EP1904180A2

EP1904180A2 - Pharmaceutical dosage form containing an active principle combination of nifedipine and/or nisoldipine and of an angiotensin ii antagonist

Info

Publication number: EP1904180A2
Application number: EP06776095A
Authority: EP
Inventors: Andreas Ohm; Klaus Benke; Hanna Tinel; Joachim Hütter
Original assignee: Bayer Healthcare AG
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2005-07-06
Filing date: 2006-06-29
Publication date: 2008-04-02
Also published as: CA2614085C; CN101257946A; AU2006265367A1; WO2007003330A3; CN101257946B; CA2614085A1; WO2007003330A2; ZA200800176B; US20090214664A1; HK1124558A1; RU2008103551A; DE102005031577A1; US8153160B2; JP2009500361A; KR20080031382A; BRPI0612681A2; IL188583A0

Abstract

The invention relates to a pharmaceutical dosage form containing an active principle combination of nifedipine and/or nisoldipine and of at least one angiotensin II antagonist, characterized in that the active principle combination is released in the body in a controlled (modified) manner, and to methods for the production thereof, their use as medicaments, their use for the prophylaxis, secondary prophylaxis and/or treatment of diseases as well as to their use for producing a medicament for the prophylaxis, secondary prophylaxis and/or treatment of diseases.

Description

Pharmaceutical dosage forms containing a combination of nifedipine and / or nisoldipine and an angiotensin II antagonist

The present invention relates to a pharmaceutical dosage form containing an active substance combination of nifedipine and / or nisoldipine and at least one angiotensin II antagonist, characterized in that the active substance combination in the body is controlled (modified), as well as methods for their production, their Use as a medicament, their use for the prophylaxis, secondary prophylaxis and / or treatment of diseases and their use for the manufacture of a medicament for the prophylaxis, secondary prophylaxis and / or treatment of diseases.

Calcium antagonists such as nifedipine and nisoldipine are successfully used in the treatment of hypertension as proven drugs. The examples listed are well known to those skilled in the art and described in the relevant literature. Due to their direct effect on the arterial blood vessels, they reliably lower the blood pressure in a large proportion of patients. However, they cause an increase in the filtration pressure on the kidney by preferential dilatation of the vasa afferentia. This can lead to an increased load of the filtration apparatus in the case of a previously damaged kidney and to become noticeable in patients in a proteinuria. This effect can be prevented by adding a therapeutically effective dose of an angiotensin II antagonist. Suitable angiotensin II antagonists are all known angiotensin II antagonists and preferably and, for example, candesartan, irbesartan, losartan, telmisartan and olmesartan. The examples listed are well known to those skilled in the art and described in the relevant literature. Since angiotensin II antagonists are dilatatorily effective also in the area of the vascular effervescence, the additional administration of these substances can prevent the undesirable increase in the filtration pressure.

As from Hayashi k; Nagahama T, Oka K, Epstein M, Sarute T: Disparate effects of calcium antagonists on renal microcirculation. Hypertens Res 1996: 19: 31-36, the combination of nifedipine and / or nisoldipin with an angiotensin II antagonist therefore causes a very good reduction in blood pressure associated with a low burden on the kidney. This represents a significant therapeutic advance. In addition, the combination may also reduce other side effects, such as peripheral edema occurring with calcium antagonists and the stimulation of the sympathetic nervous system due to reflex release of norepinephrine.

In diseases that need to be treated over a longer period, or for longer-term prophylaxis of diseases, it is desirable to reduce the frequency of use of To keep medicines as low as possible. Not only is this more comfortable for the patient, it also increases treatment safety by reducing the drawbacks of irregular revenue. The desired reduction of the frequency of administration, for example, twice a day to once daily application, can be achieved by prolonging the therapeutically effective plasma levels by modified drug release from the dosage forms.

In addition, after administration of dosage forms with modified release of active ingredient, smoothing of the plasma level profile (minimization of the so-called peak-through ratio), ie avoiding high concentrations of plasma active substance, which are frequently to be observed after the administration of rapid-release dosage forms, can lead to the occurrence of undesirable effects Concentration peaks correlated with side effects are diminished.

In particular, for the long-term therapy or prophylaxis and secondary prophylaxis of cardiovascular diseases, it is advantageous to have the active ingredients in a form which leads via a modified release of active ingredient to a reduction of the peak-through ratio and allows once daily administration ,

When developing the formulation, the physico-chemical and biological properties of the active ingredients must also be taken into account, for example the relatively low water solubility of nifedipine (about 9 mg / L) and the plasma half-life of about 2 hours. For the desired once-daily application, therefore, special galenic formulations are necessary which release modified nifedipine and / or nisoldipine in consideration of its physicochemical and biological properties.

The angiotensin-U antagonists are all marketed as immediate-release formulations in the form of their commercial products because they have an over 24-hour effect despite their short dominant plasma half-life. Nevertheless, a retarder of drug delivery, i. controlled release of the angiotensin H antagonist over many hours is beneficial in avoiding high peak-through fluctuations. Extreme plasma peak levels not needed for the effect can thus be avoided and, at the same time, the 24-hour plasma levels can be increased or ensured with a comparatively equal or even lower dose than the marketed commercial product. Due to the retardation, the active ingredient is optimally supplied to the patient for the desired effect (uniform plasma level-time profile).

With regard to the biological properties of nifedipine and / or nisoldipine and the angiotensin II antagonists, it is crucial that both active substances from the deep intestinal sections without significant loss of bioavailability. This is only the case for about 30-50% of all active ingredients and therefore the appropriate selection of combination active ingredients is of crucial importance in the development of a sustained-release combination product.

Various methods are known for the production of modified release pharmaceutical dosage forms, see, for example, B. Lippold in "Orally Controlled Release Products: Therapeutic and Biopharmaceutic Assessment" ed. U. Gundert-Remy and H. Möller, Stuttgart, Wiss.Verl.- Ges., 1989, 39-57.

For the retardation of a drug combination, especially in the case of drugs with very different phys.-chem. Properties, these systems are not generally suitable, especially if the drug release rate of the combination partners should not differ significantly from each other. Therefore, in addition to the different dosages above all the solubilities of the active ingredients must be considered. For example, the solubility in water of the angiotensin II antagonist losartan-K is classified as "free-solvating", whereas candesartan cilexetil is classified as almost insoluble in water.The combination partner nifedipine has a water solubility of 9 mg / l and nisoldipine about 2 mg / l ,

Surprisingly, it has now been found that the dosage forms according to the invention, which release the active ingredients at a specific, defined modified rate, allow a once-daily administration at comparatively constant plasma concentrations. The sustained-release medicaments according to the invention now release both active ingredients with a comparable release rate.

Particularly suitable dosage forms which release the active ingredients modified / retarded are based on osmfteftechen release systems. In this case, cores, for example capsules or tablets, preferably tablets, are surrounded by a semipermeable membrane which has at least one opening. The water-permeable membrane is impermeable to the components of the core, but allows the entry of water from outside via osmosis into the system. The infiltrated water then releases, via the resulting osmotic pressure, the active ingredient dissolved or suspended from the opening (s) in the membrane. Total drug release and release rate can be controlled substantially by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number and size of the opening (s). Advantages, formulation aspects, application forms and information on manufacturing methods are u. a. described in the following publications:

• Santus, G., Baker, R.W., "Osmotic drug delivery: a review of the patent literature",

Journal of Controlled Release 35 (1995), 1-21 - A -

• Verma, R.K., Mishra, B., Garg, S., "Osmotically Controlled Oral Drug Delivery", Drug Development and Industrial Pharmacy 26 (7), 695-708 (2000).

Verma, R.K., Krishna, D.M., Garg, S., "Formulation aspects in the development of osmotically controlled oral drug delivery system", Journal of Controlled Release 79 (2002), 7-27

• Verma, R.K., Arora, S., Garg, S., "Osmotic pumps in drug delivery", Critical Reviews in Therapeutic Drug Carrier Systems 21 (6) (2004), 477-520

US 4,327,725, US 4,765,989, US 20030161882, EP 1 024 793.

The present invention relates to a pharmaceutical dosage form containing an active ingredient combination of nifedipine or nisoldipine and at least one angiotensin II antagonist, characterized in that the active ingredient combination in the body controlled (modified) is released.

Another preferred subject of the invention is a pharmaceutical dosage form containing a combination of nifedipine or nisoldipine and at least one angiotensin II antagonist, characterized in that the active ingredient combination in the body on the basis of an osmotic drug release system controlled (modified) is released.

Preferred angiotensin II antagonists are candesartan, losartan, telmisartan, irbesartan and olmes species or their prodrugs. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body to the compounds used according to the invention (for example metabolically or hydrolytically). A prodrug of candesartan is, for example, candesartan cilexetil. This and other examples of suitable prodrugs are disclosed in J. Med. Chem. 1993 Aug 6; 36 (16): 2343-9. A prodrug of olmesartan is, for example, olmesartan medoxomil.

The dosage form according to the invention preferably contains nifedipine or nisoldipine in dosages of 5 to 60 mg, preferably in dosages of 10 to 40 mg and at least one angiotensin II antagonist in dosages of 2 to 500 mg, preferably candesartan in dosages of 2 to 32 mg from 4 to 16 mg, also preferably olmesartan in a dosage of 5 to 40 mg, preferably from 10 to 40 mg, also preferably telmisartan in a dosage of 10 to 80 mg, preferably from 10 to 40 mg, also preferably Losartan in a dosage of 25 to 100 mg, preferably from 40 to 60 mg, also preferably Irbesartan in a dosage of 50 to 500 mg, preferably from 75 to 300 mg.

If necessary, it may be necessary to deviate from the stated amounts, depending on the body weight or the type of application route, on the individual behavior towards the medicaments, the type of formulation thereof and the time or interval at which the administration takes place he follows. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded.

Another object of the invention are solid, orally administered, a drug combination of nifedipine or nisoldipine with an angiotensin II antagonist-containing pharmaceutical dosage forms for once daily application based on osmotic delivery systems, characterized in that 80% of the active ingredients (based on the declared total amount of of each active ingredient) over a period of at least 4 and at most 30 hours according to USP release method with apparatus 2 (paddle) are released. The delivery rate of the angiotensin II antagonist combined with nifedipine or nisoldipine is not significantly different from the rate of delivery in the linear phase of release of nifedipine or nisoldipin, preferably not more than 25% relative to nifedipine and / or nisoldipine, more preferably less than 15%.

In a preferred embodiment of the present invention, 80% of the active ingredients are released in a period of 8 to 24 hours according to USP Release Method 2 (Paddle).

The active compounds can be present in the pharmaceutical dosage forms according to the invention in crystalline form or in non-crystalline amorphous form or in mixtures of crystalline and amorphous active substance fractions.

Contain the dosage forms of the invention, the active ingredients in crystalline form, they are used in a preferred embodiment of the present invention in micronized form. In this case, nifedipine or nisoldipine preferably have an average particle size X ₅₀ of 2-6 μm and an X ₉₀ value (90% proportion) of less than 12 μm.

For the combination of active ingredients, both osmotic elementary osmotic pump systems and two-chamber systems (push-pull systems) are suitable.

The shell of the osmotic drug delivery system consists of a water permeable, for the components of the core both in the single-chamber and the two-chamber system impermeable material. Such shell materials are known in principle and described, for example, in EP-B1-024793, page 3-4, the disclosure of which is hereby incorporated by reference. Cellulose acetate or mixtures of cellulose acetate and polyethylene glycol are preferably used according to the invention as the shell material.

If necessary, a lacquer, for example a sunscreen and / or colored lacquer, can be applied to the shell. Suitable materials for this are, for example, polymers such as polyvinyl alcohol, hydroxypropyl cellulose and / or hydroxypropylmethyl cellulose, optionally in combination with suitable plasticizers such as polyethylene glycol or polypropylene glycol and pigments such as titanium dioxide or iron oxides.

In the osmotic one-chamber system, the core preferably contains:

• 5 to 50% of the active ingredient combination nifedipine or nisoldipine + angiotensin II antagonists,

• 10 to 50% xanthan,

5 to 40% of a vinylpyrrolidone-vinyl acetate copolymer,

where appropriate, the difference to 100% is formed by one or more additional constituents which are selected from the group of further hydrophilic, swellable polymers, osmotically active additives and pharmaceutically customary excipients. The sum of the core constituents is 100% and the% figures refer to the total mass of the core.

The osmotic one-chamber system contains as one of the essential components of the core, the hydrophilic water-swellable polymer xanthan. This is an anionic heteropolysaccharide which is commercially available, for example, under the name Rhodigel® (manufactured by Rhodia). It is present in an amount of from 10 to 50%, preferably from 20 to 40%, based on the total mass of the core constituents.

Another essential component of the core is the vinylpyrrolidone-vinyl acetate copolymer. This copolymer is known per se and can be prepared with any mixing ratios of the monomers. The preferably used commercially available Kollidon® VA64 (manufactured by BASF) is, for example, a 60:40 copolymer. It generally has a weight average molecular weight Mw, as determined by light scattering measurements, of from about 45,000 to about 70,000. The amount of vinylpyrrolidone-vinyl acetate copolymer in Core is 5 to 40%, preferably 15 to 25%, based on the total mass of the core constituents.

Optionally hydrophilic swellable polymers additionally present in the core are, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, polyacrylic acids or their salts.

Optionally, additionally present in the core osmotically active additives are, for example, all water-soluble substances, the use of which is harmless in pharmaceutics, such. the water-soluble excipients mentioned in Pharmakopoen or in "Hager" and "Remington Pharmaceutical Science". In particular, water-soluble salts of inorganic or organic acids or non-ionic organic substances with high water solubility, such as e.g. Carbohydrates, especially sugars, sugar alcohols or amino acids are used. For example, the osmotically active additives can be selected from inorganic salts such as chlorides, sulfates, carbonates and bicarbonates of alkali or alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium and phosphates, hydrogen or dihydrogen phosphates, acetates, succinates, benzoates, Citrates or ascorbates thereof. Further, pentoses such as arabinose, ribose or xylose, hexoses such as glucose, fructose, galactose or mannose, disaccharides such as sucrose, maltose or lactose or trisaccharides such as raffinose may be used. The water-soluble amino acids include glycine, leucine, alanine or methionine. Sodium chloride is particularly preferably used according to the invention. The osmotically active additives are preferably contained in an amount of up to 30% based on the total mass of the core constituents.

Optional pharmaceutically customary adjuvants additionally present in the core are, for example, buffering agents such as sodium bicarbonate, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose and / or polyvinylpyrrolidone, lubricants such as magnesium stearate, wetting agents such as sodium lauryl sulfate and / or flow regulators such as fumed silica and stabilizers such as antioxidants.

Another object of the present invention is a process for preparing an osmotic Einkammersystems invention, wherein the components of the core are mixed together, optionally wet or dry granulated, then tabletted and the resulting core is coated with the shell, optionally with a Sunscreen and / or color coat is coated and which is provided with one or more openings.

In a preferred embodiment of the present invention, in the preparation of the osmotic Einkammersystems the core components are subjected to a wet granulation, since this process step causes better wettability of the constituents of the tablet core, whereby the entering Gastrointestinalflüssigkeit better penetrates the core, which often leads to a faster and more complete release of the drug.

^" In the two-chamber osmotic system, the core consists of two layers, an active agent layer and an osmotic layer Such a two-chamber osmotic system is described in detail in, for example, DE 34 17 1 13 C2, the disclosure of which is hereby incorporated by reference.

The active substance layer preferably contains:

• 40 to 95% of one or more osmotically active polymers, preferably polyethylene oxide of medium viscosity (40 to 100 mPa-s; 5% aqueous solution, 25 ⁰ C).

The osmotic layer preferably contains:

• 40 to 90% of one or more osmotically active polymers, preferably polyethylene oxide of high viscosity (5000 to 8000 mPa-s; 1% aqueous solution, 25 ⁰ C).

5 to 40% of an osmotically active additive,

where the difference to 100% in the individual layers is independent of each other by one or more grams _. additional constituents are formed in the form of pharmaceutically customary excipients. The% figures refer to the total mass of the respective core layer.

At the core of the osmotic bicameral system, the same osmotically active additives as in the case of the single-chamber system described above can furthermore be used. Preference is given to sodium chloride.

At the core of the osmotic bicameral system, the same pharmaceutically acceptable excipients may be used as in the case of the single-chamber system described above. Binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose and / or polyvinylpyrrolidone, lubricants such as magnesium stearate, wetting agents such as sodium lauryl sulfate and / or flow control agents such as fumed silica, a color pigment such as iron oxide in one of the two layers for differentiation of active substance and osmotic layer and stabilizers / antioxidants in the active ingredient layer. Another object of the present invention is a method for producing the osmotic bicameral system according to the invention, wherein the components of the drug layer are mixed and granulated, the components of the osmotic layer are mixed and granulated and then both granules are pressed on a two-layer tablet press to form a two-layer tablet. The resulting core is then coated with a shell, the shell is provided on the active ingredient side with one or more openings and then optionally coated with a lacquer.

In a preferred embodiment of the present invention, both the components of the active substance layer and the components of the osmotic layer are each granulated in the production of the osmotic bicameral system, in particular by means of roll granulation.

Owing to the physicochemical properties of the combination of active substances, osmotic two-chamber systems (push-pull systems) in which the active substance and osmotic layer are present separately are preferably formulated according to the invention as an example and preferably as a 2-layer tablet. The advantages over osmotic single-chamber systems are the more uniform release rate over a longer period of time and the possibility of reducing the excess of active substance necessary for the system.

The present invention further provides oral medicaments which can be administered once a day and contain a solid-release pharmaceutical dosage form according to the invention containing the active ingredient combination nifedipine or nisoldipine and at least one angiotensin II antagonist.

A further and preferred subject of the present invention are oral, once-daily drugs containing a solid modified release pharmaceutical dosage form according to the invention, comprising nifedipine or nisoldipine and at least one angiotensin II antagonist, obtained by osmotic drug delivery systems.

Another object of the present invention is the use of the solid, orally applicable, a drug combination of nifedipine or nisoldipine with at least one angiotensin II antagonist-containing pharmaceutical dosage forms based on osmotic delivery systems for the prophylaxis, secondary prophylaxis and / or treatment of cardiovascular diseases, eg hypertension. Another object of the present invention is the use of the solid, orally applicable, a drug combination of nifedipine or nisoldipine with at least one angiotensin H antagonist-containing pharmaceutical dosage forms based on osmotic delivery systems for the manufacture of a medicament for the prophylaxis, secondary prophylaxis and / or treatment of cardiovascular diseases , eg hypertension.

Another object of the present invention is the use of a drug combination of nifedipine or nisoldipine with at least one angiotensin-U antagonist for the preparation of a solid, orally administered pharmaceutical dosage form according to the invention based on osmotic delivery systems.

Another object of the present invention is a method for the prophylaxis, secondary prophylaxis and / or treatment of cardiovascular diseases by administering a solid, orally administered, the active ingredient combination nifedipine or nisoldipine and at least angiotensin II antagonist containing pharmaceutical dosage form with osmotic release system.

Another object of the present invention is a triple combination of antihypertensive drugs containing nifedipine or nisoldipine, at least one angiotensin II antagonist and at least one other blood pressure lowering agent. Preferred is a diuretic and most preferably hydrochlorothiazide.

This combination is particularly suitable for the treatment of patients in whom monotherapy or dual combination therapy did not produce the desired blood pressure reduction. Refractory patients are often among the patients for whom adequate control of blood pressure is particularly important. Although both calcium antagonists and diuretics are drugs that lower blood pressure independently of the renin-angiotensin system, they differ in their mechanism of action. The calcium antagonists are primarily vasodilators with a weak natriuretic effect, while the diuretics (thiazides) are the opposite. When the renin-angiotensin system is inhibited, the diuretics add-on to the calcium antagonists. Surprisingly, it could be shown that the triple combination described above has also led to adequate control of blood pressure in therapy-resistant patients. The invention is explained in more detail below by preferred embodiments, to which it is not limited. Unless otherwise indicated, all quantities below refer to percentages by weight.

Experimental part

The in vitro release studies described below are carried out according to the USP release method using apparatus 2 (paddle). The rotational speed of the -Ruhrers is at 100 TJpM (revolutions per minute) in 900 ml of a phosphate buffer solution of pH 6.8, which was prepared from 1.25 ml Ortho phosphoric acid, 4.75 g of citric acid monohydrate and 27.46 g of disodium hydrogen phosphate dihydrate in 10 1 water. The buffer solution is added to adjust the sink conditions 1% sodium lauryl sulfate. The tablet formulations are preferably released from a sinker, according to the Japanese Pharmacopoeia.

1. Osmotic single-chamber system containing nifedipine / angiotensin II antagonist

combination

Example formulation 1.1 tablet composition in mg / tablet (declared content = 20 mg nifedipine and 8 mg candesartan / tablet)

core

Nifedipine, micronized 24.0 mg

Candesartan cilexetil 9.6 mg

Xanthan gum (Rhodigel TSC, Rhodia) 100.0 mg

Copolyvidone (Kollidon VA 64, BASF) 56.0 mg

Sodium chloride 56.0 mg

Sodium bicarbonate 17.9 mg

Sodium carboxymethyl starch 23.0 mg

Hydroxypropylmethylcellulose (5 cp) 10.0 mg

Sodium Lauryl Sulfate 0.5 mg

Highly dispersed silica (Aerosil 200, Degussa) 1.5 mg

Magnesium stearate 1.5 mg

300.0 mg

Shell (osmotic membrane) Cellulose acetate 22.8 mg

Polyethylene glycol 3.350 1.2 mg

24.0 mg production:

Xanthan gum, copolyvidone, sodium chloride, sodium bicarbonate and sodium carboxymethyl cellulose are mixed and then wet-granulated with an aqueous suspension of the active ingredients nifedipine and candesartan cilexetil and hydroxypropylmethylcellulose. After drying and sieving, Aerosil and magnesium stearate are mixed in and the press-ready mixture obtained in this way is pressed into tablets of 8 mm diameter. The tablet cores are coated with an acetone solution of cellulose acetate and polyethylene glycol and dried. Then, for each tablet, two openings of 1 mm diameter each are attached by means of a hand drill.

2. Osmotic bicameral system containing nifedipine / angiotensin II antagonist

combination

Example formulation 2.1 Tablet composition in mg / tablet (declared content = 30 mg nifedipine and 50 mg losartan potassium / tablet)

Core drug layer

Nifedipine, micronized 33.0 mg

Losartan K Granules * 155.0 mg

Hydroxypropylmethylcellulose (5 cp) 8.2 mg

Polyethylene oxide ** 122.2 mg magnesium stearate _^ 0.4 mg

318.8 mg

osmosis layer

Hydroxypropylmethylcellulose (5 cp) 8.0 mg

Sodium chloride 46.5 mg

Polyethylene oxide *** 102.9 mg

Iron oxide red 1.6 mg

Magnesium stearate 0.4 mg

159.4 mg

HIlIe (osmotic membrane) cellulose acetate 32.3 mg

Polyethylene glycol 3.350 1.7 mg

34.0 mg * Losartan K granules = mortar Lorzaar ^® Protect tablet (MSD Sharp & Dohme, hair) containing Losartan-Kaliua 50 mg »

** Polyox WSR N-80 NF (Dow); Viscosity 5% aqueous solution (25 ^° C.): 40-100 mPa · s

*** Polyox WSR Coagulant NF (Dow); Viscosity l% aqueous solution (25 ⁰ ^C): 5000-8000 mPa-s ■

production:

The components of the drug layer are mixed and granulated dry. Likewise, the components of the osmotic layer are mixed and granulated dry. On a two-layer tablet press, both granules are pressed into a two-layer tablet (diameter 10 mm). The tablets are coated with an acetone solution of cellulose acetate and polyethylene glycol and dried. Subsequently, for each tablet on the active ingredient side, an opening of 0.9 mm diameter is attached by means of a hand drill.

In vitro release of the example formulation 2.1

(USP paddle, 100 rpm, 900 ml phosphate buffer pH 6.8 + 1.0% sodium lauryl sulfate, JP sinker)

Example formulation 2.2 Tablet composition in mg / tablet

(declared content = 30mg nifedipine and 20mg telmisartan / tablet)

core

active ingredient layer

Nifedipine, micronized 33.0 mg

Telmisartan granules * 120.0 mg

Hydroxypropylmethylcellulose (5 cp) 8.2 mg

Polyethylene oxide ** 122.2 mg

Magnesium stearate 0.4 mg

283.8 mg osmosis layer

Hydroxypropylmethylcellulose (5 cp) 7.1 mg

Sodium chloride 41.4 mg

Polyethylene oxide *** 91.65 mg

Iron oxide red 1.4 mg

Magnesium Stearate 0.35 mg

141.9 mg

Shell (osmotic membrane) Cellulose acetate 32.3 mg Polyethylene glycol 3.350 1.7 mg

34.0 mg

* Telmisartan granules = Kinzalmono mortared tablet (Bayer AG, Leverkusen) containing 20 mg of telmisartan

** Polyox WSR N-80 NF (Dow); Viscosity 5% aqueous solution (25 ⁰ C): 40-100 mPa-s *** Polyox WSR Coagulant NF (Dow); Viscosity l% aqueous solution (25 ^° C.):

5000-8000 mPa-s

production:

In vitro release of the example formulation 2.1

Claims

claims

1. Pharmaceutical dosage form containing a combination of nifedipine or nisoldipine and at least one angiotensin II antagonist, characterized in that the active ingredient combination in the body controlled (modified) is released.

2. Pharmaceutical dosage form according to claim 1, wherein the angiotensin II antagonist from the group candesartan, losartan, telmisartan, irbesartan and olmesartan or one of the prodrugs of these angiotensin II antagonists is selected.

3. A pharmaceutical dosage form according to claims 1 and 2, characterized in that 80% of the active ingredients in a period of 4 to 30 hours according to USP-release-set method with apparatus 2 (paddle) are released.

4. Pharmaceutical dosage form according to claims 1 to 3, characterized in that 80% of the active ingredients in a period of 4 to 30 hours according to USP-release method with apparatus 2 (paddle) are released and the release rates of the respective active ingredients in the linear part of the release process by no more than 25%.

5. Pharmaceutical dosage form according to one of claims 1 to 4, characterized in that 80% of the active ingredient combination in a period of 8 to 24 hours according USP release method with apparatus 2 (Paddle) are released.

6. A pharmaceutical dosage form according to any of claims 1 b ^~ is 5, characterized in that 80% of the active ingredient combination 2 (paddle) are released in a period of 8 to 24 hours in the USP release method with apparatus and the release rates of their respective active ingredients in linear part of the release process by no more than 15%.

7. Pharmaceutical dosage form according to claims 1 to 6, characterized in that the pharmaceutical dosage form solid, orally administrable and based on an osmotic drug delivery system is constructed.

8. Pharmaceutical dosage form according to one of claims 1 to 7, characterized in that the active ingredients are present in crystalline or predominantly crystalline form.

9. Pharmaceutical dosage form according to one of claims 1 to 8, characterized in that the active ingredients are in micronized form.

10. A pharmaceutical dosage form according to any one of claims 1 to 7 and 9, characterized in that the active ingredients are wholly or partly in amorphous form.

11. Pharmaceutical dosage form according to one of claims 1 to 10, characterized in that nifedipine or nisoldipine is used in a minimum dose of 5 mg and a maximum dose of 60 mg.

12. Pharmaceutical dosage form according to one of claims 1 to 1 1, characterized in that nifedipine or nisoldipine is used in a minimum dose of 10 mg and a maximum dose of 40 mg.

13. A pharmaceutical dosage form according to any one of claims 1 to 12, characterized in that angiotensin-H antagonist candesartan, olmesartan, irbesartan, losartan or telmisartan.

14. Pharmaceutical dosage form according to one of claims 1 to 13, characterized in that as angiotensin II antagonist 'candesartan or one of its

Prodrugs in a dose of 2 - 32 mg is used.

15. A pharmaceutical dosage form according to any one of claims 1 to 13, characterized in that is used as the angiotensin II antagonist candesartan or one of its prodrugs in a dose of 4 - 16 mg.

16. Pharmaceutical dosage form according to one of claims 1 to 13, characterized in that the angiotensin II antagonist olmesartan or one of its prodrugs is used in a dose of 5 - 40 mg.

17. Pharmaceutical dosage form according to one of claims 1 to 13, characterized in that olmesartan or one of its prodrugs is used in a dose of 10 to 40 mg.

18. Pharmaceutical dosage form according to one of claims 1 to 13, characterized in that the angiotensin II antagonist is telmisartan and is used in a dose of 10 to 80 mg.

19. Pharmaceutical dosage form according to one of claims 1 to 13, characterized in that telmisartan is used in a dose of 10 to 40 mg.

20. A pharmaceutical dosage form according to any one of claims 1 to 12, characterized in that losartan is used in a dose of 25 to 100 mg.

21. A pharmaceutical dosage form according to any one of claims 1 to 12, characterized in that losartan is used in a dose of 40 to 60 mg.

22. Pharmaceutical dosage form according to one of claims 1 to 13, characterized in that Irbesartan is used in a dose of 50 to 500 mg.

23. Pharmaceutical dosage form according to one of claims 1 to 13, characterized in that Irbesartan is used in a dose of 75 to 300 mg.

24. Pharmaceutical dosage form according to one of claims 1 to 23 consisting of an osmotic Einkammersystem.

25. A pharmaceutical dosage form according to any one of claims 1 to 24 comprising an osmotic Einkammersystem comprising

a core containing

• 5 to 50% of a combination nifedipine or nisoldipine + angiotensin II antagonists,

• 10 to 50% xanthan,

5 to 40% of a vinylpyrrolidone-vinyl acetate copolymer,

and a shell comprising a water-permeable material impermeable to the components of the core and having at least one opening.

26. A pharmaceutical dosage form according to any one of claims 1 to 25, which additionally contains sodium chloride in the core as an osmotically active additive.

27. A pharmaceutical dosage form according to any one of claims 1 to 26, characterized in that the shell consists of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

28. Pharmaceutical dosage form according to one of claims 1 to 23, consisting of a two-chamber osmotic system.

29. A pharmaceutical dosage form according to any one of claims 1 to 23 and 28, comprising a two-chamber osmotic system comprising a core with a drug layer containing

• 5 to 50% of a combination nifedipine or nisoldipine + angiotensin! antagonists,

40 to 95% of one or more osmotically active polymers,

and an osmotic layer containing

• 40 to 90% of one or more osmotically active polymers

5 to 40% of an osmotically active additive,

30. A pharmaceutical dosage form according to any one of claims 28 and 29, which contains in the core in the drug layer polyethylene oxide having a viscosity of 40 to 100 mPa · s (5% aqueous solution, 25 ⁰ C) as osmotically active polymer and in the core in the Osmotic layer Polyethylene oxide having a viscosity of 5000 to 8000 mPa · s (1% aqueous solution, 25 ° C) as an osmotically active polymer.

31. A pharmaceutical dosage form according to any one of claims 28 to 30, characterized in that the shell consists of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

A method of making a single chamber osmotic system as defined in any one of claims 24 to 27, characterized in that the components of the core are mixed, granulated and tableted together, the core thus formed having a

Cover is coated and the shell is finally provided with one or more openings.

33. A method for producing a two-chamber osmotic system as defined in any one of claims 28 to 31, characterized in that

• the components of the active substance layer are mixed and granulated and

The components of the osmotic layer are mixed and granulated,

Subsequently, on a two-layer tablet press, both granules are pressed into a two-layer tablet,

• the resulting core is then coated with the shell and • the shell on the active ingredient side is provided with one or more openings.

34. A pharmaceutical composition containing a pharmaceutical dosage form according to one of claims 1 to 31.

35. Use of a pharmaceutical dosage form according to one of claims 1 to 31, for the prophylaxis, secondary prophylaxis and / or treatment of diseases.

36. Use of a pharmaceutical dosage form according to any one of claims 1 to 31, for the manufacture of a medicament for the prophylaxis, secondary prophylaxis and / or treatment of diseases.

37. Use according to any one of claims 35 and 36 for the prophylaxis, secondary prophylaxis and / or treatment of cardiovascular diseases.

38. Use according to any one of claims 35 to 37 for the prophylaxis, secondary prophylaxis and / or treatment of hypertension.

39. Use of a nifedipine or nisoldipine / angiotensin II antagonist combination for the manufacture of a pharmaceutical dosage form as defined in any one of claims 1 to 31.

40. Pharmaceutical dosage form according to one of claims 1 to 31, in which in addition to nifedipine or nisoldipine and the angiotensin II antagonist, another antihypertensive agent is incorporated.

41. Pharmaceutical dosage form according to one of claims 1 to 31 and 40, in which in addition to nifedipine or nisoldipine and the angiotensin II antagonist, a diuretic is incorporated.

42. Pharmaceutical dosage form according to claims 40 and 41, wherein hydrochlorothiazide is used.

43. A method for the prophylaxis, secondary prophylaxis and / or treatment of cardiovascular diseases by administering a solid, orally administered, a nifedipine or nisoldipine / angiotensin II antagonist combination containing pharmaceutical dosage form based on drug release systems, as defined in claims 1 to 31 ,