EP1663209A1 - Nouvelle forme galenique orale pour ethylester d'acide 3- (2- 4-(hexyloxycarbonylamino-imino-methyle)-phenylamino|-methyle-1-methyle-1h-benzimidazol-5-carbonyle)-pyridine-2-yle-amino|propionique et ses sels - Google Patents

Nouvelle forme galenique orale pour ethylester d'acide 3- (2- 4-(hexyloxycarbonylamino-imino-methyle)-phenylamino|-methyle-1-methyle-1h-benzimidazol-5-carbonyle)-pyridine-2-yle-amino|propionique et ses sels

Info

Publication number
EP1663209A1
EP1663209A1 EP04764593A EP04764593A EP1663209A1 EP 1663209 A1 EP1663209 A1 EP 1663209A1 EP 04764593 A EP04764593 A EP 04764593A EP 04764593 A EP04764593 A EP 04764593A EP 1663209 A1 EP1663209 A1 EP 1663209A1
Authority
EP
European Patent Office
Prior art keywords
methyl
pharmaceutical composition
amino
imino
carbonyl
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.)
Withdrawn
Application number
EP04764593A
Other languages
German (de)
English (en)
Inventor
Guido B. E. Radtke
Ulrich Busch
Achim Sauer
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.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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 Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Publication of EP1663209A1 publication Critical patent/EP1663209A1/fr
Withdrawn legal-status Critical Current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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the invention relates to an oral administration form for the active ingredient 3 - [(2 - ⁇ [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl ⁇ -1-methyl-1 H -benzimidazole-5-carbonyl) -pyridine -2-yl-amino] -propionic acid ethyl ester and its pharmacologically acceptable salts.
  • This active ingredient with the chemical formula
  • the object of the invention is to provide an improved formulation for oral use for the compound of the formula I and its pharmacologically tolerable salts (hereinafter also referred to as “active ingredient”).
  • anhydrous formulation which contains the active ingredient 3 - [(2 - ⁇ [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl ⁇ - 1 -methyl- I fy-benzimidazole- ⁇ -carbony - pyridine ⁇ -yl-aminol-propionic acid ethyl ester or one of its pharmaceutically acceptable salts in dispersed form in a lipophilic, pharmaceutically acceptable carrier system, leads to oral dosage forms which have significantly better properties.
  • the carrier system can be either solid, semi-solid or liquid his.
  • the dosage form according to the invention comprises 5 to 40% by weight of the active ingredient, 55 to 95% by weight of a pharmaceutically acceptable, lipophilic carrier system and optionally 0 to 5% by weight of one or more stabilizers, the total amount of the ingredients being 100 Add% by weight.
  • a dosage form with stabilizer is preferred.
  • a preferred dosage form according to the invention comprises 8 to 40% by weight of the active ingredient, 60 to 92% by weight of a pharmaceutically acceptable, lipophilic carrier system and optionally 1 to 4% by weight of one or more stabilizers, the amounts of the ingredients increasing add a total of 100% by weight.
  • a particularly preferred dosage form according to the invention comprises 16 to 36% by weight of the active ingredient, 61 to 81% by weight of a pharmaceutically acceptable, lipophilic carrier system and, if appropriate, 2 to 3% by weight of one or more stabilizers, the amounts of the ingredients totaling Add 100% by weight.
  • the finished formulation can be filled into hard or soft capsules, for example made of gelatin, hydroxypropylmethyl cellulose (HPMC), polulan, starch, modified starch, algae or other material that can be degraded in the gastrointestinal tract.
  • HPMC hydroxypropylmethyl cellulose
  • the active ingredient is 3 - [(2 - ⁇ [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] - methyl ⁇ -1-methyl-1 H -benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - to understand ethyl propionate or one of its pharmaceutically acceptable salts; pharmaceutically acceptable salts of 3 - [(2 - ⁇ [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl ⁇ -1-methyl-1 r ⁇ ' -benzimidazole-5-carbonyl) -pyridine-2 are preferred -yl-amino] -propionic acid ethyl ester used.
  • Particularly preferred is 3 - [(2 - ⁇ [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl ⁇ -1 - methyl-1 H-benzimidazole-5-carbonyl) -pyridin-2-yl- amino] propionic acid ethyl ester - methanesulfonate.
  • the active ingredient can be ground before use.
  • the pharmaceutically acceptable lipophilic carrier systems for the purposes of this invention include a) microemulsion concentrates such as, for example, macrogol glycerol laurates according to Ph. Eur. NT 2001 and b) low-melting lipophilic systems comprising: i) 20 to 90% by weight (based on the finished formulation) lipophilic component and ii) 0 to 90% by weight (based on the finished formulation) of a surface-active compound.
  • microemulsion concentrates such as, for example, macrogol glycerol laurates according to Ph. Eur. NT 2001
  • low-melting lipophilic systems comprising: i) 20 to 90% by weight (based on the finished formulation) lipophilic component and ii) 0 to 90% by weight (based on the finished formulation) of a surface-active compound.
  • Microemulsion concentrates are preferably used.
  • a preferred carrier system according to b) comprises i) 40 to 70% by weight (based on the finished formulation) of a lipophilic component and ii) 5 to 30% by weight (based on the finished formulation) of a surface-active compound.
  • a preferred embodiment of the low-melting lipophilic systems according to b) relates to those systems which have been homogenized under high pressure.
  • the dosage form according to the invention is that the active substance is stabilized chemically and physically by it.
  • the dosage form is characterized by good bioavailability of the active ingredient.
  • a preferred micro-emulsion concentrate is Gelucire ®, Gelucire 44/14 ® is particularly preferred, that is Gelucire ® having a melting point of 44 ° C and an HLB value (hydrophilic / lipophilic balance value) 14 days.
  • Gelucire ® is understood to mean polyglycolized glycerides which are produced by alcoholysis of natural oils with polyoxyethylene glycols. These are mixtures of monoesters, diesters and / or diesters of glycerides of long-chain fatty acids with 8 to 18 carbon atoms and polyethylene glycol mono- and / or diesters of long-chain fatty acids. These preparations have a wide range of melting points between about 33 ° C and 64 ° C and a wide range of HLB values between about 1 and 14. For the present invention are of particular Gelucires-® having an HLB value 10-14 of interest.
  • a low-melting system is a system with a melting point below 50 ° C.
  • Suitable lipophilic components (i) are fats and oils such as hard fat (e.g. Witepsol W 45), neutral oil, olive oil, corn oil, peanut oil, wheat germ oil, castor oil. Neutral oil is preferred.
  • hard fat e.g. Witepsol W 45
  • neutral oil olive oil, corn oil, peanut oil, wheat germ oil, castor oil.
  • Neutral oil is preferred.
  • lipophilic or hydrophilic emulsifiers such as mono- and di-glycerides of fatty acids having 8 to 18 carbon atoms
  • Cremophore ® ethoxylates of fatty alcohol
  • Antioxidative auxiliaries such as e.g. Tocopherols, butyihydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic or gallic acid esters, nordihydroguajaretic acid (NDGA) or other compounds such as e.g. Flavonoids are used.
  • Tocopherols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) are preferred according to the invention.
  • the use of stabilizers serves to increase the storage stability of the finished product. Tocopherol is usually used in a weight ratio of 1: 412 (tocopherol: active ingredient), BHT in a weight ratio of 1: 2306 (BHT: active ingredient).
  • pH stabilizers such as weak organic or inorganic bases (e.g. sodium bicarbonate) as well as water-binding additives, which also act as stabilizers (e.g. dried ß-cyclodextrin; ß-cyclodextrin with a water content of 4% is preferred) is advantageous.
  • compositions in particular by choosing the surface-active compound and by varying the particle size of the active ingredient, it is readily possible for the person skilled in the art to control the release profile of the dosage form according to the invention over a broad spectrum.
  • instant release instant-release formulations
  • pharmaceutical compositions with "modified release” properties can be produced.
  • the active ingredient dispersion can be prepared by the process described below:
  • the liquid (molten) carrier system is placed in a batch vessel at 50 to 70 ° C. and, if appropriate, stabilizers such as, for example, antioxidants and / or pH stabilizers and internal desiccants are dissolved or suspended therein.
  • stabilizers such as, for example, antioxidants and / or pH stabilizers and internal desiccants are dissolved or suspended therein.
  • the active ingredient is then incorporated with stirring and the dispersion homogenized.
  • the dispersion is then degassed and can then be filled into hard or soft capsules, for example.
  • an amount of dispersion corresponding to the dosage is filled on standard capsule filling machines, for example in hard capsules.
  • Suitable hard capsules are, for example, hard gelatin capsules or hard capsules made of hydroxypropylmethyl cellulose (HPMC).
  • HPMC hydroxypropylmethyl cellulose
  • the active substance content of the pharmaceutical composition in the solidified melt is 5 to 40% by weight, preferably 8 to 36% by weight, based on the
  • the dosage in the case of oral administration is expediently 25 to 300 mg of the active substance base (per capsule), preferably 50 to 200 mg, in each case 1 to 2 times a day.
  • composition of the conventional tablet is Composition of the conventional tablet:
  • the variability of the plasma level curves is significantly lower after application of the compound of formula I as an orally administered acidic solution; malabsorption was not observed.
  • the acidic solution is unpleasant in taste and unstable, so it cannot be used for commercial purposes.
  • Composition of the acidic solution :.
  • the pharmaceutical composition according to Example 1 was tested for its bioavailability in comparison to the acidic solution.
  • the formulation prepared according to Example 1 with an active substance base content of 50 mg per capsule (corresponds to 57.66 mg of the mesylate of the compound of the formula I) was clinically tested on a total of 12 test persons with regard to their bioavailability.
  • the extent of absorption was determined via the quantitative determination of the urine excretion of the active metabolite of the formula II.
  • the relative bioavailability (based on the area under the plasma concentration-time curve) was 116% compared to the acidic solution (100% in each case) with pretreatment with pantoprazole and 131% without pretreatment with pantoprazole. This made it possible to improve the bioavailability of the formulation according to the invention compared to the acidic solution.
  • the clinical trial shows a further advantage of the dosage form according to the invention containing the compound of formula I, which consists in providing a sufficient pharmaceutical composition over a conventional pharmaceutical preparation.
  • Another advantageous property of the pharmaceutical composition according to the invention is its suitability for all patients, including those in whom the gastric pH is increased by normal physiological variability, by an illness or by comedication with medicaments which increase the gastric pH is.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une nouvelle forme galénique orale pour le principe actif éthylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-méthyle)-phénylamino]-méthyle}-1-méthyle-1H-benzimidazol-5-carbonyle)-pyridine-2-yle-amino] propionique et ses sels pharmaceutiquement tolérables.
EP04764593A 2003-09-03 2004-08-28 Nouvelle forme galenique orale pour ethylester d'acide 3- (2- 4-(hexyloxycarbonylamino-imino-methyle)-phenylamino|-methyle-1-methyle-1h-benzimidazol-5-carbonyle)-pyridine-2-yle-amino|propionique et ses sels Withdrawn EP1663209A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10341043A DE10341043A1 (de) 2003-09-03 2003-09-03 Neue oral zu applizierende Darreichungsform für 3-[(2-{[4-Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester und dessen Salze
PCT/EP2004/009619 WO2005023249A1 (fr) 2003-09-03 2004-08-28 Nouvelle forme galenique orale pour ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyle)-phenylamino]-methyle-1-methyle-1h-benzimidazol-5-carbonyle)-pyridine-2-yle-amino]propionique et ses sels

Publications (1)

Publication Number Publication Date
EP1663209A1 true EP1663209A1 (fr) 2006-06-07

Family

ID=34223394

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04764593A Withdrawn EP1663209A1 (fr) 2003-09-03 2004-08-28 Nouvelle forme galenique orale pour ethylester d'acide 3- (2- 4-(hexyloxycarbonylamino-imino-methyle)-phenylamino|-methyle-1-methyle-1h-benzimidazol-5-carbonyle)-pyridine-2-yle-amino|propionique et ses sels

Country Status (5)

Country Link
EP (1) EP1663209A1 (fr)
JP (1) JP2007504190A (fr)
CA (1) CA2537480A1 (fr)
DE (1) DE10341043A1 (fr)
WO (1) WO2005023249A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2009000602A (es) * 2006-07-17 2009-01-28 Boehringer Ingelheim Int Nuevas indicaciones para los inhibidores directos de la trombina en el campo cardiovascular.
JP2013521318A (ja) 2010-03-08 2013-06-10 ラティオファルム ゲー・エム・ベー・ハー ダビガトランエテキシラートを含有する医薬組成物
PL2588090T3 (pl) 2010-07-01 2017-12-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Doustne farmaceutyczne postacie dawkowania zawierające eteksylan dabigatranu i jego farmaceutycznie dopuszczalne sole
PL2603503T3 (pl) 2010-09-27 2015-12-31 Ratiopharm Gmbh Sól bismesylanowa eteksylanu dabigatranu, postacie stałe i sposób ich otrzymywania
PL2550966T3 (pl) 2011-07-25 2017-03-31 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Estry kwasu amidooksymokarboksylowego dabigatranu jako proleki i ich zastosowanie jako lek

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE121699A1 (es) * 1997-02-18 1999-12-08 Boehringer Ingelheim Pharma Heterociclos biciclicos disustituidos como inhibidores de la trombina
US6200968B1 (en) * 1998-08-06 2001-03-13 Cephalon, Inc. Particle-forming compositions containing fused pyrrolocarbazoles
GB0029843D0 (en) * 2000-12-07 2001-01-24 Univ Belfast Drug delivery system
DE10133786A1 (de) * 2001-07-16 2003-02-06 Boehringer Ingelheim Pharma Verwendung von Thrombin-Inhibitoren zur Behandlung von Arthritis
CA2476054C (fr) * 2002-03-07 2011-11-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Forme pharmaceutique pour administration orale a base d'ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique ou dw ses sels pharmaceutiquement acceptables

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005023249A1 *

Also Published As

Publication number Publication date
CA2537480A1 (fr) 2005-03-17
DE10341043A1 (de) 2005-03-31
JP2007504190A (ja) 2007-03-01
WO2005023249A1 (fr) 2005-03-17

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