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WO2003032954A1 - Formulations pharmaceutiques stabilisees contenant du maleate d'amlodipine - Google Patents

Formulations pharmaceutiques stabilisees contenant du maleate d'amlodipine Download PDF

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Publication number
WO2003032954A1
WO2003032954A1 PCT/US2002/022908 US0222908W WO03032954A1 WO 2003032954 A1 WO2003032954 A1 WO 2003032954A1 US 0222908 W US0222908 W US 0222908W WO 03032954 A1 WO03032954 A1 WO 03032954A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
amlodipine
weight
amlodipine maleate
blend
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
Application number
PCT/US2002/022908
Other languages
English (en)
Inventor
Dinesh Dayaramji Chakole
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys Laboratories Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dr Reddys Laboratories Ltd filed Critical Dr Reddys Laboratories Ltd
Priority to US10/244,048 priority Critical patent/US20030180354A1/en
Priority to US10/417,810 priority patent/US20040001886A1/en
Publication of WO2003032954A1 publication Critical patent/WO2003032954A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K9/2013—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
    • A61K9/2009—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
    • A61K9/2022—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

  • Amlodipine belongs to dihydropyridine group of compounds having chemical name ( ⁇ )-2-[(2-Aminoethoxy) methy ⁇ ]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl- 6-methyl-l, 4-dihydropyridine and molecular formula C 0 -H 25 -C1-N 2 -
  • Besylate is commercially available as Norvasc in the form of oral tablets by Pfizer in 2.5 mg, 5 mg and 10 mg base preparations.
  • Therapeutically Amlodipine belongs to the class of antianginals and antihypertensives. The main mechanism of action of Amlodipine is the inhibition of calcium channels. It is also available in combination with diuretics and angiotensin converting enzyme inhibitors.
  • Amlodipine is well absorbed through gut. Oral bioavailability of
  • Amlodipine in man was found to be 64%. Plasma protein binding for Amlodipine is high in man corresponding to 97%.
  • Patent specification AU1354000 discloses a method for treating hypertension, angina and other disorders using optically pure (-) Amlodipine.
  • U.S. Patent 6,080,761 discloses the inhibition of smooth muscle migration by (R) Amlodipine. Flynn J T et al. describes the Treatment of hypertensive children with Amlodipine in Am. J. Hypertens. (AJHYE6,
  • Patent specification KR217240 discloses a method for the preparation of
  • U.S. Patent 4,879,303 teaches that besylate salt of Amlodipine has a number of advantages over the known salt of Amlodipine, and has a unique combination of good formulation properties that make it particularly suitable for preparation of pharmaceutical formulations of Amlodipine.
  • Besylate salt of Amlodipine is particularly disclosed in U.S. Patent 4,879,303 as having good processability, solubility, stability and nonhygroscopicity.
  • the teaching of U.S. Patent 4,879,303 suggests that maleate salts of
  • Amlodipine are more prone to degradation especially in solution form.
  • the question of stability of Amlodipine has long been a part of the discussion in the prior art.
  • U.S. Patent 4,879,303 describes besylate salt of Amlodipine as possessing superior antiadhesion properties as compared to the maleate salt. It has been observed that Amlodipine Maleate is very sensitive to moisture and interacts with certain formulation excipients to undergo degradation. It has been observed that Amlodipine Maleate along with having stability constraints poses a problem of sticking during manufacturing of tablets. Sticking causes drug to accumulate on the punch surfaces resulting in pitted tablets which is unacceptable. The sticking of the tablets in this way results in high ejection forces when removing the tablets from the machine.
  • Suitable diluents include but are not limited to polyols selected from mannitol, sorbitol, and xylitol; sugars selected from sucrose, lactose, and dextrose; cellulose derivatives selected from microcrystalline cellulose, hydroxypropyl cellulose, and powdered cellulose; and saccharides selected from dextrates, maltodextrans, starches, pregelatinized starch, cyclodextrin and the like.
  • the disintegrants that may be used include but are not limited to one or more clays selected from bentonite, vegum and the like; one or more gums selected from sodium alginate, xanthan gum, veegam, guar gum and the like; one or more polymers selected from sodium starch glycolate, crosscarmellose sodium, crosslinked polyvinyl- pyrrolidone, crospovidone, and the like.
  • the polymer as used herein refers to polymeric disintegrants typically used in the pharmaceutical industry.
  • the composition comprises about 0.25 to about 7% by weight of amlodipine maleate, about 50 to about 97% by weight of microcrystalline cellulose, about 0.5 to about 10% by weight of sodium starch glycolate, about 0.25 to about 2%> by weight of magnesium stearate; and about 0.1% to about 2.5%o by weight of colloidal silicon dioxide.
  • the composition comprises about 0.25% to about 7%> by weight of amlodipine maleate, about 50% to about 97% by weight of pregelatinized starch, about 0.5% to about 10% by weight of crospovidone, about 0.25% to about 2% by weight of magnesium stearate and about 0.25 to about 2.5 by weight of colloidal silicon dioxide.
  • the direct compression method is used to produce the stable Amlodipine Maleate tablets.
  • the problem of sticking commonly observed with Amlodipine Maleate formulations has been reduced or eliminated and stable formulations of Amlodipine Maleate have been produced without using any stabilizing agent.
  • the prepared Amlodipine Maleate tablets were also found to be bioequivalent with the Amlodipine Besylate tablet commercially available as Norvasc in the US market.
  • bioequivalent refers to pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions.
  • a test drug and a reference listed drug shall be considered bioequivalent if:
  • the rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or
  • bioequivalence refers to the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.
  • the total impurity including impurity 2 and 6 should not exceed more than 2% during the shelf life of the product.
  • the meaning of stable according to this invention should not be construed to limit to the temperature exposures period/conditions and impurity 2 or 6 as described in this specification. Stable also refers to the oral formulations of Amlodipine Maleate which satisfy the criteria of
  • oral formulations of this invention maybe in the form of tablets, caplets and capsules. Other solid oral formulation are also within the scope of the invention.
  • the antihypertensive or antianginal alleviating effective amount of Amlodipine Maleate comprises from 2.0 mg to 10 mg dosage of Amlodipine Maleate.
  • Amlodipine Maleate, microcrystalline cellulose and dibasic calcium phosphate are passed through mesh # 40 screen and blended together.
  • Polyvinylpyrrolidone is dissolved in water and this solution is used as granulating solution to prepare granules of the above blend.
  • the granules after drying were blended with magnesium stearate previously sifted through mesh # 40.
  • the final blend thus obtained was compressed into tablets. Stability profile
  • the stability studies are carried out at 40°C and 75%> relative humidity conditions.
  • Example 1 It was observed that the granules obtained by the wet granulation method of Example 1 were very fragile and colour of granules changed to pale yellow on standing. It was observed that Amlodipine Maleate shows degradation and yielded impurities as degradation products referred to as impurity 2 and impurity 6. It is noted that the above method includes the use of water to prepare the binder solution of polyvinylpyrrolidone. Since the active ingredient used in the above formulation, Amlodipine Maleate, is susceptible to hydrolytic degradation, as supported by prior art, it may be presumed that the impurities generated were because of the presence of water or moisture in the formulation process.
  • Example 2 In order to confirm the above observation another tablet formulation of Amlodipine Maleate was tried which minimizes the use of water in the manufacturing steps. In this formulation isopropyl alcohol is used as granulating solution, which is presented below as Example 2.
  • Example 2 In this formulation isopropyl alcohol is used as granulating solution, which is presented below as Example 2.
  • Polyoxyl-40-hydrogenated castor oil was dissolved in sufficient quantity of water. Care was taken to keep the water used to minimum i.e. sufficient enough to facilitate dissolution of Polyoxyl-40-hydrogenated castor oil.
  • the above Polyoxyl-40- hydrogenated castor oil solution was added to isopropyl alcohol taken in a quantity sufficient to dissolve polyoxyl-40-hydrogentated castor oil and dibasic calcium phosphate mixture used in the weight ratio of 1 : 1.
  • Amlodipine Maleate was then added to above mixture for solubilization. This solution was then mixed with previously sifted microcrystalline cellulose (# 40) to obtain a weight mass. The wet mass thus obtained was dried at 50°C for 30 minutes. Dried mass was passed through # 40 screen and mixed with sodium starch glycolate and magnesium stearate (previously sifted through # 40) with proper blending in double cone blender for about 10 minutes. The final blend thus obtained was compressed into tablets.
  • the stability studies are carried out at 40°C and 75%> relative humidity conditions.
  • Amlodipine Maleate are listed below.
  • the pH of the above tablet formulation was found to be 6.95 in contrast to the pH of the Amlodipine Besylate tablet, Norvasc, which was 7.79.
  • Amlodipine showed degradation and the level of impurity 6 still increased.
  • Relative retention time about 0.71%.
  • This impurity is not mentioned in European Pharmacopoeia but this can be identified by European Pharmacopoeia HPLC method.
  • This impurity is known as Dimethoxy Carbonyl Amlodipine impurity.
  • This impurity is formed due to presence of methyl, 4-chloro acetoacetate in the raw material ethyl, 4-chloro acetoacetate.
  • This impurity is controlled by the quality of raw material ethyl, 4-chloro acetoacetate. The limit for this impurity is fixed as not more than 0.2% by weight.
  • Impuritv 6 3-ethyl-5-methyl-2- ⁇ 2-(N-succinyl)amino ethoxy>methyll-4- ⁇ 2-chlorophenyl ⁇ -6- methyl- 1 ,4-dihydropyridine-3 ,5-dicarboxylate Relative retention time: about 0.91%.
  • This impurity is not mentioned in European Pharmacopoeia but this can be identified by European Pharmacopoeia HPLC method and elutes at about 0.9%> relative retention time.
  • This impurity is formed by reacting the amino group of Amlodipine base at the alpha carbon of Maleic acid. Higher temperatures and basic conditions are favorable to form this impurity. It is found that this impurity is enhanced during the formulation of Amlodipine Maleate. This impurity can be controlled by the reaction condition. The limit for this impurity has not been fixed.
  • Example 6 The stability of above Amlodipine Maleate tablet formulation was compared with Amlodipine Besylate tablets commercially available as Norvasc 6.
  • Norvasc composition The commercially available NORVASC comprises Dibasic calcium phosphate, Microcrystalline cellulose, Sodium starch glycolate, Magnesium stearate and Amlodipine Besylate.
  • impurity 6 is not observed with Norvasc 10 mg tablet formulations.
  • the impurity 4 is characterized as 3,5- dimethyl -(4 RS)-4-(2-chlorophenyl)-2-[(2-aminoethoxy) methyl] -6-methyl-l, 4- dihydropyridine-3, 5-dicarboxylate (diethoxy Amlodipine) with the RRT (relative retention time) of 1.60.
  • Example 7 Coated Tablets containing Amlodipine Maleate 10 mg
  • Opadry is a mixture of hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol 400 and Synthetic iron oxide.
  • Double cone blender for about 30 minutes. Magnesium stearate and colloidal silicon is added to the above blend and the resulting final blend is then compressed into tablets.
  • Opadry OY 0754937 is a mixture of hydroxypropylmethylcellulose (63.65%), titanium dioxide (29.32 %), polyethylene glycol 400 (6.3%), Synthetic iron oxide (0.73%).
  • Example 11 DISSOLUTION PROFILE Comparative dissolution profile of Amlodipine Maleate vs. Amlodipine Besylate (Norvasc) tablets at various pH: l. pH 2.1 simulated gastric fluid fasted Apparatus: USP apparatus II (paddles) RPM: 50 Volume: 900 ml
  • pH 7.2 phosphate buffer Apparatus USP apparatus II (paddles), RPM: 50, Volume: 900 ml
  • Present invention provides the stable solid orally administrable pharmaceutical formulations comprising Amlodipine Maleate.
  • the invention also eliminated the common problem of sticking observed while processing Amlodipine Maleate.
  • the present formulation is proved to be bioequivalent with Amlodipine
  • the present invention presents the direct compression method to produce stable pharmaceutical formulations of Amlodipine Maleate.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique stable et solide de maléate d'amlodipine qui s'administre par voie orale; le processus de préparation de telles formulations stables et plus spécifiquement un procédé de production, par compression directe, de formulations sous forme de comprimés. La formulation de maléate d'amlodipine sous forme de comprimés ainsi préparée est biologiquement équivalente aux comprimés contenant le sel de bésylate d'amlodipine disponible dans le commerce sous le nom de marque Norvasc. Cette formulation permet également d'éliminer le problème courant d'effet collant rencontré pendant la fabrication.
PCT/US2002/022908 2001-10-17 2002-07-18 Formulations pharmaceutiques stabilisees contenant du maleate d'amlodipine Ceased WO2003032954A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/244,048 US20030180354A1 (en) 2001-10-17 2002-09-13 Amlodipine maleate formulations
US10/417,810 US20040001886A1 (en) 2001-10-17 2003-04-17 Stabilized pharmaceutical formulations containing amlodipine maleate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN852CH2001 2001-10-17
IN852/MAS/2001 2001-10-17

Publications (1)

Publication Number Publication Date
WO2003032954A1 true WO2003032954A1 (fr) 2003-04-24

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051364A1 (fr) * 2001-12-17 2003-06-26 EGIS Gyógyszergyár Rt. Comprimes d'amlopidine bezylate possedant une stabilite amelioree
WO2010033954A3 (fr) * 2008-09-22 2010-10-21 Novartis Ag Formulations galéniques de composés organiques
CN102028662B (zh) * 2009-09-30 2011-10-19 江西施美制药有限公司 苯磺酸左旋氨氯地平片及其制备及有关物质的控制方法
US9301918B2 (en) 2013-03-15 2016-04-05 Mallinckrodt Llc Abuse deterrent solid dosage form for immediate release with functional score
US9993422B2 (en) 2012-04-18 2018-06-12 SpecGx LLC Immediate release, abuse deterrent pharmaceutical compositions
EP2344141B1 (fr) 2008-09-30 2019-05-01 Egis Gyógyszergyár Zrt. Composition pharmaceutique contenant de l'amilodipine et du bisoprolol
CN113440490A (zh) * 2021-07-07 2021-09-28 海南锦瑞制药有限公司 一种苯磺酸左旋氨氯地平片及其制备方法
US11478426B2 (en) 2018-09-25 2022-10-25 SpecGx LLC Abuse deterrent immediate release capsule dosage forms
US11517521B2 (en) 2014-07-03 2022-12-06 SpecGx LLC Abuse deterrent immediate release formulations comprising non-cellulose polysaccharides
EP3595667B1 (fr) 2017-03-14 2023-12-20 Galapagos NV Compositions pharmaceutiques comprenant un inhibiteur de jak

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE20116428U1 (de) * 2000-12-29 2002-01-10 Bioorganics B.V., Nijmegen Pharmazeutische Zusammensetzungen umfassend Amlodipinmaleat
EP1181932A2 (fr) * 2000-08-23 2002-02-27 Pfizer Limited Composition thérapeutique contenant un excès d'énantiomère d'amlidopine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1181932A2 (fr) * 2000-08-23 2002-02-27 Pfizer Limited Composition thérapeutique contenant un excès d'énantiomère d'amlidopine
DE20116428U1 (de) * 2000-12-29 2002-01-10 Bioorganics B.V., Nijmegen Pharmazeutische Zusammensetzungen umfassend Amlodipinmaleat

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051364A1 (fr) * 2001-12-17 2003-06-26 EGIS Gyógyszergyár Rt. Comprimes d'amlopidine bezylate possedant une stabilite amelioree
US8613949B2 (en) 2008-09-22 2013-12-24 Novartis Ag Galenical formulations of organic compounds
WO2010033954A3 (fr) * 2008-09-22 2010-10-21 Novartis Ag Formulations galéniques de composés organiques
EP2344141B1 (fr) 2008-09-30 2019-05-01 Egis Gyógyszergyár Zrt. Composition pharmaceutique contenant de l'amilodipine et du bisoprolol
EP2359815B1 (fr) 2008-09-30 2020-01-08 Egis Gyógyszergyár Zrt. Composition pharmaceutique contenant de l'amilodipine et du bisoprolol
CN102028662B (zh) * 2009-09-30 2011-10-19 江西施美制药有限公司 苯磺酸左旋氨氯地平片及其制备及有关物质的控制方法
US9993422B2 (en) 2012-04-18 2018-06-12 SpecGx LLC Immediate release, abuse deterrent pharmaceutical compositions
US9301918B2 (en) 2013-03-15 2016-04-05 Mallinckrodt Llc Abuse deterrent solid dosage form for immediate release with functional score
US11517521B2 (en) 2014-07-03 2022-12-06 SpecGx LLC Abuse deterrent immediate release formulations comprising non-cellulose polysaccharides
US11583493B2 (en) 2014-07-03 2023-02-21 SpecGx LLC Abuse deterrent immediate release formulations comprising non-cellulose polysaccharides
US11617712B2 (en) 2014-07-03 2023-04-04 SpecGx LLC Abuse deterrent immediate release formulations comprising non-cellulose polysaccharides
EP3595667B1 (fr) 2017-03-14 2023-12-20 Galapagos NV Compositions pharmaceutiques comprenant un inhibiteur de jak
US11478426B2 (en) 2018-09-25 2022-10-25 SpecGx LLC Abuse deterrent immediate release capsule dosage forms
CN113440490A (zh) * 2021-07-07 2021-09-28 海南锦瑞制药有限公司 一种苯磺酸左旋氨氯地平片及其制备方法

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