WO2000027396A1 - Medicaments a base de combinaisons de lacidipine et de telmisartan ou de derives physiologiques - Google Patents

Medicaments a base de combinaisons de lacidipine et de telmisartan ou de derives physiologiques Download PDF

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Publication number
WO2000027396A1
WO2000027396A1 PCT/EP1999/008226 EP9908226W WO0027396A1 WO 2000027396 A1 WO2000027396 A1 WO 2000027396A1 EP 9908226 W EP9908226 W EP 9908226W WO 0027396 A1 WO0027396 A1 WO 0027396A1
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WO
WIPO (PCT)
Prior art keywords
lacidipine
telmisartan
combination
treatment
sorbitol
Prior art date
Application number
PCT/EP1999/008226
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English (en)
Inventor
Giovanni Gaviraghi
Mauro Quartaroli
Original Assignee
Glaxo Group Limited
Boehringer Ingelheim International Gmbh
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
Priority claimed from PCT/GB1998/003336 external-priority patent/WO2000027397A1/fr
Application filed by Glaxo Group Limited, Boehringer Ingelheim International Gmbh filed Critical Glaxo Group Limited
Priority to AU11575/00A priority Critical patent/AU1157500A/en
Publication of WO2000027396A1 publication Critical patent/WO2000027396A1/fr

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Classifications

    • 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
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to therapeutic combinations comprising diethyl (E) -4-[2-[(tert-butyloxycarbonyl)vinyl]phenyl-1 ,4-dihydro-2,6-dimethylpyridine-3,5 dicarboxylate(lacidipine) and 4'-[[2-n-propyl-4-methyl-6-(1-methylbenziimidazol- 2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid (telmisartan), to pharmaceutical compositions containing said combinations and their use in the treatment of cardiovascular disorders including hypertension.
  • Lacidipine which is described in British patent no. 2164336 , is a potent long acting calcium antagonist which is particularly useful for treating hypertension.
  • the compound may be also useful for the treatment of other cardiovascular disorders including atherosclerosis, peripheral vascular disease, ischaemic heart disease and congestive heart failure.
  • Telmisartan which is described in European patent no. 0502314, is an angiotensin-ll-antagonist which is useful for treating hypertension and cardiac insufficiency and for treating other cardiovascular disorders including ischaemic peripheral circulation disorders, myocardial ischaemia (angina).
  • European patent no. 0502314 teaches that the angiotensin-ll-antagonists described therein may be administered in combination with other active substances including calcium antagonists. There is however no specific disclosure of such combinations with lacidipine.
  • the improvement of blood pressure control achieved by using such a drug combination may afford a better protection from the associated diseases which are induced by hypertension.
  • a combination comprising lacidipine and telmisartan or a physiologically functional derivative thereof and more particularly a combination comprising lacidipine and telmisartan.
  • physiologically functional derivative includes any physiologically acceptable solvate, salt, ester, salt of such ester, or solvates of any such salt or ester, of telmisartan.
  • Preferred esters in accordance with the invention are independently selected from the following group: (1) carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n- butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C alkyl, or C alkoxy), or amino; (2) sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); and (4) phosphonate esters.
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
  • Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
  • Any aryl moiety present in such esters advantageously comprises a phenyl group. Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX + (wherein X is C alkyl) or ammonium salts, formed with amino acids (e.g lysine and arginine) and organic bases (e.g procaine, phenylbenzylamine, ethanolamine and N-methyl glucosamine). Salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
  • an appropriate base such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX + (wherein X is C alkyl) or ammonium salts, formed with amino acids (e.g lysine and arginine) and organic bases (e
  • the present invention thus provides a method for the treatment of hypertension in a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a combination of lacidipine and telmisartan or a physiologically functional derivative thereof.
  • Reference herein to treatment extends to prophylaxis as well as the treatment of established hypertension or symptoms.
  • the compounds of the combination or composition may be administered simultaneously, either in the same or different pharmaceutical formulations or sequentially. If there is sequential administration, the delay in administering the second and any subsequent active ingredient should not be such as to lose the benefit of a synergistic therapeutic effect of the combination of the active ingredients. It will also be understood that the compounds of the combination or the physiologically functional derivatives of any thereof, whether presented simultaneously or sequentially, may be administered individually or in multiples or in any combination thereof.
  • the present invention provides the use of lacidipine in the manufacture of a medicament for administration simultaneously or sequentially with telmisartan or a physiologically functional derivative thereof for the treatment and/or prophylaxis of hypertension.
  • the synergistic effects of the combination of lacidipine and telmisartan may be seen over a wide ratio of combinations, for example, of 1: 100 to 1 : 1 , such as 1:50 to 1:2 (lacidipine:telmisartan by weight), preferably of 1 :40 to 1:3.33(lacidipine:telmisartan by weight).
  • Examples of such combinations include those wherein the ratio (lacidipine.telmisartan by weight) of lacidipine to telmisartan is 1.1.5 ;1 :5; 1 :10, 1 :20; 1 :40; 1 :6.67 or 1 :13.33.
  • each compound will be employed in the combination in an amount at which it exhibits an antihypertensive effect when used alone.
  • the amount of a combination of lacidipine and telmisartan required to be effective as antihypertensive may, of course, vary and is ultimately at the discretion of the medical practitioner.
  • the factors to be considered include the route of administration and nature of the formulation, the animal's body weight, age and general condition and the nature and severity of the disease to be treated.
  • a suitable dose of lacidipine for administration to a human for the treatment of hypertension may be in the range of 0.1 to 10 mg per day, preferably in the range of 1 to 6 mg per day and most preferably in the range 2- 6 mg per day.
  • Lacidipine is advantageously administered by oral route once a day.
  • a suitable dose of telmisartan for administration to a human may be in the range of 5 to 120 mg per day, advantageously in the range of 20 to 80 mg per day. Telmisartan is advantageously administered by oral route once a day.
  • the desired dose may preferably be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day.
  • the components of the combination which may be referred to as active ingredients may be administered for therapy to an animal e.g. a mammal including a human in a conventional manner.
  • compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof.
  • the individual components of the combination are administered separately they are generally each presented as a pharmaceutical formulation.
  • the references hereinafter to formulations refer, unless otherwise stated, to formulations containing either the combination or a component thereof.
  • a combination of lacidipine and telmisartan or a physiologically functional derivative thereof may conveniently be presented as a pharmaceutical formulation in a unitary dosage form.
  • a convenient unitary dosage formulation contains lacidipine in an amount from 1mg to 6 mg and telmisartan in an amount from 10 mg to 100 mg.
  • a particularly convenient unitary dosage formulation contains lacidipine in an amount from 2 mg to 6 mg, more particularly in an amount from 2mg to 4 mg, and telmisartan in amount from 20mg to 80 mg.
  • Patient kit-packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient kit-pack, normally missing in traditional prescriptions.
  • the inclusion of a package insert has been shown to improve patient compliance with the physician's instructions and, therefore, lead generally to more successful treatment.
  • kits-pack for example, double or triple, kit-pack comprising at least lacidipine and telmisartan or a physiologically functional derivative thereof and an information insert containing directions on the use of the combination of the invention.
  • Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropyl methyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, sodium croscarmellose cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • the tablets may optionally be coated or scored any may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or polyethylene glycols.
  • Topical administration may also be by means of a transdermal iontophoretic device.
  • Formulations suitable for vaginal administration may be presented as tablets, pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, preservatives and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
  • the pharmaceutical composition of the invention containing the two active ingredients may be prepared according to conventional techniques well known in the pharmaceutical industry.
  • the lacidipine and telmisartan may be admixed together with suitable excipients such as those described above for the formulation of each of the active ingredients separately.
  • Tablets may be prepared, for example by direct compression of such a mixture or using other conventional methods.
  • Bilayer tablets may be prepared according to conventional procedure.
  • Capsules may be prepared by filling the blend along with suitable excipients into gelatin capsules, using a suitable filling machine.
  • Controlled release forms for oral or rectal administration may be formulated in a conventional manner associated with controlled release forms.
  • the advantageous profile of the antihypertensive activity obtained with the administration of lacidipine with telmisartan may be demonstrated in male spontaneously hypertensive rats.
  • Lacidipine (0.2mg/kg), telmisartan (1mg/kg) and a combination of lacidipine
  • Vehicle (Methocel TM 0.5% (10 ml/kg) , lacidipine (0.2 mg/kg) and telmisartan (0.3 mg/kg) and a combination of lacidipine(0.2 mg/kg) and telmisartan(0.3 mg/kg) were administered to male spontaneously hypertensive rats.
  • DBP AUC (0-24) reduction was significantly greater than that predicted from the sum of the monotherapy response. Furthermore, the combination does not significantly increase HR. Consequently, tachycardia was not observed.
  • the combination of lacidipine and telmisartan also improves the duration of action up to 24 hours after treatment .
  • Lacidipine (0.2 mg/kg) and telmisartan (0.3 mg/kg) alone or in combination were administrered once daily for 5 days and the effects on blood pressure and heart rate were d etected .
  • Lacidipine may be prepared by the method described in British Patent N° 2164336 which is incorporated herein by reference hereto.
  • Telmisartan or a physiologically functional derivative thereof may be prepared by the method described in European Patent N°502314 which is incorporated herein by reference or by known methods described for analogous compounds
  • lacidipine and telmisartan may be formulated in a conventional manner.
  • lacidipine may be formulated as described in British Patent N° 2164336 and telmisartan may be formulated as described in European Patent N° 0502314.
  • lacidipine and telmisartan are formulated in a single pharmaceutical composition.
  • Example 1 The following formulation was prepared by mixing lacidipine granulated containing monohydrate lactose and telmisartan spray dried granulate with sorbitol, followed by addition of magnesium stearate and compression.
  • the following formulation was prepared by mixing telmisartan spray dried granule with sorbitol and magnesium stearate. Then lacidipine granule was mixed with the remaining magnesium stearate and eventually with sorbitol. The two blends were separetely compressed in a suitable tabletting machine with two filling stations to produce bilayer tablets.
  • Sorbitol 184.1 The following formulations (Exa-3d) may be prepared by mixing a granulate containing lacidipine, sorbitol and povidone with telmisartan spray dried granulate, sorbitol, followed by addition of magnesium stearate and compression.
  • the following formulation was prepared by granulating telmisartan spray dried granule and sorbitol with lacidipine and povidone followed by addition of sorbitol and magnesium stearate and compression.
  • Examples 5a and 5b The following formulations (5a, 5b) were prepared by mixing lacidipine granulated containing sorbitol and colloidal silica and telmisartan spray dried granulate with sorbitol, followed by addition of magnesium stearate and compression

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
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  • Heart & Thoracic Surgery (AREA)
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  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention porte sur des combinaisons comprenant du diéthyl (E)4-[2-[tert-butyloxycarbonyl)vinyl]phényl-1,4-dihydro-2,6-diméthylpyridine-3,5 dicarboxylate(lacidipine) et de l'acide 4'-[[2-n-propyl-4-méthyl-6-(1-méthylbenzimidazol-2-yl)-benzimidazol-1-yl]-méthyl]-biphényl-2-carboxylique (telmisartan). L'invention concerne également les compositions pharmaceutiques contenant lesdites combinaisons ainsi que leur utilisation dans le traitement des troubles cardiovasculaires, y compris l'hypertension.
PCT/EP1999/008226 1998-11-06 1999-11-03 Medicaments a base de combinaisons de lacidipine et de telmisartan ou de derives physiologiques WO2000027396A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU11575/00A AU1157500A (en) 1998-11-06 1999-11-03 Medicaments based on combinations of lacidipine and telmisartan or of physiological derivatives thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
PCT/GB1998/003336 WO2000027397A1 (fr) 1998-11-06 1998-11-06 Medicaments antihypertenseurs a base de lacidipine et de telmisartan
GBPCT/GB98/03336 1998-11-06
US09/304,884 US6071939A (en) 1998-11-06 1999-05-04 Medicaments for the treatment of hypertension
US09/304,884 1999-05-04

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WO2000027396A1 true WO2000027396A1 (fr) 2000-05-18

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060009502A1 (en) * 2003-01-31 2006-01-12 Sankyo Company, Limited Medicine for prevention of and treatment for arteriosclerosis and hypertension
JP2006502194A (ja) * 2002-09-24 2006-01-19 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング テルミサルタンを含有する新規固形医薬調合物およびその調製方法
CN1298389C (zh) * 2005-01-18 2007-02-07 广东省人民医院 一种含替米沙坦和钙离子拮抗剂的复方降压制剂及其应用
JP2008285501A (ja) * 2002-01-16 2008-11-27 Boehringer Ingelheim Pharma Gmbh & Co Kg 実質的にアモルファスであるテルミサルタンの製法
WO2010063997A1 (fr) * 2008-12-04 2010-06-10 Arrow International Limited Formulations de telmisartan

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0796617A1 (fr) * 1996-03-18 1997-09-24 Sanofi Utilisation de composés antiarythmiques dansla réduction de la mortalité post infarctus
WO1997036874A1 (fr) * 1996-03-29 1997-10-09 Smithkline Beecham Corporation Dihydrate d'eprosartan, procede de fabrication et formulation
FR2760364A1 (fr) * 1997-03-10 1998-09-11 Sanofi Sa Utilisation de composes antiarythmiques pour reduire la mortalite apres infarctus du myocarde

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0796617A1 (fr) * 1996-03-18 1997-09-24 Sanofi Utilisation de composés antiarythmiques dansla réduction de la mortalité post infarctus
WO1997036874A1 (fr) * 1996-03-29 1997-10-09 Smithkline Beecham Corporation Dihydrate d'eprosartan, procede de fabrication et formulation
FR2760364A1 (fr) * 1997-03-10 1998-09-11 Sanofi Sa Utilisation de composes antiarythmiques pour reduire la mortalite apres infarctus du myocarde

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008285501A (ja) * 2002-01-16 2008-11-27 Boehringer Ingelheim Pharma Gmbh & Co Kg 実質的にアモルファスであるテルミサルタンの製法
JP2006502194A (ja) * 2002-09-24 2006-01-19 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング テルミサルタンを含有する新規固形医薬調合物およびその調製方法
US20060009502A1 (en) * 2003-01-31 2006-01-12 Sankyo Company, Limited Medicine for prevention of and treatment for arteriosclerosis and hypertension
US20060252805A1 (en) * 2003-01-31 2006-11-09 Sankyo Company Limited Medicine for prevention of and treatment for arteriosclerosis and hypertension
US20080176910A1 (en) * 2003-01-31 2008-07-24 Daiichi Sankyo Company, Limited Methods for prevention and treatment of arteriosclerosis and restenosis
US20080214626A1 (en) * 2003-01-31 2008-09-04 Daiichi Sankyo Company, Limited Methods for prevention and treatment of diseases causes by hypertension
EP3045174A1 (fr) * 2003-01-31 2016-07-20 Daiichi Sankyo Company, Limited Médicament pour la prévention et le traitement de l'artériosclérose et de l'hypertension
CN1298389C (zh) * 2005-01-18 2007-02-07 广东省人民医院 一种含替米沙坦和钙离子拮抗剂的复方降压制剂及其应用
WO2010063997A1 (fr) * 2008-12-04 2010-06-10 Arrow International Limited Formulations de telmisartan

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