EP1827424A1 - Combination therapy comprising telmisartan and hydrochlorothiazide - Google Patents

Combination therapy comprising telmisartan and hydrochlorothiazide

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Publication number
EP1827424A1
EP1827424A1 EP05814002A EP05814002A EP1827424A1 EP 1827424 A1 EP1827424 A1 EP 1827424A1 EP 05814002 A EP05814002 A EP 05814002A EP 05814002 A EP05814002 A EP 05814002A EP 1827424 A1 EP1827424 A1 EP 1827424A1
Authority
EP
European Patent Office
Prior art keywords
telmisartan
composition
hydrochlorothiazide
angiotensin
receptor antagonist
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Withdrawn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
EP05814002A
Other languages
German (de)
English (en)
French (fr)
Inventor
Helmut E. Schumacher
Peter Böhm
Axel Riedel
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
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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 EP1827424A1 publication Critical patent/EP1827424A1/en
Withdrawn legal-status Critical Current

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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
    • A61K31/41—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
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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 a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredients about 80 mg of the angiotensin Il receptor antagonist (ARB) telmisartan and about 25 mg of the diuretic hydrochlorothiazide (HCTZ) and a pharmaceutical composition which comprises about 160 mg telmisartan and about 50 mg hydrochlorothiazide and can be split into halves.
  • the composition is used to treat hypertension in patients with an insufficient blood pressure reduction upon treatment either with an angiotensin Il receptor antagonist, due to low plasma levels of renin or with a pharmaceutical composition of an angiotensin Il receptor antagonist and lower doses of hydrochlorothiazide.
  • Telmisartan a white to slightly yellowish solid, is an angiotensin Il receptor antagonist developed for the treatment of hypertension and other medical indications as disclosed in EP-A-502314. It is a nonpeptide molecule chemically described as 4'-[(1 ,4'-dimethyl-2'-propyl[2,6'-bi-1 Hbenzimidazol]-r-yl)methyl]-[1 ,r-biphenyl]-2- carboxylic acid or 4'-[2-n-propy!-4-methyl-6 ⁇ (1 -methylbenzimidazol-2-yl)- benzimidazoM-ylmethyll-biphenyl ⁇ -carboxylic acid. Its empirical formula is C 33 H 30 N 4 O 2 , its molecular weight is 514.63, and its structural formula is:
  • Telmisartan is manufactured and supplied in the free acid form. It is characterized by its very poor solubility in aqueous systems at the physiological pH range of the gastro-intestinal tract of between pH 1 to 7. As disclosed in WO 00/43370, crystalline telmisartan exists in two polymorphic forms having different melting points. Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A.
  • Hydrochlorothiazide a white, odorless, crystalline powder with a molecular weight of 297.74, is a diuretic used in the treatment of edema and hypertension. It is chemically described as 6-chloro-3,4-dihydro-2H-1 ,2,4-benzothiadiazine-7- sulfonamide-1 ,1 -dioxide. Its empirical formula is C 7 H 8 CIN 3 O 4 S 2 , and its structural formula is:
  • a target blood pressure of ⁇ 140/90 mmHg is recommended and an even lower target of ⁇ 130/80 mmHg for patients with co-morbidities such as diabetes or chronic kidney disease.
  • ARB angiotensin-ll-receptor antagonist
  • HCTZ a synergistic BP-lowering effect
  • available combination products combine the ARB with either a low dose of HCTZ or a high dose of HCTZ, wherein low dose means less then 15 mg, preferably 12.5 mg of HCTZ and high dose means more than 15 mg, preferalby 25 mg of HCTZ.
  • the test In the most commonly used renin assay, the test actually determines, by a procedure called radioimmunoassay, the rate of angiotensin I generation per unit time, while the plasma renin concentration (PRC) measures the maximum renin effect. Both the PRA and the PRC are difficult to measure. Not only is renin itself unstable, but the patient's body position and the time of day affect the results. Also, the sample must be collected properly: drawn into a chilled syringe and collection tube, placed on ice, and sent to the performing laboratory immediately. Even if all these procedures are followed, results can vary significantly.
  • the current invention is based on the surprising finding, that administering a daily dose of 80 mg of telmisartan in combination with 25 mg instead of 12.5 mg of hydrochlorothiazide, results in an unexpected strong increase of the responder rate compared to patients treated with telmisartan or another ARB such as candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, pratosartan, ripisartan, telmisartan, valsartan or zolasartan or a combination of those, including telmisartan, with a low dose of the diuretic HCTZ.
  • Said option comprises the manufacture of a pharmaceutical composition comprising 80 mg telmisartan and 25 mg - A -
  • hydrochlorothiazide or a pharmaceutical composition which comprises about 160 mg telmisartan and about 50 mg hydrochlorothiazide and can be split into halves.
  • substantially amorphous refers to a product comprising amorphous constituents in a proportion of at least 90%, preferably at least 95%, as determined by X-ray powder diffraction measurement.
  • dissolving tablet matrix refers to a pharmaceutical tablet base formulation having instant release (fast dissolution) characteristics that readily dissolves in a physiological aqueous medium.
  • disintegrating tablet matrix refers to a pharmaceutical tablet base formulation having instant release characteristics that readily disintegrates in a physiological aqueous medium.
  • the present invention comprises a pharmaceutical composition which can be used in a method for the treatment of hypertension comprising as active ingredients about 80 mg of the angiotensin Il receptor antagonist telmisartan and about 25 mg of the diuretic hydrochlorothiazide and another pharmaceutical composition for the treatment of hypertension, which can be split into halves, comprising as active ingredients about 160 mg of telmisartan and about 50 mg hydrochlorothiazide.
  • telmisartan is generally supplied in its free acid form, although pharmaceutically acceptable salts such as the sodium salt may also be used. Since during subsequent processing telmisartan is normally dissolved and transformed into a substantially amorphous form, its initial crystal morphology and particle size are frequently of little importance for the physical and biopharmaceutical properties of the pharmaceutical formulation. It is, however, preferred to remove agglomerates from the starting material, e.g. by sieving, in order to facilitate wetting and dissolution during further processing.
  • the diuretic is usually used as a fine-crystalline powder, optionally in fine-milled, peg- milled or micronized form.
  • the particle size distribution of hydrochlorothiazide as determined by the method of laser light scattering in a dry dispersion system (Sympatec Helos/Rodos, focal length 100 mm) is preferably as follows:
  • dio ⁇ 20 ⁇ m, preferably 2 to 10 ⁇ m d ⁇ o : 5 to 50 ⁇ m, preferably 10 to 30 ⁇ m dgo : 20 to 100 ⁇ m, preferably 40 to 80 ⁇ m
  • Preferred embodiments of the above pharmaceutical composition are tablets or capsules. Particularly preferred are bilayer tablets consisting of a first tablet layer comprising telmisartan in a dissolving tablet matrix having instant release (fast dissolution) characteristics and a separate second tablet layer comprising the active ingredient HCTZ in a disintegrating tablet matrix.
  • the dissolving tablet matrix may have neutral or basic properties, although a basic tablet matrix is preferred.
  • composition of the present invention comprisies telmisartan in substantially amorphous form which may be produced by any suitable method known to those skilled in the art, for instance, by freeze drying of aqueous solutions, coating of carrier particles in a fluidized bed, and solvent deposition on sugar pellets or other carriers.
  • the substantially amorphous telmisartan is prepared by the specific spray-drying method described in WO03/059327.
  • composition of the present invention preferably comprises as inactive ingredients sodium hydroxide, meglumine, povidone, sorbitol, magnesium stearate, lactose monohydrate, microcristalline cellulose, maize starch and sodium starch glycolate.
  • a dissolving matrix of a telmisartan tablet layer may comprise a basic agent, a water- soluble diluent and, optionally, other excipients and adjuvants.
  • suitable basic agents are alkali metal hydroxides such as NaOH and KOH; basic amino acids such as arginine and lysine; and meglumine (N-methyl- D-glucamine), NaOH and meglumine being preferred.
  • suitable water-soluble diluents are carbohydrates such as monosaccharides like glucose; oligosaccharides like sucrose, anhydrous lactose and lactose monohydrate; and sugar alcohols like sorbitol, mannitol, erythrol and xylitol. Sorbitol is a preferred diluent.
  • excipients and/or adjuvants are, for instance, selected from binders, carriers, fillers, lubricants, flow control agents, crystallization retarders, solubilizers, coloring agents, pH control agents, surfactants and emulsifiers, specific examples of which are given below in connection with the second tablet layer composition.
  • the excipients and/or adjuvants for a telmisartan tablet layer composition are preferably chosen such that a non-acidic, fast dissolving tablet matrix is obtained.
  • Such a first tablet layer composition generally comprises 3 to 50 wt.%, preferably 5 to 35 wt.%, of active ingredient; 0.25 to 20 wt.%, preferably 0.40 to 15 wt.%, of basic agent; and 30 to 95 wt.%, preferably 60 to 80 wt.% of water-soluble diluent (filler).
  • Other (optional) constituents may, for instance, be chosen from one or more of the following excipients and/or adjuvants in the amounts indicated:
  • coloring agents 0.05 to 1.5 wt.%, preferably 0.1 to 0.8 wt.%, of coloring agents; 0.5 to 10 wt.%, preferably 2 to 8 wt.%, of pH control agents;
  • Such a telmisartan tablet layer may be produced by spray-drying an aqueous solution comprising telmisartan and a basic agent to obtain a spray-dried granulate, mixing said spray-dried granulate with a water-soluble diluent to obtain a premix, mixing said premix with a lubricant to obtain a final blend and compressing the final blend to form the first tablet layer.
  • a separate second tablet layer comprising HCTZ in a fast disintegrating tablet matrix preferably comprises one or more fillers, a binder or polymer, a disintegrant, a lubricant and, optionally, other excipients and adjuvants.
  • Preferred fillers are selected from the group consisting of pregelatinized starch, microcristalline cellulose, low-substituted hydroxypropylcellulose, cellulose, mannitol, erythritol, lactose, saccharose, claciumhydrogenphosphate, sorbitol, and xylitol.
  • Particularly preferred are pregelatinized starch, microcristalline cellulose, mannitol and lactose monohydrate.
  • Particularly preferred are anhydrous lactose, spray-dried lactose and lactose monohydrate.
  • Preferred disintegrants are selected from the group consisting of croscarmellose sodiun salt (cellulose carboxymethylether sodium salt, crosslinked), sodium starch glycolate, crosslinked polyvinylpyrrolidone (crospovidone), corn starch and low-substituted hydroxypropylcellulose. Particularly preferred are sodium starch glycolate and croscarmellose sodium salt.
  • Preferred binders are selected from the group consisting of polyvinyl pyrrolidone (Povidone), copolymers of vinylpyrrolidone with other vinyderivatives (Copovidone), hydroxypropylmethylcellulose, methylcellulose, hydroxypropyl-cellulose and low- substituted hydroxypropyl-cellulose. Particularly preferred are hydroxypropyl- methylcellulose and Copovidone.
  • Preferred lubricants are sodium stearylfumarate and magnesium stearate.
  • excipients and adjuvants are preferably selected from - diluents and carriers such as cellulose powder, microcrystalline cellulose, cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxy-propylmethylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch, polyvinyl pyrrolidone (Povidone) etc.; - lubricants such as stearic acid, magnesium stearate, sodium stearylfumarate, glycerol tribehenate, etc.;
  • - flow control agents such as colloidal silica, talc, etc.
  • - crystallization retarders such as Povidone, etc.
  • - solubilizers such as Pluronic, Povidone, etc.
  • - coloring agents including dyes and pigments such as Iron Oxide Red or Yellow, titanium dioxide, talc, etc.;
  • - pH control agents such as citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate, dibasic sodium phosphate, etc.
  • - surfactants and emulsifiers such as Pluronic, polyethylene glycols, sodium carboxymethyl cellulose, polyethoxylated and hydrogenated castor oil, etc.
  • the layers can be differentiated by using different colors.
  • a separate second tablet layer comprising HCTZ generally comprises 1.5 to 35 wt.%, preferably 2 to 15 wt.%, of active ingredient; 25 to 75 wt.%, preferably 35 to 65 wt.%, of filler; 10 to 40 wt.%, preferably 15 to 35 wt.%, of dry binder; 0.5 to 5 wt.%, preferably 1 to 4 wt.%, of wet granulation binder; and 1 to 10 wt.%, preferably 2 to 8 wt.%, of disintegrant.
  • the other excipients and adjuvants are generally employed in the same amount as in the first tablet layer composition.
  • the first and second tablet layer compositions may be compressed in the usual manner in a bilayer tablet press, e.g. a high-speed rotary press in a bilayer tableting mode.
  • a bilayer tablet press e.g. a high-speed rotary press in a bilayer tableting mode.
  • the ratio of the compression force applied during compression of the first tablet layer to the compression force applied during compression of both the first and second tablet layers is in the range of from 1 :10 to 1 :2.
  • the first tablet layer may be compressed at moderate force of 4 to 8 kN, whereas the main compression of first plus second layer is performed at a force of 10 to 20 kN.
  • adequate bond formation between the two layers is achieved by virtue of distance attraction forces (intermolecular forces) and mechanical interlocking between the particles.
  • the tablets obtained release the active ingredients rapidly and in a largely pH- independent fashion, with complete release occurring within less than 60 min and release of the major fraction occurring within less than 15 min.
  • the dissolution/- disintegration kinetics of the multilayer tablet may be controlled in different ways.
  • the layers may dissolve/disintegrate simultaneously.
  • the tablet layer comprising HCTZ disintegrates first whereas the layer comprising telmisartan dissolves subsequently.
  • At least 70% and typically at least 90% of the active ingredients are dissolved after 30 min.
  • Bilayer tablets according to the present invention tend to be slightly hygroscopic and are therefore preferably packaged using a moisture-proof packaging material such as aluminium foil blister packs, or polypropylene tubes and HDPE bottles which preferably contain a desiccant.
  • a moisture-proof packaging material such as aluminium foil blister packs, or polypropylene tubes and HDPE bottles which preferably contain a desiccant.
  • a preferred method of producing the bilayer tablet according to the present invention comprises
  • a first tablet layer composition by a) preparing an aqueous solution of telmisartan, at least one basic agent and, optionally, a solubilizer and/or a crystallization retarder; b) spray-drying said aqueous solution to obtain a spray-dried granulate; c) mixing said spray-dried granulate with a water-soluble diluent to obtain a premix; d) mixing said premix with a lubricant to obtain a final blend for the first layer; e) optionally, adding other excipients and/or adjuvants in any of steps a) to d); (ii) providing a second tablet comprising HCTZ; (iii) compressing both the first and the second tablet layer composition to form a tablet layer; and (v) compressing the separate tablet layers to form a biilayer tablet.
  • an aqueous alkaline solution of telmisartan is prepared by dissolving the active ingredient in purified water with the help of one or more basic agents like sodium hydroxide and meglumine.
  • a solubilizer and/or a recrystallization retarder may be added.
  • the dry matter content of the starting aqueous solution is generally 10 to 40 wt.%, preferably 20 to 30 wt.%.
  • the aqueous solution is then spray-dried at room temperature or preferably at increased temperatures of, for instance, between 50 and 100 0 C in a co-current or countercurrent spray-drier at a spray pressure of, for instance, 1 to 4 bar.
  • the spray-drying conditions are preferably chosen in such a manner that a spray-dried granulate having a residual humidity of ⁇ 5 wt.%, preferably ⁇ 3.5 wt.%, is obtained in the separation cyclone.
  • the outlet air temperature of the spray-drier is preferably kept at a value of between about 80 and 90 0 C while the other process parameters such as spray pressure, spraying rate, inlet air temperature, etc. are adjusted accordingly.
  • the spray-dried granulate obtained is preferably a fine powder having the following particle size distribution:
  • d-io ⁇ 20 ⁇ m, preferably ⁇ 10 ⁇ m d 50 : ⁇ 80 ⁇ m, preferably 20 to 55 ⁇ m dgo : ⁇ 350 ⁇ m, preferably 50 to 150 ⁇ m
  • the active ingredient telmisartan as well as the excipients contained in the spray-dried granulate are in a substantially amorphous state with no crystallinity being detectable.
  • the spray-dried granulate is a solidified solution or glass having a glass transition temperature T 9 of preferably > 50 0 C 1 more preferably > 8O 0 C.
  • the spray-dried granulate preferably contains 5 to 200 parts by weight of basic agent and, optionally, solubilizer and/or crystallization retarder.
  • the water-soluble diluent is generally employed in an amount of 30 to 95 wt.%, preferably 60 to 80 wt.%, based on the weight of the first tablet layer composition.
  • the lubricant is generally added to the premix in an amount of 0.1 to 5 wt.%, preferably 0.3 to 2 wt.%, based on the weight of the first tablet layer composition. Mixing is carried out in two stages, i.e.
  • the spray-dried granulate and the diluent are admixed using , e.g., a high-shear mixer or a free-fall blender, and in a second mixing step the lubricant is blended with the premix, preferably also under conditions of high shear.
  • the method of the invention is however not limited to these mixing procedures and, generally, alternative mixing procedures may be employed in steps c), d), and also in the subsequent steps f) and g), such as, e.g., container mixing with intermediate screening.
  • the constituent components may be prepared by dry-mixing, e.g. by means of a high-intensity mixer or a free-fall blender.
  • the second tablet layer composition is prepared using a wet granulation technique wherein an aqueous solution of a wet granulation binder is added to a premix and subsequently the wet granulate obtained is dried, e.g. in a fluidized-bed dryer or drying chamber. The dried mixture is screened and then a lubricant is admixed, e.g. using a tumbling mixer or free-fall blender.
  • First and second tablet layer compositions as described above can be compressed into bilayer tablets of the target tablet weight with appropriate size and crushing strength, using an appropriate tablet press, e.g. a rotary press in the bilayer tableting mode.
  • an appropriate external lubricant spray system for dies and punches can be used during manufacturing of tablets in order to improve lubrication.
  • any granulate residues should be carefully removed during tableting by intense sucction of the die table within the tableting chamber.
  • composition according to the present invention can also be used to treat or prevent a condition selected from the group consisting of stroke, myocardial infarction, transient ischaemic attack, congestive heart failure, cardivascular disease, insulin resistance, impaired glucose tolerance, pre-diabetes, type 2 diabetes mellitus, metabolic syndrome (syndrome X), obesity, hypertriglyceridemia, elevated serum concentrations of C-reactive protein, elevated serum concentrations of lipoprotein(a), elevated serum concentration of homocysteine, elevated serum concentration of low-density lipoprotein (LDL)- cholesterol, elevated serum concentration of lipoprotein-associated phospholipase (A2), reduced serum concentration of high density lipoprotein (HDL)-cholesterol, reduced serum concentration of HDL(2b)-cholesterol, reduced serum concentration of adiponectin, cognitive decline and dementia.
  • Example 1 Surprising responder rate using 80mg telmisartan + 25 mg HCTZ
  • telmisartan An important goal of up-titrating antihypertensive medication is to increase the number of patients adequately responding to treatment. Surprisingly improved responder rates have become obvious when the current clinical database of telmisartan was analysed, in particular with respect to compare the responder rates upon treatment with telmisartan 80 mg /HCTZ 25 mg to those with telmisartan 80 mg /HCTZ 12.5 mg.
  • Responders are defined as having DBP ⁇ 90 mm Hg or a reduction of at least 10 mm Hg.
  • SBP an adequate response is defined as SBP ⁇ 140 or a reduction of at least 10 mm Hg.
  • telmisartan 80 mg/HCTZ 25 mg When comparing telmisartan 80 mg/HCTZ 25 mg with telmisartan 80 mg/HCTZ 12.5 mg and applying the above mentioned definitions the diastolic (DBP) response rates increased by 6.6 % for patients in controlled studies and by 15.4 % for patients from follow-up studies. Systolic (SBP) response rates improved by 7.8% for patients from controlled and from follow-up studies.
  • DBP diastolic
  • telmisartan 80 mg/HCTZ 25 mg combination does consistently provide higher clinical efficacy in terms of blood pressure lowering and, especially, responder rates.
  • responder rates due to the increased dose of HCTZ the extent of the observed effect for the combination of telmisartan 80 mg and HCTZ 25 mg goes far beyond what was to be expected.
  • Example 2 Composition of a 680 mg total wheight bilayer tablet comprising 80mg telmisartan and 25 mg HCTZ
  • Example 3 Confirmation of the surprising high responder rate using 80mg telmisartan + 25 mg HCTZ in a separate clinical trial
  • telmisartan + 25 mg HCTZ the corresponding responder rate was determined for a clinical trial actually designed to compare the safety and efficacy of a 80 mg telmisartan + 25 mg hydrochlorothiazide combination with the currently available 160 mg valsartan + 25 mg hydrochlorothiazide combination in patients with Stage 1 and Stage 2 hypertension (confirmation study).
  • This study was a randomized, double-blind, double- dummy, placebo-controlled, forced-titration trial, with a total duration of up to 12 weeks (eight weeks active treatment).
  • the target population included both male and female hypertensive patients, at least 18 years of age.
  • the primary objective of this study was to show that the combination of MICARDIS® HCT (telmisartan 80 mg / hydrochlorothiazide 25 mg) is superior to placebo in lowering DBP and SBP, at least as effective as DIOVAN® HCT (valsartan 160 mg / hydrochlorothiazide 25 mg) in lowering DBP, and possibly superior to DIOVAN® HCT in lowering DBP and SBP in patients with Stage 1 and Stage 2 hypertension as measured by seated trough cuff blood pressure.
  • MICARDIS® HCT telmisartan 80 mg / hydrochlorothiazide 25 mg
  • DIOVAN® HCT valsartan 160 mg / hydrochlorothiazide 25 mg
  • the primary endpoints were the change from baseline (Visit 2) for in-clinic mean seated trough cuff diastolic (DBP) and systolic blood pressure (SBP) at the end of an eight week (Visit 6) treatment period (i.e., two weeks treatment with MICARDIS® 80 mg or DIOVAN® 160 followed by six weeks treatment MICARDIS® HCT 80/25 mg or DIOVAN® HCT 160/25 mg respectively, or placebo for the entire eight weeks).
  • DBP in-clinic mean seated trough cuff diastolic
  • SBP systolic blood pressure
  • Measurements of blood pressure were made at trough (i.e., within 23 - 26 hours after most recent intake of the study medication).
  • DBP Control Mean seated DBP ⁇ 90 mmHg at trough
  • DBP Response Mean seated DBP ⁇ 90 mmHg at trough and/or a change from baseline of ⁇ IO mmHg
  • SBP Response Mean seated SBP ⁇ 140 mmHg at trough and/or a change from baseline of ⁇ IOmmHg
  • Normal BP Mean seated SBP ⁇ 130 mmHg at trough and mean seated DBP ⁇ 85 mmHg at trough
  • Patient inclusion criteria were 1. Ability to provide written informed consent. 2. Age 18 years or older.
  • Pre-menopausal women (last menstruation ⁇ 1 year prior to start of run-in period) who: a. were not surgically sterile; and/or b. were nursing or pregnant. c. were of child-bearing potential and were NOT practicing acceptable means of birth control, did NOT plan to continue using this method throughout the study and did NOT agree to submit to periodic pregnancy testing during participation in studies of >three-months duration. Acceptable methods of birth control included oral, implantable or injectable contraceptives. 2. Known or suspected secondary hypertension.
  • Hepatic and/or renal dysfunction as defined by the following laboratory parameters: a. SGPT (ALT) or SGOT (AST) >two times the upper limit of normal range, or b. Serum creatinine >3.0 mg/dL or creatinine clearance ⁇ 0.6 ml/sec.
  • Contra-indication to a placebo run-in period e.g. stroke within the past six months, Ml 1 cardiac surgery, PTCA or angina within the past three months prior to start of run-in period.
  • the detailed responder rate values for 80mg telmisartan + 25 mg HCTZ (T80/H25) and 160mg valsartan + 25 mg HCTZ (Val160/H25) are:

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EP05814002A 2004-12-17 2005-12-09 Combination therapy comprising telmisartan and hydrochlorothiazide Withdrawn EP1827424A1 (en)

Applications Claiming Priority (2)

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US63706204P 2004-12-17 2004-12-17
PCT/EP2005/013224 WO2006063737A1 (en) 2004-12-17 2005-12-09 Combination therapy comprising telmisartan and hydrochlorothiazide

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EP (1) EP1827424A1 (enrdf_load_stackoverflow)
JP (1) JP2008524136A (enrdf_load_stackoverflow)
KR (1) KR20070097511A (enrdf_load_stackoverflow)
CN (1) CN101080225A (enrdf_load_stackoverflow)
AR (1) AR052052A1 (enrdf_load_stackoverflow)
AU (1) AU2005315855A1 (enrdf_load_stackoverflow)
BR (1) BRPI0519656A2 (enrdf_load_stackoverflow)
CA (1) CA2589493A1 (enrdf_load_stackoverflow)
EA (1) EA200701159A1 (enrdf_load_stackoverflow)
IL (1) IL183944A0 (enrdf_load_stackoverflow)
NO (1) NO20072325L (enrdf_load_stackoverflow)
PE (1) PE20060768A1 (enrdf_load_stackoverflow)
TW (1) TW200637546A (enrdf_load_stackoverflow)
UY (1) UY29274A1 (enrdf_load_stackoverflow)
WO (1) WO2006063737A1 (enrdf_load_stackoverflow)

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IL183944A0 (en) 2007-10-31
TW200637546A (en) 2006-11-01
AR052052A1 (es) 2007-02-28
NO20072325L (no) 2007-07-06
KR20070097511A (ko) 2007-10-04
BRPI0519656A2 (pt) 2009-03-03
EA200701159A1 (ru) 2007-12-28
AU2005315855A1 (en) 2006-06-22
JP2008524136A (ja) 2008-07-10
PE20060768A1 (es) 2006-09-29
WO2006063737A1 (en) 2006-06-22
UY29274A1 (es) 2006-07-31
CA2589493A1 (en) 2006-06-22
CN101080225A (zh) 2007-11-28

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