CN101080225A - Combination therapy comprising telmisartan and hydrochlorothiazide - Google Patents

Abstract

A pharmaceutical composition comprising about 80 mg telmisartan and about 25 mg hydrochiorothiazide or about 160 mg telmisartan and about 50 mg hydrochlorothiazide for the treatment of hypertension in patients with an insufficient blood pressure reduction upon treatment either with an angiotensin II receptor antagonist, or a pharmaceutical composition of an angiotensin II receptor antagonist and a low dose of hydrochiorothiazide.

Description

Combination therapy consisting of telmisartan and hydrochlorothiazide

The present invention relates to a pharmaceutical composition comprising as active ingredients about 80 mg of the angiotensin II receptor antagonist (ARB) telmisartan (telmisartan) and about 25 mg of the diuretic hydrochlorothiazide (HCTZ), and a pharmaceutical composition comprising A pharmaceutical composition of about 160 mg telmisartan and about 50 mg hydrochlorothiazide which can be divided into two halves. The composition is indicated for the treatment of insufficient reduction in blood pressure following treatment with an angiotensin II receptor antagonist (due to low plasma levels of renin) or a pharmaceutical combination of an angiotensin II receptor antagonist with low doses of hydrochlorothiazide patients with high blood pressure.

Background of the invention

Telmisartan, a white to pale yellow solid, is an angiotensin II receptor antagonist developed for the treatment of hypertension and other medical indications as disclosed in EP-A-502314. It is a non-peptide molecule, chemically described as 4'-[(1,4'-dimethyl-2'-propyl[2,6'-di-1Hbenzimidazol]-1'-yl)methyl ]-[1,1'-biphenyl]-2-carboxylic acid or 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzo imidazol-1-ylmethyl]-biphenyl-2-carboxylic acid. Its experimental formula is C ₃₃ H ₃₀ N ₄ O ₂ , its molecular weight is 514.63, and its structural formula is:

Telmisartan is prepared and supplied in the free acid form. It is characterized by very poor solubility in aqueous systems within the physiological pH range of the gastrointestinal tract between pH 1 and 7. As disclosed in WO 00/43370, crystalline Telmisartan exists in two polymorphic forms with different melting points. Under the influence of heat and humidity, the lower melting polymorph B is irreversibly converted to the higher melting polymorph A.

Hydrochlorothiazide (HCTZ), 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 ClN ₃ O ₄ S ₂ , and its structural formula is:

Contents of the invention

There is a significant relationship between hypertension and cardiovascular morbidity and mortality, ie, with increased blood pressure, there is an increased risk of myocardial infarction, heart failure, stroke, or kidney disease. Among individuals between the ages of 40 and 70, a 20 mmHg increase in systolic blood pressure or a 10 mmHg increase in diastolic blood pressure doubles the risk of cardiovascular disease. Therefore, for patients with co-morbidity (such as diabetes or chronic kidney disease), a target blood pressure of less than 140/90 mmHg and a lower target of less than 130/80 mmHg are recommended.

Many patients require two or more antihypertensive drugs to achieve this goal. One of the possible combination partners is a thiazide-diuretic, which promotes salt and water excretion. A synergistic BP-lowering effect has been reported for the combination of an angiotensin II receptor antagonist (ARB) and HCTZ, while additional ARB treatment resulted in few additional side effects. Combination products can be used to combine ARBs with low doses of HCTZ less than 15 mg, preferably 12.5 mg, and high doses of HCTZ greater than 15 mg, preferably 25 mg HCTZ, or high doses of HCTZ. Unfortunately, a small group of hypertensive patients still does not respond adequately to treatment with ARBs or combinations of ARBs plus low-dose diuretics, meaning that target blood pressure levels as suggested by the latest guidelines are not achieved in all patients, especially For patients with complications. In affected patients, low plasma renin activity (PRA) is often observed. Renin is an enzyme released by the kidneys to help control the body's sodium-potassium balance, fluid volume, and blood pressure. Renin itself cannot actually be measured in the PRA test because it is difficult to measure renin in routine laboratory assays. In the most commonly used renin assay, the test actually measures the rate of angiotensin I production per unit time by a procedure called radioimmunoassay, while the plasma renin concentration (PRC) measures the maximal renin effect. Both PRA and PRC are difficult to measure. Not only is renin itself unstable, but the patient's body position and time of day also affect the results. In addition, samples must be collected correctly: drawn into cooled syringes and collection tubes, placed on ice, and sent immediately to the performing laboratory. Even following all of these procedures, results could vary significantly.

The present invention is based on the surprising discovery that compared to telmisartan or other ARBs such as candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan, pratosartan, ripisartan, telmisartan, valsartan, or zolasartan, or these In patients treated with a combination of telmisartan and a low dose of the diuretic HCTZ, administration of a daily dose of 80 mg telmisartan in combination with 25 mg instead of 12.5 mg of hydrochlorothiazide resulted in a surprisingly large increase in the proportion of responders. It is therefore an object of the present invention to provide an alternative treatment option for patients whose blood pressure is not adequately controlled by an ARB or a combination of an ARB and a low dose of the diuretic HCTZ. This option comprises preparing a pharmaceutical composition comprising 80 mg telmisartan and 25 mg hydrochlorothiazide or a pharmaceutical composition comprising about 160 mg telmisartan and about 50 mg hydrochlorothiazide which can be divided into two halves.

definition

As used herein, the term "essentially amorphous" means that the product comprises an amorphous component in a proportion of at least 90%, preferably at least 95%, as determined by X-ray powder diffraction measurements.

The term "dissolving tablet matrix" refers to pharmaceutical tablet matrix formulations that are readily soluble in physiological aqueous media and have immediate release (fast dissolution) characteristics.

The term "disintegrating tablet matrix" refers to a pharmaceutical tablet matrix formulation with immediate release characteristics that rapidly disintegrates in a physiological aqueous medium.

Description of the invention

The present invention comprises a pharmaceutical composition useful in a method of treating hypertension, comprising as active ingredients about 80 mg of angiotensin II receptor antagonist telmisartan and about 25 mg of a diuretic hydrochlorothiazide, and another drug for A pharmaceutical composition for treating hypertension, which can be divided into two halves, comprising about 160 mg of telmisartan and about 50 mg of hydrochlorothiazide as active ingredients.

The active ingredient telmisartan is generally supplied in the free acid form, although pharmaceutically acceptable salts such as the sodium salt may also be used. Since telmisartan usually dissolves and transforms into a substantially amorphous form during subsequent processing, its initial crystal morphology and particle size are often of little importance for the physical and biopharmaceutical properties of the pharmaceutical formulation. Preferably, however, lumps are removed from the starting material (for example by sieving) in order to facilitate wetting and dissolution during further processing.

The diuretic is usually used as a fine-crystalline powder, optionally in finely ground, peg-milled or micronized form. For example, the particle size distribution of hydrochlorothiazide, as determined by the laser light scattering method in a dry dispersion system (Sympatec Helos/Rodos, focal length 100 mm), is preferably as follows:

d ₁₀ : ≤ 20 μm, preferably 2 to 10 μm

d ₅₀ : 5 to 50 μm, preferably 10 to 30 μm

d ₉₀ : 20 to 100 μm, preferably 40 to 80 μm

A preferred embodiment of the above-mentioned pharmaceutical composition is a tablet or a capsule. Especially preferred are bilayer tablets consisting of a first tablet layer of telmisartan contained in a dissolving tablet matrix with immediate release (fast dissolution) characteristics and telmisartan contained in a disintegrating tablet matrix. The active ingredient HCTZ consists of a separate second tablet layer. The dissolving tablet base may be of neutral or basic character, although a basic tablet base is preferred.

For convenience, the compositions of the present invention comprise substantially amorphous telmisartan, which may be prepared by any suitable method known to those of ordinary skill in the art, such as by freeze-drying an aqueous solution, coating a carrier on a fluidized bed Granules and solvent deposition on sugar pellets or other supports. However, preferably, the substantially amorphous telmisartan is prepared by the specific spray-drying method described in WO 03/059327.

In addition, the composition of the present invention preferably comprises as inactive ingredients sodium hydrochloride, meglumine, povidone, sorbitol, magnesium stearate, lactose monohydrate, microcrystalline cellulose, corn starch and starch hydroxyl sodium acetate.

The dissolving matrix of the telmisartan tablet layer may contain an alkaline agent, a water-soluble diluent and optionally other excipients and adjuvants.

Specific examples of 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), preferably NaOH and meglumine.

Specific examples of suitable water-soluble diluents are carbohydrates, such as: monosaccharides, such as glucose; oligosaccharides, such as sucrose, anhydrous lactose, and lactose monohydrate; sugar alcohol. Sorbitol is the preferred diluent.

Other excipients and/or adjuvants are, for example, selected from binders, carriers, fillers, lubricants, flow control agents, crystallization retarders, solubilizers, colorants, pH control agents, surfactants and emulsifiers, Specific examples thereof are given below together with the composition of the second tablet layer. The excipients and/or adjuvants used in the telmisartan tablet layer composition are preferably selected to obtain a non-acidic, rapidly dissolving tablet matrix.

The first tablet layer composition generally comprises: 3 to 50wt.%, preferably 5 to 35wt.% active ingredient; 0.25 to 20wt.%, preferably 0.40 to 15wt.% alkaline agent; and 30 to 95wt.% , preferably 60 to 80 wt.% of water-soluble diluent (filler).

Other (optional) components may for example be selected from one or more of the following excipients and/or adjuvants in the indicated doses:

10 to 30wt.%, preferably 15 to 25wt.%, binder, carrier and filler, thereby replacing the water-soluble diluent;

0.1 to 5 wt.%, preferably 0.5 to 3 wt.% lubricant;

0.1 to 5 wt.%, preferably 0.3 to 2 wt.% flow control agent;

1 to 10 wt.%, preferably 2 to 8 wt.%, of a crystallization retardant;

1 to 10 wt.%, preferably 2 to 8 wt.% of solubilizer;

0.05 to 1.5 wt.%, preferably 0.1 to 0.8 wt.%, of colorants;

0.5 to 10wt.%, preferably 2 to 8wt.% pH control agent;

0.01 to 5 wt.%, preferably 0.05 to 1 wt.%, of surfactants and emulsifiers.

The telmisartan tablet layer can be prepared through the steps of: spray drying an aqueous solution comprising telmisartan and an alkaline agent to obtain spray-dried granules; mixing the spray-dried granules with a water-soluble diluent to obtaining a preblend; mixing the preblend with a lubricant to obtain a final blend; and compressing the final blend to form the first tablet layer.

The separate second tablet layer comprising HCTZ in a rapidly disintegrating tablet matrix preferably comprises one or more fillers, binders or polymers, disintegrants, lubricants and optionally other excipients and adjuvants. agent.

Preferred fillers are selected from the group consisting of pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cellulose, mannitol, erythritol, lactose, sucrose, calcium hydrogen phosphate, sorbitol and xylitol . Especially preferred are pregelatinized starch, microcrystalline cellulose, mannitol and lactose monohydrate. Especially preferred are anhydrous lactose, spray-dried lactose and lactose monohydrate.

Preferred disintegrants are selected from the group consisting of croscarmellose sodium salt (cross-linked cellulose carboxymethyl ether sodium salt), sodium starch glycolate, cross-linked polyvinylpyrrolidone (crospovidone), corn starch And low substituted hydroxypropyl cellulose. Especially preferred are sodium starch glycolate and croscarmellose sodium salt.

Preferred binders are selected from the group consisting of: polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone and other vinyl derivatives (copovidone, copovidone), hydroxypropylmethylcellulose, methylcellulose, hydroxyl Propyl cellulose and low-substituted hydroxypropyl cellulose. Especially preferred are hydroxypropylmethylcellulose and copovidone.

Preferred lubricants are sodium stearylfumarate and magnesium stearate.

If other excipients and adjuvants are used, they are preferably selected from:

-Diluents and carriers such as cellulose powder, microcrystalline cellulose, cellulose derivatives (such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose), phosphoric acid Hydrogen calcium, corn starch, pregelatinized starch, polyvinylpyrrolidone (povidone), etc.;

-Lubricants, such as stearic acid, magnesium stearate, sodium stearyl fumarate, glyceryl tribehenate, etc.;

- flow control agents, such as silica gel, talc, etc.;

- Crystallization retarders, such as povidone, etc.;

- Solubilizers, such as Pluronic, povidone, etc.;

- Colorants, 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, calcium hydrogen phosphate, disodium hydrogen phosphate, etc.;

-Surfactants and emulsifiers, such as Planic, polyethylene glycol, sodium carboxymethylcellulose, polyethoxylated and hydrogenated castor oil, etc.;

-Antioxidants;

And a mixture of two or more of these excipients and/or adjuvants.

Layers can be distinguished by using different colors.

The separated second tablet layer comprising HCTZ generally comprises: 1.5 to 35 wt.%, preferably 2 to 15 wt.% active ingredient; 25 to 75 wt.%, preferably 35 to 65 wt.% filler; 10 to 40 wt.%, Preferably 15 to 35 wt.% dry binder; 0.5 to 5 wt.%, preferably 1 to 4 wt.% wet granulation binder; and 1 to 10 wt.%, preferably 2 to 8 wt.% disintegration agent. Other excipients and adjuvants are generally used in the same amounts as in the first tablet layer composition.

To prepare the bilayer tablet of the present invention, the first and second tablet layer compositions can be compressed in the usual manner in a bilayer tablet press, eg a high-speed rotary press in bilayer compression mode. However, care should be taken not to use excessive compression force on the first tablet layer. Preferably, the ratio of the compression force applied during compression of the first tablet layer to the compression force applied during compression of the first and second tablet layers is in the range from 1:10 to 1:2. For example, the first tablet layer may be compressed at a moderate force of 4 to 8 kN, while the main compression of the first plus second layer is performed at a force of 10 to 20 kN.

During bilayer tablet compression, proper bond formation between the two layers is achieved by distance attractive forces (intermolecular forces) and mechanical interlocking between particles.

The resulting tablet releases the active ingredient rapidly and in a substantially pH-independent manner, with complete release occurring in less than 60 minutes and a major part of the release occurring in less than 15 minutes. The dissolution/disintegration kinetics of multilayer tablets can be controlled in different ways. For example, the layers can dissolve/disintegrate simultaneously. Preferably, the HCTZ-containing tablet layer disintegrates first, while the telmisartan-containing layer dissolves next.

According to the invention, at least 70% and usually at least 90% of the active ingredient is dissolved after 30 minutes.

Bilayer tablets according to the invention have a slight tendency to absorb moisture and are therefore preferably packaged using moisture-resistant packaging materials such as aluminum foil blister packs or polypropylene tubes and HDPE bottles, preferably containing a desiccant.

A preferred method of preparing bilayer tablets according to the invention comprises:

(i) The first tablet layer composition is provided by the following steps:

a) preparing an aqueous solution of telmisartan, at least one basic agent and optionally a solubilizer and/or a crystallization retarder;

b) spray drying the aqueous solution to obtain spray dried particles;

c) mixing the spray-dried granules with a water-soluble diluent to obtain a premix;

d) mixing the premix with lubricant to obtain the 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 layer comprising HCTZ;

(iii) compressing the first and second tablet layer compositions to form tablet layers; and

(iv) Compressing the separated tablet layers to form a bilayer tablet.

To provide the first tablet layer composition, an alkaline aqueous solution of telmisartan is prepared by dissolving the active ingredient in purified water with the help of one or more alkaline agents such as sodium hydroxide and meglumine . Optionally, solubilizers and/or recrystallization retarders 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 in a parallel-flow or counter-current spray dryer at a spray pressure of, for example, 1 to 4 bar at room temperature or preferably at elevated temperature, for example between 50 and 100°C. In general, the spray-drying conditions are preferably selected in such a way that spray-dried particles are obtained with a residual humidity of less than 5 wt.%, preferably less than 3.5 wt.%, in the separating vortex. To this end, the outlet air temperature of the spray dryer is preferably maintained between about 80 and 90° C., while other process parameters such as spray pressure, spray rate, inlet air temperature, etc. are adjusted accordingly.

The resulting spray-dried granules are preferably fine powders with the following particle size distribution:

d ₁₀ : ≤20 μm, preferably ≤10 μm

d ₅₀ : ≤80 μm, preferably 20 to 55 μm

d ₉₀ : ≤350 μm, preferably 50 to 150 μm

After spray-drying, the spray-dried granules contain the active ingredient telmisartan together with the excipients in a substantially amorphous state with no detectable crystallinity. From a physical point of view, the spray-dried particles are a solidified solution or glass with a glass transition temperature Tg preferably greater than 50°C, more preferably greater than 80°C.

Based on 100 parts by weight of the active ingredient telmisartan, the spray-dried granules preferably contain 5 to 200 parts by weight of an alkaline agent and optionally a solubilizer and/or a crystallization retarder.

The water-soluble diluent is generally used 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.

The mixing is carried out in two stages, i.e. in a first mixing step, the spray-dried granules are mixed with the diluent using, for example, a high shear mixer or a free-fall blender, and in a second mixing step, preferably also in The lubricant is blended with the premix under high shear conditions. However, the method of the invention is not limited to these mixing procedures and in general alternative mixing procedures can be used for steps c), d) and also for subsequent steps f) and g), e.g. tank mixing with intermediate screening .

To provide the second tablet layer composition comprising HCTZ, the constituent components can be prepared by dry blending, for example by a high intensity mixer or a free fall blender. Alternatively and preferably, the second tablet layer composition is prepared using wet granulation techniques, wherein an aqueous solution of a wet granulation binder is added to the premix and subsequently dried, for example in a fluid bed drier or drying chamber The resulting wet granules. The dried mixture is screened and the lubricant is then mixed, for example, using a tumble mixer or a free fall blender.

The first and second tablet layer compositions described above can be compressed into target tablets of appropriate size and compressive strength using a suitable tablet press, such as a rotary press in bi-layer tableting mode bilayer tablet by weight. Optionally a suitable external lubricant spray system for the dies and punches may be used to improve lubrication during tablet manufacture. To avoid any cross-contamination between tablet layers (which could lead to breakdown of HCTZ), any particulate residues should be carefully removed during compression by vigorous suction of the die station within the compression chamber.

In addition to the treatment of hypertension, the composition according to the invention can also be used for the treatment or prevention of diseases selected from the group consisting of stroke, myocardial infarction, transient ischemic attack, congestive heart failure, cardiovascular disease, insulin Tolerance, impaired glucose tolerance, pre-diabetes, type 2 diabetes, metabolic syndrome (syndrome X), obesity, hypertriglyceridemia, high serum C-reactive protein concentration, high serum Lipoprotein(a) concentration, high serum homocysteine concentration, high serum low-density lipoprotein (LDL)-cholesterol concentration, high serum lipoprotein-associated phospholipase (A2) concentration, low serum high-density lipoprotein (HDL) - Cholesterol concentration, low serum HDL(2b)-cholesterol concentration, low serum adiponectin concentration, cognitive decline and dementia.

To further illustrate the invention, the following non-limiting examples are given.

Example

Example 1: Surprising Responder Ratio Using 80mg Telmisartan + 25mg HCTZ

An important goal of upregulating the effect of antihypertensive drug therapy is to increase the number of patients who respond adequately to treatment. When analyzing the current clinical database for telmisartan, a strikingly improved responder ratio has become apparent, especially when comparing the responder ratio after treatment with Telmisartan 80mg/HCTZ 25mg with Telmisartan 80mg/ The proportion of responders after HCTZ 12.5mg treatment was compared. Responders were defined as DBP < 90 mmHg or a decrease of at least 10 mmHg. Regarding SBP, adequate responders were defined as SBP <140 or a decrease of at least 10 mmHg. When comparing Telmisartan 80mg/HCTZ 25mg with Telmisartan 80mg/HCTZ 12.5mg and applying the above definitions, there was a 6.6% increase in diastolic (DBP) response rates for patients in the control study and 6.6% for patients from the follow-up study. In patients it increased by 15.4%. For patients from controlled and follow-up studies the systolic (SBP) response rate was increased by 7.8%.

The following table shows the detailed blood pressure response data of Telmisartan 80mg/HCTZ 25mg compared with Telmisartan 80mg/HCTZ 12.5mg from the project database:

Table 1: Proportion of Diastolic Responders diastolic pressure patients from controlled studies treat N proportion of non-responders responder ratio T80/H12.5T80/H25 528134 35.0% 28.4% 65.0% 71.6% Patients from follow-up studies treat N proportion of non-responders responder ratio T80/H12.5T80/H25 799442 41.9% 26.5% 58.1% 73.5%

Table 2: Proportion of Contraction Responders systolic blood pressure patients from controlled studies treat N proportion of non-responders responder ratio T80/H12.5T80/H25 528134 24.2% 16.4% 75.8% 83.6% Patients from follow-up studies treat N proportion of non-responders responder ratio T80/H12.5T80/H25 799442 27.3% 19.5% 72.7% 80.5%

When comparing Telmisartan 80mg/HCTZ 25mg to Telmisartan 80mg/HCTZ 12.5mg and applying updated response criteria (SBP <140 or reduction of at least 20mm Hg) for the proportion of patients responding from controlled studies There was an increase of 5.7% (from 61.5% to 67.2%) and for patients from the follow-up study it increased by 9.4% (from 56.2% to 65.6%).

Analysis of the available evidence from the clinical database on telmisartan suggests that the combination telmisartan 80mg/HCTZ 25mg does consistently provide higher clinical efficacy in terms of blood pressure reduction and especially the proportion of responders. Despite the expected increase in the proportion of responders due to increasing doses of HCTZ, the magnitude of the effect observed for the combination of telmisartan 80 mg and HCTZ 25 mg was far greater than expected.

Example 2: A bilayer tablet composition with a total weight of 680 mg comprising 80 mg Telmisartan and 25 mg HCTZ

Telmisartan ingredients mg per tablet Telmisartan 80.00 sodium hydroxide 6.720 Povidone K25 24.000 meglumine 24.000 pure water (400.00) Sorbitol 337.280 Magnesium stearate 8.000 Total Telmisartan layer 480.000

Hydrochlorothiazide layer ingredients mg per tablet Hydrochlorothiazide 25.000 lactose monohydrate 99.100 microcrystalline cellulose 64.000 corn starch 6.000 iron oxide 0.900 Sodium starch glycolate 4.000 pure water (64.000) Magnesium stearate 1.000 total hydrochlorothiazide layer 200.000

Example 3: Demonstration of the Surprisingly High Responder Ratio Using 80mg Telmisartan + 25mg HCTZ in an Independent Clinical Test

In order to confirm the surprising responder ratio of 80 mg telmisartan + 25 mg HCTZ found after analysis of the available clinical telmisartan database, the corresponding responder ratio was determined for the clinical trial (confirmation study), the clinical trial actually The above was designed to compare the safety and efficacy of the combination of 80 mg telmisartan + 25 mg hydrochlorothiazide with the currently available combination of 160 mg valsartan + 25 mg hydrochlorothiazide in patients with stage 1 and stage 2 hypertension. The study was a randomized, double-blind, double-mute, placebo-controlled, forced-titration trial with a total duration of up to 12 weeks (8 weeks as active treatment). The target group includes male and female hypertensive patients who are at least 18 years old.

The primary objective of this study was to show that in patients with stage 1 and stage 2 hypertension, as measured by seated trough cuff blood pressure, the MICARDIS ^(R) HCT combination (alternative Misartan 80 mg/hydrochlorothiazide 25 mg) was superior to placebo in reducing DBP and SBP, was at least as effective as DIOVAN ^(R) HCT (valsartan 160 mg/hydrochlorothiazide 25 mg) in reducing DBP, and was probably superior in reducing DBP and SBP DIOVAN ^(R) HCT.

The primary endpoint was the recumbent mean seated trough cuff diastolic blood pressure (DBP) and systolic blood pressure (SBP) during the 8-week (Visit 6) treatment period (i.e., with ^MICARDIS® 80 mg or ^DIOVAN® 160, respectively. Change from Baseline (Visit 2) at the end of 2 weeks of treatment followed by 6 weeks of treatment with MICARDIS ^(R) HCT 80/25 mg or DIOVAN ^(R) HCT 160/25 mg, or placebo throughout 8 weeks).

Blood pressure measurements were taken at trough time (ie, within 23-36 hours after the most recent study drug intake).

Secondary efficacy endpoints in this study, as measured by in-clinic trough cuff blood pressure at the end of the 8-week treatment period, included:

1.) The percentage of patients who responded to treatment was defined as:

DBP control: average sitting DBP<90mmHg in the valley

DBP response: mean seated DBP < 90 mmHg and/or change from baseline ≥ 10 mmHg at trough

SBP response: mean sitting SBP <140 mmHg and/or change from baseline ≥10 mmHg at trough

Normal BP: mean seated SBP < 130 mmHg in troughs and mean seated DBP < 85 mmHg in troughs

Normal height: mean seated SBP ≥ 130 mmHg and < 140 mmHg in trough and mean seated DBP ≥ 85 mmHg and < 90 mmHg in trough

2.) Percentage of patients with uncontrolled HTN defined as systolic BP > 180 mmHg and/or diastolic BP > 120 mmHg at the end of the study.

Safety was assessed by review of adverse events and by measuring changes from baseline in physical examination, laboratory parameters and vital signs (mean SBP, mean DBP) and pulse rate. Patients with mean horizontal SBP > 180 mmHg and/or DBP > 120 mmHg will be withdrawn from the study for safety reasons at any time during the study. The average value was calculated from three consecutive supine blood pressure measurements taken two minutes apart after resting quietly for five minutes in a seated position.

The patient selection criteria are

1. Able to provide written consent.

2. Age 18 or older.

3. Ability to discontinue current antihypertensive therapy without unacceptable risk to the patient (investigator's judgment).

4. Seated rubber band cuff DBP ≥ 95 mmHg at Visit 2 (baseline).

Patient exclusion criteria are

1. Premenopausal women (last menstrual period ≤ 1 year before the start of the run-in period), whose

a. is not surgically infertile; and/or

b. Breastfeeding or pregnancy.

c. Are of childbearing potential and are not practicing an acceptable form of birth control, do not plan to continue using this method throughout the study and have not consented to periodic pregnancy testing during study participation greater than three months in duration. Acceptable methods of birth control include oral, implantable, or injectable birth control pills.

2. Known or suspected secondary hypertension.

3. Mean seated SBP > 180 mmHg or mean seated DBP > 120 mmHg at any time during the study.

4. Hepatic and/or renal dysfunction as defined by the following laboratory parameters:

a. SGPT (ALT) or SGOT (AST) greater than twice the upper limit of the normal range, or

b. Serum creatinine greater than 3.0mg/dL or creatinine clearance less than 0.6ml/sec.

5. Bilateral renal artery stenosis, renal artery stenosis of a single kidney, after kidney transplantation or only one kidney.

6. Clinically relevant hypokalaemia or hyperkalaemia.

7. Uncorrected volume depletion.

8. Uncorrected calcium deficiency.

9. Primary aldosteronism.

10. Hereditary fructose intolerance.

11. Biliary obstructive disorder, cholestatis, or moderate to severe liver insufficiency.

12. Patients who have previously experienced symptoms characteristic of angioedema during treatment with ACE inhibitors or angiotensin II receptor antagonists.

13. History of drug or alcohol dependence within six months before the start of the run-in period.

14. Long-term administration of any drugs known to affect blood pressure, except those allowed by the agreement.

15. Any investigational drug therapy within one month of the start of the run-in period.

16. Known hypersensitivity to any component of the preparation study drug (telmisartan, valsartan or hydrochlorothiazide).

17. Contraindications to the placebo run-in period (eg, stroke within the past six months, MI in the past three months, cardiac surgery, PTCA, or angina before the start of the run-in period).

18. Any other clinical condition that, in the opinion of the principal investigator, does not allow the safe completion of the protocol and the safe administration of telmisartan, valsartan or hydrochlorothiazide.

19. Night shift workers.

20. Clinically significant ventricular tachycardia, atrial fibrillation, atrial flutter, or other clinically relevant arrhythmias determined by the investigator.

21.NYHA functional classification CHF III-IV.

22. Hypertrophic obstructive cardiomyopathy, aortic stenosis, hemodynamically related aortic or mitral stenosis.

23. Patients with unstable and uncontrolled diabetes mellitus for at least the past three months, as defined by HbA1C ≥ 10%.

24. Concomitant use of lithium or cholestyramine or colestipol resin (drugs that may interact with hydrochlorothiazide).

25. History of non-compliance with prescribed medications or protocol procedures.

Analysis of data from this study showed that the proportion of responders for 80mg telmisartan + 25mg HCTZ (T80/H25) was higher than after analyzing the clinical telmisartan database. In addition, this proportion of responders was higher than that of 160 mg valsartan + 25 mg HCTZ (Val160/H25), however, this difference cannot be interpreted as statistically significant.

The detailed responder ratio values for 80 mg telmisartan + 25 mg HCTZ (T80/H25) and 160 mg valsartan + 25 mg HCTZ (Val160/H25) are: T80/H25 (confirmation study) T80/H25 (control study of Example 1) T80/H25 (follow-up study of Example 1) Val160/H25 (confirmation study) DBP response: 82.4% 71.6% 73.5% 78.7% SBP response: 87.6% 83.6% 80.5% 84.8% New EMEA SBP response criteria 75.2% ^* 67.2% 65.6% 68.7% ^**

^* Aggregated percentage of responders for non-black (76.6%) and black patients (70.6%).

^** Aggregate of responder proportions for non-black (71.6%) and black patients (59.5%).

Claims (24)

CLAIMS 1. A pharmaceutical composition for treating hypertension, comprising about 80 mg of angiotensin II receptor antagonist telmisartan and about 25 mg of diuretic hydrochlorothiazide as active ingredients. 2. A pharmaceutical composition for the treatment of hypertension, comprising as active ingredients about 160 mg of the angiotensin II receptor antagonist telmisartan and about 50 mg of the diuretic hydrochlorothiazide, which can be divided into two halves. 3. The composition according to claim 1 or 2, wherein the pharmaceutical composition is a tablet or a capsule. 4. The composition of claim 3, wherein the pharmaceutical composition contains the telmisartan component in a dissolvable tablet matrix with immediate release characteristics. 5. The composition of claim 3, wherein the diuretic hydrochlorothiazide forms a separate layer in a disintegrating pharmaceutical matrix. 6. The composition of claim 3, wherein telmisartan or a salt thereof is in substantially amorphous form. 7. The composition according to claim 3, comprising as inactive ingredients sodium hydrochloride, meglumine, povidone, sorbitol, magnesium stearate, lactose monohydrate, microcrystalline cellulose, Corn starch and sodium starch glycolate. 8. The composition of claim 4, wherein the dissolvable tablet matrix comprises an alkaline agent, a water-soluble diluent and optionally other excipients and adjuvants. 9. The composition as claimed in claim 8, wherein the alkaline agent is selected from the group consisting of alkali metal hydroxides, basic amino acids and meglumine. 10. The composition as claimed in claim 8, wherein the water-soluble diluent is selected from monosaccharides such as glucose; oligosaccharides such as sucrose and lactose; and sugar alcohols such as sorbitol, mannitol, erythritol and xylose alcohol. 11. The composition of claim 8, wherein other excipients and adjuvants are selected from the group consisting of binders, carriers, fillers, lubricants, flow control agents, crystallization retarders, solubilizers, colorants, pH control agents agents, surfactants and emulsifiers. 12. compositions as claimed in claim 8, wherein this tablet matrix is to prepare through the following steps: spray dry the aqueous solution that comprises telmisartan and alkaline agent to obtain the granule through spray drying; The granules are mixed with a water-soluble diluent to obtain a preblend; the preblend is mixed with a lubricant to obtain a final blend; and the final blend is compressed to form the first tablet layer. 13. The composition of claim 5, wherein the disintegrating tablet matrix comprises fillers, binders, disintegrants and optionally other excipients and adjuvants. 14. The composition of claim 13, wherein other excipients and adjuvants are selected from the group consisting of carriers, diluents, lubricants, flow control agents, solubilizers, antioxidants, colorants, pH control agents, surfactants and emulsifiers. 15. The composition of claim 1, wherein the pharmaceutical composition is packaged in moisture-proof packaging materials such as aluminum foil blister packs or polypropylene tubes and HDPE bottles. 16. A method of treating hypertension in a patient comprising administering a pharmaceutical composition combining 25 mg of the diuretic hydrochlorothiazide and 80 mg of the angiotensin II receptor antagonist telmisartan. 17. The method of claim 16, wherein the patient's blood pressure is not adequately controlled by therapy with an angiotensin II receptor antagonist or a combination of an angiotensin II receptor antagonist and low dose HCTZ. 18. The method of claim 17, wherein the patient has low plasma renin activity or plasma renin concentration. 19. The pharmaceutical composition of claim 16, wherein a disease selected from the group consisting of stroke, myocardial infarction, transient ischemic attack, congestive heart failure, cardiovascular disease, insulin resistance is also treated or prevented , impaired glucose tolerance, prediabetes, type 2 diabetes, metabolic syndrome (syndrome X), obesity, hypertriglyceridemia, high serum C-reactive protein concentration, high serum lipoprotein(a) concentration, high Serum homocysteine concentration, high serum low-density lipoprotein (LDL)-cholesterol concentration, high serum lipoprotein-associated phospholipase (A2) concentration, low serum high-density lipoprotein (HDL)-cholesterol concentration, low serum HDL ( 2b) - Cholesterol concentration, low serum adiponectin concentration, cognitive decline and dementia. 20. A method of preparing a pharmaceutical unit dosage form comprising the angiotensin II receptor antagonist telmisartan and the diuretic hydrochlorothiazide for the treatment of hypertension in a patient whose blood pressure utilizes the angiotensin II receptor antagonist Or the therapy of the combination of angiotensin II receptor antagonist and low dose diuretic HCTZ can not be controlled sufficiently, wherein the weight ratio of telmisartan and hydrochlorothiazide allows the daily dose of about 80 mg telmisartan and about 25 mg hydrochlorothiazide dose to treat the patient. 21. The method of claim 20, wherein the dosage form comprises about 80 mg telmisartan and about 25 mg hydrochlorothiazide. 22. The method of claim 20, wherein the dosage form comprises about 40 mg telmisartan and about 12.5 mg hydrochlorothiazide. 23. The method of claim 20, wherein the dosage form comprises about 160 mg telmisartan and about 50 mg hydrochlorothiazide, and is divisible in half. 24. The purposes of telmisartan and HCTZ in preparing the pharmaceutical composition as claimed in claim 1 or 2.