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WO2008062435A2 - Stabilised dosage forms of amlodipine besylate - Google Patents

Stabilised dosage forms of amlodipine besylate Download PDF

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Publication number
WO2008062435A2
WO2008062435A2 PCT/IN2007/000385 IN2007000385W WO2008062435A2 WO 2008062435 A2 WO2008062435 A2 WO 2008062435A2 IN 2007000385 W IN2007000385 W IN 2007000385W WO 2008062435 A2 WO2008062435 A2 WO 2008062435A2
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Prior art keywords
solid dosage
dosage form
stable solid
polyols
combination
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Ceased
Application number
PCT/IN2007/000385
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French (fr)
Other versions
WO2008062435A3 (en
Inventor
Sandeep G. Datarkar
Mavuleti Krishna Prasad
Vemula Sathya Narayana
Samprada Singh
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Alkem Laboratories Ltd
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Alkem Laboratories Ltd
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Publication of WO2008062435A3 publication Critical patent/WO2008062435A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/44221,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the technical field of present invention relates to a stable solid dosage form of amlodipine besylate comprising polyols and having reduced levels of total impurities on stability and especially impurity D (defined below).
  • the invention has been developed primarily for use as a solid oral dosage fprm and will be described hereinafter with reference to this application.
  • Amlodipine besylate is chemically described as3-Ethyl-5-methyl( ⁇ )-2-[(2- aminoethoxy ⁇ ethylJ ⁇ -chlorophenyO-l ⁇ -dihydro- ⁇ -methyl-SjS pyridinedicarboxylate,monobenzenesulphonate.
  • This compound is used for the preparation of a medicament having calcium channel blocking activity that is useful, inter alia, in the nianagement of hypertension, congestive heart failure and angina pectoris.
  • Polyols have been successfully used in food and confectionery applications for more than 30 years. Originally introduced in "sugar-free candies for diabetic diets, polyols have gained wide acpeptance for enhancing processing, stability, shelf-life, and texture in sugar applications as well Polyols are sugar-free sweeteners. Polyols are carbohydrates but they are not sugars. Unlike high potency sweeteners like aspartame, which is Used in very small amount, polyols are used in the same quantity as sucrose. Chemically, polyols are considered polyhydric alcohols or sugar alcohols because part of their structure resembles sugar and part is similar to alcohols. However, these sugar-free sweetenefs are neither sugars nor alcohols, as these words are commonly used.
  • polyols are derived from carbohydrates whose carbonyl group (aldehyde or ketone, reducing sugar), has been reduced to a primary or secondary hydroxyl group.
  • the most widely used polyols are sorbitol, mannitol, and maltitol. Sorbitol is derived from glucose, mannitol frqm fructose, and maltitol frotn high maltose corn syrup. There are a number of different polyols
  • U.S. Pat. No. 4,879,303 and corresponding EP 244 944 Edward Davison describes the commercial product of amlodipine (NORV ASC® by Pfizer, Inc.), which contains amlodipine besylate.
  • This patent discloses a singly form of amlodipine besylate, namely a crystalline anhydrous besylate salt of amlodipine.
  • the inactive ingredients in the Norvasc tablets include microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.
  • Nagaprasad relates to stable solid dosage forms of amlodipine base and process of preparation, which it free of dicalcium phosphate.
  • the stable amlodipine solid dosage form includes amlodipine base, microcrystalline cellulose, is substantially free of dicalcium phosphate, and has less than about 0.5% concentration (w/w) of Impurity D after three months at 40 Q C and 75% relative humidity.
  • WO Patent No 03051364Al Fek ⁇ te relates to amlodipine bezylate tablets with improved ⁇ Stability of the active ingredient and reduced in weight containing microcrystalline cellulose, a lubricant and a disintegrating agent.
  • the invention also relates to a process for the preparation of the said tablets.
  • microcrystalline cellulose also absorbs the moisture and amlodipine degrades and generates impurity in presence of moisture.
  • amlodipine salt form dis ⁇ losed in the above patents is suitable for a commercial product, but they suffer from some drawbacks in terms of stability, and impurity profiling. Further it has been disclosed in the prior art that free base compositions, which include microcrystalline cellulose as diluents lead to process related issues.
  • the present invention relates to a stable solid dosage form comprising 2-20 % by weight of amlodipine besylate, 10-70 % by weight polyols, and at least a known pharmaceutical excipieni Particulalry, it relates to a stable solid dosage form of amlodipine besylate comprising polyols and having reduced levels of Impurity D and total impurities.
  • Another aspect of the invention includes use of pregelatinised starch to improve the processing of the formulation.
  • stable refers to chemical stability of amlodipine in solid dosage forms.
  • the dosage form includes one or more pharmaceutical excipients selected from diluents, binders, de$iccants, disintegrants, coloring agents, flavoring agents, surfactants, lubricants/glidants, plasticizers and preservatives.
  • disintegrants examples include sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like.
  • binders include dry ⁇ and wet binders like methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragarcanth, sodium alginate, and the like.
  • diluents include- dextrates, dextrins, dextrose excipients, fructose, kaolin* lactitol, mannitol, sorbitol, xyletol, and other polyols, starch pregelatinized, sucrose, sugar compressible sugar confectioners, and the like.
  • lubricants and glidants include colloidal silicon dioxide, magnesium stearate, and colloidal anhydrous silica, stearic acid, magnesium stearate, and calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, fumarates and the like.
  • coloring agents include any FDA approved colors for oral use.
  • stable solid dosage forms of amlodipine besylate along with other pharmaceutically accepted excipients more specifically the preferred embodiment is a composition of amlodipine besylate comprising polyols and having significantly reduced level of total impurities, especially impurity D.
  • the stable amlodipine tablets were prepared as follows:
  • step 5 was added to that of step 4 & lubricated for 5 minutes.
  • step 6 The above blend obtained in step 6 was compressed with their respective punch.
  • the tablets obtained above were subjected to stability evaluation on both enclosed and open exposure at 40°C and 75% relative humidity.
  • the formulation was also subjected to stress studies like autoclaving.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a stable solid dosage form comprising 2-20 % by weight of amlodipine besylate, 10-70 % by weight polyols, at least a known pharmaceutical excipient, and having levels of impurity D (3-ethyl-5-methyl-2[(2-aminoethoxy)-methyl]-4-(2- chlorophenyl)-6-methylpyridine-3,5 dicarboxylate) less than 0,5 %.

Description

TITLE
STABILISED DOSAGE FORMS OF AMLODEPINE BESYLATE
T1IELD OF INVENTION
The technical field of present invention relates to a stable solid dosage form of amlodipine besylate comprising polyols and having reduced levels of total impurities on stability and especially impurity D (defined below).
The invention has been developed primarily for use as a solid oral dosage fprm and will be described hereinafter with reference to this application.
BACKGROUND OF THE INVENTION
Amlodipine besylate is chemically described as3-Ethyl-5-methyl(±)-2-[(2- aminoethoxy^ethylJ^^-chlorophenyO-l^-dihydro-ό-methyl-SjS pyridinedicarboxylate,monobenzenesulphonate. This compound is used for the preparation of a medicament having calcium channel blocking activity that is useful, inter alia, in the nianagement of hypertension, congestive heart failure and angina pectoris.
DESCRIPTION OF THE PRIOR ART:
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.
Prior literature discloses that Amlodipine is highly hydroscopic and absorbs moisture, which leads to degradation via the catalytic oxidative process, which is pH dependent. The major related substances produced are {3-ethyl 5-methyl (4RS) 4-(2-chlorophenyl)- 6-methyI-2-[[2-&lsήb;[2(methylcarbamoyl) benzoyl&rsqb amino] ethoxy] methyl&rsqb ;-l,4-dihydropyridine-3,5 dicarboxylate}(Impurity B){3-ethyl-5-methyl-2-[ (2-aminoethόxy) methyl] 4- (2-chlorophenyl)-6-methylpyridine-3,5 dicarboxylate} ("Impurity D"); and {3- ethyl $-methyl (4RS) 4-(2-chlorophenyl)-2[[2-(l,3-dioxo- dihydro-2H-isoindol-2- yl) ethoxy]methyl]-6-methyI-l,4-4ihydropyridine-3, 5 dicarboxylate} ("Impurity A"), along with some unknown impurities.
Polyols have been successfully used in food and confectionery applications for more than 30 years. Originally introduced in "sugar-free candies for diabetic diets, polyols have gained wide acpeptance for enhancing processing, stability, shelf-life, and texture in sugar applications as well Polyols are sugar-free sweeteners. Polyols are carbohydrates but they are not sugars. Unlike high potency sweeteners like aspartame, which is Used in very small amount, polyols are used in the same quantity as sucrose. Chemically, polyols are considered polyhydric alcohols or sugar alcohols because part of their structure resembles sugar and part is similar to alcohols. However, these sugar-free sweetenefs are neither sugars nor alcohols, as these words are commonly used. They are derived from carbohydrates whose carbonyl group (aldehyde or ketone, reducing sugar), has been reduced to a primary or secondary hydroxyl group. The most widely used polyols are sorbitol, mannitol, and maltitol. Sorbitol is derived from glucose, mannitol frqm fructose, and maltitol frotn high maltose corn syrup. There are a number of different polyols
The varipus compositions of amlodipine can be known from the prior patents as follows:
For example; U.S. Pat. No. 4,879,303 and corresponding EP 244 944 Edward Davison describes the commercial product of amlodipine (NORV ASC® by Pfizer, Inc.), which contains amlodipine besylate. This patent discloses a singly form of amlodipine besylate, namely a crystalline anhydrous besylate salt of amlodipine. The inactive ingredients in the Norvasc tablets include microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.
WO Patent No 04075825A2, Nagaprasad relates to stable solid dosage forms of amlodipine base and process of preparation, which it free of dicalcium phosphate. The stable amlodipine solid dosage form includes amlodipine base, microcrystalline cellulose, is substantially free of dicalcium phosphate, and has less than about 0.5% concentration (w/w) of Impurity D after three months at 40QC and 75% relative humidity.
WO Patent No 03051364Al Fekςte relates to amlodipine bezylate tablets with improved \ Stability of the active ingredient and reduced in weight containing microcrystalline cellulose, a lubricant and a disintegrating agent. The invention also relates to a process for the preparation of the said tablets.
A great deal of research has been done in this area to inporporate amlodipine with other pharmaceutically accepted excipients but it always results in stability problems.
To overcome the problems associated with the prior arts, an intensive and thorough research resulted in providing the most advantageous solid formulation in terms of both stability and processing characteristics. This inclμdes ariilodipine besylate along with polyols to overcome the shortcomings of microcrystalline cellulose. Besides this, results in reduced levels of Impurity D and total impurities.
It is well known that microcrystalline cellulose also absorbs the moisture and amlodipine degrades and generates impurity in presence of moisture.
While the amlodipine salt form disςlosed in the above patents is suitable for a commercial product, but they suffer from some drawbacks in terms of stability, and impurity profiling. Further it has been disclosed in the prior art that free base compositions, which include microcrystalline cellulose as diluents lead to process related issues.
OBJECT1 OF THE INVENTION
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
It is an object of the invention in its preferred form to provide stable solid dosage forms of amlodipine besylate and pro, cess of preparation thereof comprising polyols and which have reduced levels of total impurities arid especially impurity D on stability.
SUMMARY OF THE INVENTION
The present invention relates to a stable solid dosage form comprising 2-20 % by weight of amlodipine besylate, 10-70 % by weight polyols, and at least a known pharmaceutical excipieni Particulalry, it relates to a stable solid dosage form of amlodipine besylate comprising polyols and having reduced levels of Impurity D and total impurities.
Another aspect of the invention includes use of pregelatinised starch to improve the processing of the formulation. The term "stable" as used herein refers to chemical stability of amlodipine in solid dosage forms.
The dosage form includes one or more pharmaceutical excipients selected from diluents, binders, de$iccants, disintegrants, coloring agents, flavoring agents, surfactants, lubricants/glidants, plasticizers and preservatives.
Examples of disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like.
Examples of binders include dry^ and wet binders like methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragarcanth, sodium alginate, and the like.
Examples of diluents include- dextrates, dextrins, dextrose excipients, fructose, kaolin* lactitol, mannitol, sorbitol, xyletol, and other polyols, starch pregelatinized, sucrose, sugar compressible sugar confectioners, and the like.
Examples of lubricants and glidants include colloidal silicon dioxide, magnesium stearate, and colloidal anhydrous silica, stearic acid, magnesium stearate, and calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, fumarates and the like. Examples of coloring agents include any FDA approved colors for oral use.
PREFERRED EMBODIMENT OF THE INVENTION
In accordance with one preferred embodiment there is provided stable solid dosage forms of amlodipine besylate along with other pharmaceutically accepted excipients, more specifically the preferred embodiment is a composition of amlodipine besylate comprising polyols and having significantly reduced level of total impurities, especially impurity D.
Preferred embodiments are further illustrated in the following examples. Example: 1
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
The stable amlodipine tablets were prepared as follows:
1. Amlodipine Besylate was Weighed based on its potency. 2. Mannitol (Perlitol SD 200)» PG search, Ac-Di-SoI, Aerosil 200 and Magnesium Stearate were weighed.
3. Amlodipine Besylate, Mannitol (Eerlitoϊ SD 200), PG starch, Ac-Di-Soi, Aerosil 21OO were sieved separately through sieve size of mesh 40. 4. AU of the above ingredients were mixed in a blender for 30 minutes.
5. Equal quantities of above blend & Magnesium Stearate were miiced properly,
6. Finally, the blend of step 5 was added to that of step 4 & lubricated for 5 minutes.
7. The above blend obtained in step 6 was compressed with their respective punch.
The tablets obtained above were subjected to stability evaluation on both enclosed and open exposure at 40°C and 75% relative humidity.
40°c/75%RH Amlodipine Besylate tablets compilation data (stability chamber) of lixiample-5
Amlodipine besylate Tablets lOmg
Figure imgf000011_0001
40°C/75%RH AMLODIPINE BESYLATE TABLETS COMPILATION DATA (Stability chamber)
Stability Batch VI
Amlodipine besylate Tablets lOmg
Figure imgf000012_0001
The formulation was also subjected to stress studies like autoclaving.
All the above studies indicated that amlodipine tablets without dicalcium phosphate and microcrystalline cellulose are more stable and had significantly lower levels of total impurities especially impurity D, which was less than 0.5%. Although the invention has been described with reference to a specific example, it will be appreciated by those skilled in the art that trie invention may be embodied in many other forms.

Claims

CLAIMS:
1. A stable solid dosage form comprising 2-20 % by weight of amiodipine besylate, 10-70 % by weight polyols, and at least a known pharmaceutical excipient.
2. A stable solid dosage form as claimed in Claim I^ wherein said pharmaceutical excipient is selected from known diluents, binders, desiccants, disintegranfe, coloring agents, flavoring agents, surfactants, lubricants/glidants, plasticizers or preservatives.
3. A stable solid dosage form as claimed in Claim 1 or 2, wherein said polyols is mannitol, sorbitol, maltitol, xylitol, lactitol or erythritol.
4. A stable solid dosage form as claimed in Claim 2, wherein said disintegrants is sodium starch glycolate, croscarmellose sodium, crospovidone or low substituted hydroxypropyl cellulose or any combination thereof.
5. A- stable solid dosage form as claimed in Claim 2, wherein said binders include dry and wet binders like rήethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylceJIulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragarcanth or sodium alginate or any combination thereof.
6. A stable solid dosage form as claimed in Claim 2, wherein said diluents include dextrates, dextrins, dextrose excipients* fructose, kaolin, lactitol, mannitbl, sorbitol, xyletol, and other known polyols, starch pregelatinized, sucrose or sugar compressible sugar confectioners or any combination thereof.
7. A stable solid dosage forμi as- claimed in Claim 2, wherein said lubricants and glidants include colloidal silicon dioxide, magnesium stearate, and Colloidal anhydrQus silica, stearic acid, magnesium stearate, aad calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystallϊne wax, yellow beeswax, white beeswax or fumarates or any combination thereof.
8. The stable solid dosage form as claimed in any of the aforesaid Claims having levels of impurity D less than 0.5%.
9. The stable solid dosage form according to Claim 8 wherein the levels of total impurities are less than 1.0%.
10. A stable solid dosage form substantially described herein with reference to the examples accompanying the specification.
PCT/IN2007/000385 2006-08-15 2007-08-27 Stabilised dosage forms of amlodipine besylate Ceased WO2008062435A2 (en)

Applications Claiming Priority (2)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011060944A2 (en) 2009-11-20 2011-05-26 Gp Pharm, S.A. Active pharmaceutical ingredient capsules and polyunsaturated fatty acid esters
WO2014138603A1 (en) * 2013-03-07 2014-09-12 Amneal Pharmaceuticals, LLC Stabilization of moisture-sensitive drugs
WO2016156550A1 (en) * 2015-04-01 2016-10-06 Ceva Sante Animale Oral solid dosage form of amlodipine and veterinary uses thereof
US10350171B2 (en) 2017-07-06 2019-07-16 Dexcel Ltd. Celecoxib and amlodipine formulation and method of making the same
CN112162047A (en) * 2020-09-25 2021-01-01 宁波大红鹰药业股份有限公司 Method for determining content of genotoxic impurities in amlodipine besylate

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2124445A1 (en) * 1991-11-26 1993-06-10 James W. Young Methods and compositions for treating hypertension, angina and other disorders using optically pure (-) amlodipine
KR100604034B1 (en) * 2003-10-08 2006-07-24 주식회사유한양행 Oral fast disintegrating tablet containing amlodipine free base and compositions thereof
CN1546024A (en) * 2003-12-09 2004-11-17 成都圣诺科技发展有限公司 Orally disintegrating tablet of amlodipine besylate and its preparation process
CN1686121A (en) * 2005-04-19 2005-10-26 昆明金殿制药有限公司 Phenylsulfonic acid amido chloro diping dispersion tablet and its preparation method
WO2006118210A1 (en) * 2005-04-28 2006-11-09 Eisai R & D Management Co., Ltd. Method of preventing dihydropyridine compound from degradation
JP2008013489A (en) * 2006-07-06 2008-01-24 Ohara Yakuhin Kogyo Kk Tablet comprising amlodipine besylate

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011060944A2 (en) 2009-11-20 2011-05-26 Gp Pharm, S.A. Active pharmaceutical ingredient capsules and polyunsaturated fatty acid esters
WO2014138603A1 (en) * 2013-03-07 2014-09-12 Amneal Pharmaceuticals, LLC Stabilization of moisture-sensitive drugs
US9629805B2 (en) 2013-03-07 2017-04-25 Amneal Pharmaceuticals Llc Stabilization of moisture-sensitive drugs
WO2016156550A1 (en) * 2015-04-01 2016-10-06 Ceva Sante Animale Oral solid dosage form of amlodipine and veterinary uses thereof
WO2016155815A1 (en) * 2015-04-01 2016-10-06 Ceva Sante Animale Oral solid dosage form of amlodipine and veterinary uses thereof
AU2016239689B2 (en) * 2015-04-01 2021-06-24 Ceva Sante Animale Oral solid dosage form of amlodipine and veterinary uses thereof
US11147804B2 (en) 2015-04-01 2021-10-19 Ceva Sante Animale Oral solid dosage form of amlodipine and veterinary uses thereof
US10350171B2 (en) 2017-07-06 2019-07-16 Dexcel Ltd. Celecoxib and amlodipine formulation and method of making the same
US10945960B2 (en) 2017-07-06 2021-03-16 Dexcel Ltd. Celecoxib and amlodipine formulation and method of making the same
CN112162047A (en) * 2020-09-25 2021-01-01 宁波大红鹰药业股份有限公司 Method for determining content of genotoxic impurities in amlodipine besylate
CN112162047B (en) * 2020-09-25 2022-08-02 宁波大红鹰药业股份有限公司 Method for determining content of genotoxic impurities in amlodipine besylate

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