shortly after the dose application. On the other hand, when next dose is taken, plasma level is quite low.
EP 0673649 describes the extended release form prepared with a coat made of a polymer insoluble in water and a plastifiying agent. Cellulose or acrylic acid derivatives were use for coating and acetyl or dibutyl sebacoat as plastifying agent. JP61212517 describes trimetazidine matrix tablet in which hydroxypropyl methylcellulosephytalate, cellulose acetate phytalate as polymeric matrix.
EP 1108424 describes the extended release trimetazidine tablets prepared by wet granulation in which cellulose derivatives were used as matrix. The characteristic of the patent is the controlling of extended release by a cellulose derivative polymer chosen among cellulose ethers, hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethy!cellulose, methyl cellulose, hydroxypropyl methyl cellulose. Hydroxy propyl methyl cellulose was preferentially used as a cellulose derivative. EP1195160 describes the extended release form, generated with trimetazidine and at least one or more hydrocolloidal material, one or more hydrophobic polymer and at least one or more other hydrophobic materials.
EP1448173 describes the spheres of trimetazide, extended release of which were provided by coating with polymers insoluble in water.
WO2009034541 describes the matrix tablets prepared by polymers insoluble or swelling in water or a mix of these two. Xanthane gum was used as polymer swelling in water.
Description of the Invention:
The compounds stated as impurities in European Pharmacopeia, Monograph of Trimetazidine Dihydrochloride are analyzed by HPLC method. Relative retension times for these compounds were stated in the pharmacopeia (impurity D= approx. 0.2; impurity C=approx. 0.4; impurity H=approx. 0.6; impurity A and I = approx. 0.9; impurity E = approx. 0.95; impurity F = approx. 1.4; impurity B = approx. 1.8 Nevertheless, one more impurity called Y-145, which is not present in pharmacopeia (Computer Assisted Optimization and Validation of LC Analysis of Trimetazidine dihydrochloride and its Impurities, J. Chrom.ScL.Vol 46 May/June 2008). This compound is chemically 4-(2,3,4-trimethoxybenzyl)- 1-piperazinecarbaldehyde hydrochloride compound. Relative retension time of this
compound was found to be 0.31 in HPLC test performed in conformity with European Pharmacopeia.
During the stability studies on trimetazidine extended release tablets, it was found out that, Y-145 impurity with 0.31 relative retention time which is out of the relative retention times of the impurities determined in European Pharmacopeia Trimetazidine Dihydrochloride monograph exceeded the 0.2% limit predicted for the unknown impurities in ICH Guide (Q3B(R2)) A similar event was observed with 20 mg conventional tablet and 35 mg SR tablet, known to be a matrix tablet and containing hydroxypropyl methylcellulose. In the impurity tests performed on these tablets under normal circumstances, Y-145 impurity was found to be exceeding 0.2% limit (Table 1).
Table 1. Y-145 impurity level of the commercially available tablets
It was targeted to keep the Y-145 impurity level below 0.2% value during the shelf life with various formulation trials. In order to do this, the formulations given in Table 2 were studied.
Developed formulation content and production technique allowed to keep the impurities of products in the limits defined in ICH guides during their shelf life. Polyethylene oxide, used in the formulation, is a water soluble resin and is also known by the trade name Polyox WSR 303. Viscosity of 1% solution is 7500-10000. It is used in 15-40%, preferably 28-32% concentration in the formulation.
Due to pH buffer agent calcium phosphate dibasic dihydrate in the formulation, similar release was observed in all pH levels of the digestive system. It is used in 45-70%, preferably 50-54%) concentration in the formulation.
As the formulation was produced with direct compressing method, it is cost- and time- efficient.
Table 2. Tested formulations
Not: Formula 1-3 was prepared by wet granulation and 4-5 by direct compressing.
1 mix of maize starch and pregelatinized starch
2 polyvinylpyrrolidone
3 polyethylene oxide
4 colloidal silicon dioxide
6 hours of test was applied to all formulations with pedal type dissolution device in 50 rpm in 500 ml 6.8 phosphate buffer and the results of the test were given below.
Table 3. Results of the dissolution test
When 3 months of stability test was applied to these formulations in 40°C, impurity levels with 0.31 relative retention time were given in the table below.
Table 4. Y-145 impurity level in the stability test
These results demonstrate the developed formulations are stable in the terms of impurities with 0.31 relative retention time.
Dissolution profile studies were performed in 3 different pH values for formulation 4. Similar release was observed in three pH levels as shown in Table 5. This suggests that, release profile does not alter in different pH levels representing stomach, duodenum and intestines.
Table 5. 3 different release profiles for formulation 4
Description of the figures
Figure 1: Dissolution profile of formulation 4 and Vastarel 35 mg tablet is in pH 6.8
Figure 2: Dissolution profile of formulation 4 in pH:1.2. 5.4 and 6.8 environment.
Claims
1. An extended release tablet composition comprising trimetazidine hydrochloride characterized in that the composition comprises polyethylene oxide as release control agent and calcium phosphate dibasic dihydrate as buffer agent.
2. An extended release tablet composition according to claim 1 characterized in that the Y- 145 impurity of Trimetazidine is below 0.2% after 3 months in 40°C degrees.
3. An extended release tablet composition according to claim 1 characterized in that the viscosity of polyethylene dioxide measured as a 1% aqueous solution is 7500-10000 cps.
4. An extended release tablet composition according to claim 1 characterized in that the amount of polyethylene oxide in the tablet is 15-40% (w/w).
5. An extended release tablet composition according to claim 1 characterized in that the amount of polyethylene oxide in the tablet is 28-32% (w/w).
6. An extended release tablet composition according to claim 1 characterized in that the amount of calcium phosphate dibasic dihydrate in the tablet is 45-70% (w/w).
7. An extended release tablet composition according to claim 1 characterized in that the amount of calcium phosphate dibasic dihydrate in the tablet is 50-54% (w/w).
8. An extended release tablet composition according to previous claims characterized in that said tablet is produced by direct compression.
9. Trimetazidine extended release tablet:
Trimetazidine Dihydrochloride 35.0 mg
Dicalcium Phosphate Dihydrate 104.0 mg
Polyethylene oxide 58.9 mg
Colloidal silicon dioxide 0.6 mg
Magnesium stearate 1.5 mg
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2010/01902 | 2010-03-12 | ||
| TR2010/01902A TR201001902A2 (en) | 2010-03-12 | 2010-03-12 | Trimetazidine tablets with extended release |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011112160A1 true WO2011112160A1 (en) | 2011-09-15 |
Family
ID=43244791
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2010/000173 Ceased WO2011112160A1 (en) | 2010-03-12 | 2010-09-01 | Extended release trimetazidine tablets |
Country Status (2)
| Country | Link |
|---|---|
| TR (1) | TR201001902A2 (en) |
| WO (1) | WO2011112160A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102885795A (en) * | 2012-10-31 | 2013-01-23 | 广州帝奇医药技术有限公司 | Trimetazidine dihydrochloride sustained-release tablet and preparation method thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61212517A (en) | 1985-03-18 | 1986-09-20 | Nippon Chemiphar Co Ltd | Long-acting tablet |
| EP0673649A1 (en) | 1994-03-24 | 1995-09-27 | Adir Et Compagnie | Pharmaceutical compositions for the prolonged release of trimetazidine after oral administration |
| EP1108424A1 (en) | 1999-12-17 | 2001-06-20 | Adir Et Compagnie | Matrix tablet for sustained release of trimetazidine after oral administration |
| EP1195160A1 (en) | 2000-10-05 | 2002-04-10 | USV Ltd. | Sustained release trimetazidine pharmaceutical compositions and a method of their preparation |
| EP1448173A2 (en) | 2001-11-21 | 2004-08-25 | Themis Laboratories Private Limited | A process for manufacture of a sustained release pharmaceutical composition containing microbeads of trimetazidine dihydrochloride |
| WO2006123073A1 (en) * | 2005-05-18 | 2006-11-23 | Les Laboratoires Servier | Sustained release solid pharmaceutical composition of 1-(2,3,4-trimethoxybenzyl)piperazine and a method for the preparation thereof |
| WO2009034541A2 (en) | 2007-09-11 | 2009-03-19 | Ranbaxy Laboratories Limited | Controlled release pharmaceutical dosage forms of trimetazidine |
| WO2009066315A2 (en) * | 2007-08-08 | 2009-05-28 | Usv Limited | Sustained release compositions of trimetazidine and process for preparation thereof |
-
2010
- 2010-03-12 TR TR2010/01902A patent/TR201001902A2/en unknown
- 2010-09-01 WO PCT/TR2010/000173 patent/WO2011112160A1/en not_active Ceased
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61212517A (en) | 1985-03-18 | 1986-09-20 | Nippon Chemiphar Co Ltd | Long-acting tablet |
| EP0673649A1 (en) | 1994-03-24 | 1995-09-27 | Adir Et Compagnie | Pharmaceutical compositions for the prolonged release of trimetazidine after oral administration |
| EP1108424A1 (en) | 1999-12-17 | 2001-06-20 | Adir Et Compagnie | Matrix tablet for sustained release of trimetazidine after oral administration |
| EP1195160A1 (en) | 2000-10-05 | 2002-04-10 | USV Ltd. | Sustained release trimetazidine pharmaceutical compositions and a method of their preparation |
| EP1448173A2 (en) | 2001-11-21 | 2004-08-25 | Themis Laboratories Private Limited | A process for manufacture of a sustained release pharmaceutical composition containing microbeads of trimetazidine dihydrochloride |
| WO2006123073A1 (en) * | 2005-05-18 | 2006-11-23 | Les Laboratoires Servier | Sustained release solid pharmaceutical composition of 1-(2,3,4-trimethoxybenzyl)piperazine and a method for the preparation thereof |
| WO2009066315A2 (en) * | 2007-08-08 | 2009-05-28 | Usv Limited | Sustained release compositions of trimetazidine and process for preparation thereof |
| WO2009034541A2 (en) | 2007-09-11 | 2009-03-19 | Ranbaxy Laboratories Limited | Controlled release pharmaceutical dosage forms of trimetazidine |
Non-Patent Citations (2)
| Title |
|---|
| "Computer Assisted Optimization and Validation of LC Analysis of Trimetazidine dihydrochloride and its Impurities", J. CHROM.SCI., vol. 46, May 2008 (2008-05-01) |
| MEDENICA MIRJANA B ET AL: "Computer-assisted optimization and validation of LC analysis of trimetazidine dihydrochloride and its impurities", JOURNAL OF CHROMATOGRAPHIC SCIENCE, PRESTON PUBLICATIONS, NILES, IL, US, vol. 46, no. 5, 1 May 2008 (2008-05-01), pages 430 - 435, XP009142314, ISSN: 0021-9665 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102885795A (en) * | 2012-10-31 | 2013-01-23 | 广州帝奇医药技术有限公司 | Trimetazidine dihydrochloride sustained-release tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| TR201001902A2 (en) | 2011-04-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1202812C (en) | Direct comperession polymer tablet core | |
| US20090324718A1 (en) | Imatinib compositions | |
| US20230190732A1 (en) | Pharmaceutical composition containing nitroxoline prodrug, and preparation method and application therefor | |
| TR201900350T4 (en) | A pharmaceutical composition containing candesartan cilexetil and amlodipine. | |
| EP3793529A1 (en) | Stable pharmaceutical compositions of dpp-iv inhibitors in combination with metformin in the form of immediate release tablets | |
| EP2833871A1 (en) | Prasugrel-containing immediate release stable oral pharmaceutical compositions | |
| WO2009034540A1 (en) | Pharmaceutical composition of sevelamer | |
| WO2011112160A1 (en) | Extended release trimetazidine tablets | |
| WO2022225489A1 (en) | A bilayer tablet formulation comprising amorphous dapagliflozin and metformin | |
| Gudigennavar et al. | Development and evaluation of gastro-retentive drug delivery systems of cefuroxime axetil | |
| BR112015014430B1 (en) | TABLET COMPOSITION | |
| TR202019592A2 (en) | Solid pharmaceutical formulations of amorphous dapagliflozin | |
| EP2545907A1 (en) | Aqueous wet granulation process for cross-linked polyallylamine polymers | |
| CN112294770A (en) | Isosorbide mononitrate compound preparation and application and preparation method thereof | |
| Setti et al. | Preparation and evaluation of controlled release tablets of carvedilol | |
| KR101460783B1 (en) | Pharmaceutical composition of candesartan cilexetil with improved stability and method for preparing thereof | |
| EP1628642B1 (en) | Controlled drug release composition resistant to in vivo mechanic stress | |
| RU2749719C1 (en) | Drug for treatment of anemia associated with chronic kidney disease and method for its obtaining | |
| WO2023136797A2 (en) | A bilayer tablet composition comprising amorphous dapagliflozin and metformin | |
| CN103768034A (en) | Sustained or controlled release solid composition comprising bupropion hydrochloride | |
| WO2022119543A1 (en) | A process for tablet formulations comprising amorphous dapagliflozin and metformin hydrochloride | |
| CN108785263B (en) | Solid pharmaceutical composition of pramipexole or pharmaceutical salt thereof and preparation method thereof | |
| CA2735008C (en) | Extended release formulation for optimized delivery of an hiv attachment inhibitor | |
| Kumar et al. | Formulation and release kinetic study of Hydrogel containing Acarbose using polymers as Hydroxypropylmethyl cellulose and Guar gum | |
| Bumbu et al. | Influence of the composition of hydroxypropyl cellulose/maleic acid-alt-styrene copolymer blends on their properties as matrix for drug release |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10769093 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 10769093 Country of ref document: EP Kind code of ref document: A1 |