WO2008132756A1 - Compositions pharmaceutiques stables de ramipril - Google Patents

Compositions pharmaceutiques stables de ramipril Download PDF

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Publication number
WO2008132756A1
WO2008132756A1 PCT/IN2007/000417 IN2007000417W WO2008132756A1 WO 2008132756 A1 WO2008132756 A1 WO 2008132756A1 IN 2007000417 W IN2007000417 W IN 2007000417W WO 2008132756 A1 WO2008132756 A1 WO 2008132756A1
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WO
WIPO (PCT)
Prior art keywords
ramipril
pharmaceutical composition
effective amount
lactic acid
hydrolysis
Prior art date
Application number
PCT/IN2007/000417
Other languages
English (en)
Inventor
Manish Meghshyam Dudhani
Shrenik Annasahib Kole
Makrand Krishnakumar Avachat
Original Assignee
Lupin Limited
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 Lupin Limited filed Critical Lupin Limited
Publication of WO2008132756A1 publication Critical patent/WO2008132756A1/fr

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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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to stable pharmaceutical compositions comprising ramipril or pharmaceutically acceptable salts thereof, which are susceptible to degradation, and processes for the preparation thereof.
  • ACE inhibitors or inhibitors of Angiotensin Converting Enzymes, are drugs useful in the treatment of cardiovascular disorders, especially hypertension.
  • ACE inhibitors are susceptible to breakdown, especially due to degradation and/or cyclization between the time of manufacture and the time of desired usage. Breakdown of ACE inhibitors has been found to occur both in solid and in liquid states. As breakdown of ACE inhibitor increases, the concentration of available, functional ACE inhibitor decreases.
  • Ramipril and other related ACE inhibitors like containing compositions suffer from the drawback that they degrade readily in pharmaceutical dosage forms giving rise to a diketo piperazine also known as DKP (the internal cyclization product) and a diacid (the ester hydrolysis product).
  • DKP the internal cyclization product
  • diacid the ester hydrolysis product
  • ACE inhibitors include, quinapril, enalapril, spirapril, perindopril, indolapril, lisinopril, alacepril, trandolapril, benazapril, libenzapril, delapril, cilazapril and combinations thereof; which also degrade readily in dosage forms. It is believed that one or more of these types of degradation including oxidation cause the discoloration in pharmaceutical compositions containing ACE inhibitors.
  • U.S. Pat. No. 4,793,998 discloses that certain ACE inhibitors, and in particular, quinapril and its acid addition salts can be stabilized by making solid compositions that include ascorbic acid, and optionally one or more acids selected from citric, fumaric and maleic acids.
  • U.S. Pat. No. 4,830,853 discloses that certain ACE inhibitors, and in particular, quinapril and its acid addition salts can be stabilized by making solid compositions that include ascorbic acid or a metal or ammonium ascorbate.
  • U.S. Pat. Nos. 5,151,433 and 5,442,008 relate to method for stabilization of ramipril which comprises coating ramipril or its pharmaceutically acceptable salt, with a polymeric protective film, or comprises mixing ramipril or its pharmaceutically acceptable salt with a physiologically tolerated buffer which ensures that a pH in the weakly acid to weakly alkaline range is set up in a formulation in the presence of moisture, and ramipril which has been stabilized by a polymeric protective film or by mixture with a buffer.
  • the patent teaches that decomposition of ramipril is favored by mechanical stress during formulating the dosage form as well as with increasing temperature and moisture that the formulation may be subjected to, during storage.
  • the use of a protective coating of polymeric film-formers around the ramipril counteracts the decomposition of ramipril due to mechanical stress.
  • the invention of this patent uses a layer or coating of a polymer having a defined thickness to prevent damage to ramipril due to mechanical stress.
  • WO 2005/067887A2 claims a stable tablet formulation comprising ramipril, calcium sulphate dihydrate and sodium hydrogen carbonate optionally in combination with a disintegrant, binder and lubricant and other excipients
  • WO 2005/011737 A3 relates to a pharmaceutical composition in combination, with at least one stabilising agent comprising at least one carbonate salt of an amino acid optionally together with one or more saccharides, whereby the stabilising agent can provide a protective stabilising effect for the at ' least one therapeutic agent susceptible to degradation when present in a pharmaceutical formulation.
  • US Pat. Appln 2006/0188568 Al relates to a stabilized pharmaceutical solid composition of ACE inhibitor comprising an ACE inhibitor and a selective dosage formulation thereof comprising of meglumine.
  • US Pat. Appln 2006/0134213A1 claims a pharmaceutical composition, comprising ramipril coated by a blending agent, wherein the blending agent is selected from; glyceryl behenate, glyceryl stearate, stearyl alcohol, macrogol stearate ether, palmitostearate, ethylene glycol, polyethylene glycol, stearic acid, cetyl alcohol, lauryl alcohol, amylopectin, poloxymer or combinations thereof.
  • the blending agent is selected from; glyceryl behenate, glyceryl stearate, stearyl alcohol, macrogol stearate ether, palmitostearate, ethylene glycol, polyethylene glycol, stearic acid, cetyl alcohol, lauryl alcohol, amylopectin, poloxymer or combinations thereof.
  • US Pat. Appln 2006/0177498 Al relates to a solid pharmaceutical compositions comprising ramipril with suitably low water content, and processes for preparing said compositions.
  • the invention provides stable pharmaceutical compositions comprising ramipril or pharmaceutical acceptable salts thereof and stabilizer (s), which include magnesium salts.
  • Another embodiment of the present invention provides stable pharmaceutical compositions comprising ramipril or pharmaceutical acceptable salts thereof and stabilizer (s), which include magnesium salts along with lactic acid.
  • Preferred magnesium salts include magnesium carbonate, magnesium oxide and magnesium hydroxide.
  • Yet another embodiment of the present invention provides a stable pharmaceutical composition
  • ramipril or pharmaceutical acceptable salts thereof wherein the formation of an internal cyclization product, and/or ester hydrolysis product, and/or oxidation
  • Yet another embodiment of the present invention provides stable pharmaceutical compositions comprising ramipril or pharmaceutical acceptable salts thereof wherein the stabilizer consists essentially of magnesium oxide.
  • packaging materials are containers including lid composed of polyethylene and/or polypropylene and/or glass, and blisters or strips composed of aluminium or high-density polyethylene.
  • Preferred desiccants include Silica gel, Activated alumina, Magnesium sulfate.
  • the present invention provides a pharmaceutical composition comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril- diketopiperazine is less than about 0.1 %, of the total weight of ramipril during the first, month when the pharmaceutical composition is stored at 40° C/75% RH.
  • the present invention provides a pharmaceutical composition comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril- ramipril- diacid is less than about 0.2 %, of the total weight of ramipril during the first, month when the pharmaceutical composition is stored at 40° C/75% RH.
  • the present invention provides a pharmaceutical composition comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril- diketopiperazine is less than about 0.3 %, of the total weight of ramipril during the third, month when the pharmaceutical composition is stored at 40° C/75% RH.
  • the present invention provides a pharmaceutical composition comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril- ramipril- diacid is less than about 0.45 %, of the total weight of ramipril during the third, month when the pharmaceutical composition is stored at 40° C/75% RH.
  • the present invention provides a pharmaceutical composition comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril- diketopiperazine is less than about 0.15 %, of the total weight of ramipril during the third, month when the pharmaceutical composition is stored at 25° C/60% RH.
  • the present invention provides a pharmaceutical composition comprising ramipril, wherein the rate of decomposition of the ramipril to ramipril- ramipril- diacid is less than about 0.25 %, of the total weight of ramipril during the third, month when the pharmaceutical composition is stored at 25° C/60% RH.
  • ramipril or pharmaceutical acceptable salts thereof are enabled to be stable in the presence of a stabilizing effective amount of magnesium salts and lactic acid.
  • compositions comprising ramipril magnesium can be made using ramipril or an acid addition salt thereof, by reacting the ramipril or acid addition salt with an alkaline magnesium compound, so as to convert all or substantially all of the ramipril or acid addition salt to ramipril magnesium.
  • all or substantially all means that the remaining quantity of ramipril or acid addition salt thereof, if any, will be small enough that any degradation thereof will not be significant to the stability of the final product. Hence “all or substantially all” will be understood to mean that at least about 80% of the ramipril or addition salt thereof is converted to ramipril magnesium, preferably at least 90%, more preferably at least 95%, and most preferably 100% or virtually 100%.
  • a reaction to convert the ramipril or acid addition salt thereof to ramipril magnesium can be accomplished simply by mixing the ramipril or acid addition salt together with the alkaline magnesium compound in dry state or by reacting ramipril or acid addition salt and the alkaline magnesium compound with the aid of solvent, which may be water or organic solvent or a mixture of water and organic solvent, and then evaporating the solvent to obtain a dry substance.
  • the solvent will preferably be a water or mixture of water and organic solvent. After the solvent is evaporated, the dried material obtained is further processed into a dosage form, such as tablets or capsules.
  • Additional stabilizers such as Lactic acid can be added to the dried material.
  • stabilizing effective amount means any amount, which will effectively retard or prevent degradation of the ramipril or pharmaceutically acceptable salts thereof.
  • the quantity of the stabilizer component to be used may lie between about 0.1% w/w and 50% w/w, preferably about 0.1% w/w to about 10% w/w. In general, any amount, which will effectively retard or prevent degradation of the ramipril or pharmaceutically acceptable salts thereof, can be used.
  • the solid dosage form may further comprise diluent and other formulating agents such as binder, disintegrant, lubricant and glidant.
  • Diluents may be, for example, any pharmaceutically acceptable, non-toxic diluent. Particular examples include lactose, dextrose, sucrose, maltose, microcrystalline cellulose, starch, calcium hydrogen phosphate, mannitol and the like. Binders may be, for example, starch, sugars, gums, low molecular weight hydroxypropyl methylcellulose, hydroxypropylcellulose or the like. Disintegrant may be, for example, croscarmellose sodium, crosspovidone, sodium starch glycolate, bentonite, sodium alginate, hydroxypropylmethylcellulose or the like.
  • Lubricants may be, for example, talc, magnesium stearate, calcium stearate, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, sodium benzoate or the like.
  • Glidants may be, for example, colloidal silicon dioxide (aerosil), talc or the like. Any techniques for processing the products of the invention, which are appropriate, can be employed.
  • step 1 1.Disperse magnesium oxide in water. 2.Add slowly weighed qty of Ramipril in step one. 3.Mix the resultant mixture of step 2 for 15 minutes. 4. Sift lactose monohydrate through a suitable mesh, and adsorb lactic acid on the lactose. 5. Granulate step 4 blend with step three dispersion. ⁇ .Dry in Tray dryer at 40 0 C till a desired LOD is achieved. 7.Pass the dried granules through a suitable mesh.
  • ramipril or pharmaceutically acceptable salts thereof occur mainly via two pathways: the hydrolysis to ramipril diacid (also known as impurity E) and the cyclization to ramipril diketopiperazide (also known as impurity D).
  • Table 1, 2 and 3 show a comparative stability data between the formulation and packaging materials.
  • Table I Comparative stability profile of formulation containing MgO and Lactic acid and formulation without MgO and Lactic acid ,

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

Abstract

L'invention porte sur une composition pharmaceutique qui comprend du ramipril ou des sels pharmaceutiquement acceptables de ce dernier, et des sels de magnésium et de l'acide lactique dans une quantité efficace pour empêcher la cyclisation et l'hydrolyse du ramipril et d'autres inhibiteurs ACE associés. L'invention concerne également un procédé qui permet de stabiliser le ramipril ou des sels pharmaceutiquement acceptables de ce dernier contre la cyclisation, lequel procédé consiste à mettre le médicament en contact avec: (a) une quantité de stabilisation efficace d'oxyde de magnésium et/ou (b) une quantité de stabilisation efficace d'acide lactique.
PCT/IN2007/000417 2007-05-01 2007-09-19 Compositions pharmaceutiques stables de ramipril WO2008132756A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN667KO2007 2007-05-01
IN667/KOL/2007 2007-05-01

Publications (1)

Publication Number Publication Date
WO2008132756A1 true WO2008132756A1 (fr) 2008-11-06

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011034513A1 (fr) 2009-08-17 2011-03-24 Mahmut Bilgic Granules à solubilité et stabilité améliorées
WO2012073077A1 (fr) * 2010-12-03 2012-06-07 Raouf Rekik Combinaison acide folique - ramipril : compositions ophtalmologiques cellulo-protectrices, neuroprotectrices et rétinoprotectrices
WO2013121233A1 (fr) 2012-02-17 2013-08-22 Egis Gyógyszergyár Nyilvánosan Működö Részvénytársaság Formule pharmaceutique à stabilité améliorée
WO2015022560A1 (fr) 2013-08-16 2015-02-19 Egis Gyógyszergyár Zrt. Composition pharmaceutique stable contenant du bisoprolol et du ramipril
WO2020109319A1 (fr) 2018-11-27 2020-06-04 Zaklady Farmaceutyczne Polpharma S.A Composition pharmaceutique comprenant du ramipril et de l'indapamide

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062560A1 (fr) * 1998-06-05 1999-12-09 Warner-Lambert Company Stabilisation de compositions contenant des inhibiteurs de l'enzyme de conversion d'angiotensine utilisant de l'oxyde de magnesium
WO2002011709A2 (fr) * 2000-08-05 2002-02-14 Hexal Ag Formulation pharmaceutique effervescente contenant du ramipril
WO2003059388A1 (fr) * 2002-01-15 2003-07-24 Delta Hf. Formulations de quinapril et inhibiteurs des ace correspondants
WO2005002548A1 (fr) * 2003-06-26 2005-01-13 Teva Pharmaceutical Industries Ltd. Composition pharmaceutique stable de derives de l'acide 2-aza-bicyclo[3.3.0]-octane-3-carboxylique
WO2005082420A1 (fr) * 2004-02-27 2005-09-09 Niche Generics Limited Composition pharmaceutique stable comportant un inhibiteur ace
WO2006018024A2 (fr) * 2004-08-18 2006-02-23 Ace Aps Compositions cosmetiques et pharmaceutiques contenant des inhibiteurs de l'eca et/ou des antagonistes des recepteurs de l'angiotensine ii
US20060134213A1 (en) * 2004-11-05 2006-06-22 Wilson Edward S Stabilized ramipril compositions and methods of making
WO2008000040A1 (fr) * 2006-06-30 2008-01-03 Alphapharm Pty Ltd Composition stabilisée comprenant des inhibiteurs de l'eca

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062560A1 (fr) * 1998-06-05 1999-12-09 Warner-Lambert Company Stabilisation de compositions contenant des inhibiteurs de l'enzyme de conversion d'angiotensine utilisant de l'oxyde de magnesium
WO2002011709A2 (fr) * 2000-08-05 2002-02-14 Hexal Ag Formulation pharmaceutique effervescente contenant du ramipril
WO2003059388A1 (fr) * 2002-01-15 2003-07-24 Delta Hf. Formulations de quinapril et inhibiteurs des ace correspondants
WO2005002548A1 (fr) * 2003-06-26 2005-01-13 Teva Pharmaceutical Industries Ltd. Composition pharmaceutique stable de derives de l'acide 2-aza-bicyclo[3.3.0]-octane-3-carboxylique
WO2005082420A1 (fr) * 2004-02-27 2005-09-09 Niche Generics Limited Composition pharmaceutique stable comportant un inhibiteur ace
WO2006018024A2 (fr) * 2004-08-18 2006-02-23 Ace Aps Compositions cosmetiques et pharmaceutiques contenant des inhibiteurs de l'eca et/ou des antagonistes des recepteurs de l'angiotensine ii
US20060134213A1 (en) * 2004-11-05 2006-06-22 Wilson Edward S Stabilized ramipril compositions and methods of making
WO2008000040A1 (fr) * 2006-06-30 2008-01-03 Alphapharm Pty Ltd Composition stabilisée comprenant des inhibiteurs de l'eca

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011034513A1 (fr) 2009-08-17 2011-03-24 Mahmut Bilgic Granules à solubilité et stabilité améliorées
WO2012073077A1 (fr) * 2010-12-03 2012-06-07 Raouf Rekik Combinaison acide folique - ramipril : compositions ophtalmologiques cellulo-protectrices, neuroprotectrices et rétinoprotectrices
CN103338758A (zh) * 2010-12-03 2013-10-02 拉乌夫·雷基克 叶酸-雷米普利组合：具细胞保护性、神经保护性及视网膜保护性的眼科组合物
AU2011334617B2 (en) * 2010-12-03 2017-01-12 Raouf Rekik Folic acid - Ramipril combination: cellprotective, neuroprotective and retinoprotective ophtalmologic compositions
WO2013121233A1 (fr) 2012-02-17 2013-08-22 Egis Gyógyszergyár Nyilvánosan Működö Részvénytársaság Formule pharmaceutique à stabilité améliorée
EP3501501A1 (fr) 2012-02-17 2019-06-26 Egis Gyógyszergyár Zrt. Formule pharmaceutique à stabilité améliorée
WO2015022560A1 (fr) 2013-08-16 2015-02-19 Egis Gyógyszergyár Zrt. Composition pharmaceutique stable contenant du bisoprolol et du ramipril
WO2020109319A1 (fr) 2018-11-27 2020-06-04 Zaklady Farmaceutyczne Polpharma S.A Composition pharmaceutique comprenant du ramipril et de l'indapamide

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