WO2002006253A1 - Valsartan salts - Google Patents
Valsartan salts Download PDFInfo
- Publication number
- WO2002006253A1 WO2002006253A1 PCT/EP2001/008253 EP0108253W WO0206253A1 WO 2002006253 A1 WO2002006253 A1 WO 2002006253A1 EP 0108253 W EP0108253 W EP 0108253W WO 0206253 A1 WO0206253 A1 WO 0206253A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- valsartan
- water
- pharmaceutically acceptable
- weak
- Prior art date
Links
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- 239000004072 C09CA03 - Valsartan Substances 0.000 claims abstract description 130
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-
- 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
- A61P9/08—Vasodilators for multiple indications
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- 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 invention relates to new salts of the AT-i receptor antagonist (S)-N-(1 -carboxy-2-methyl- prop-1 -yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) of formula
- the active ingredient valsartan is the free acid which is described specifically in EP 0443983, especially in example 16; it has two acidic hydrogen atoms: (i) the hydrogen atom (H atom) of the carboxyl group, and (ii) that of the tetrazole ring. Accordingly, one acidic H atom (primarily the carboxyl H atom) or both acidic H atoms may be replaced by a monovalent or higher valent, e.g. divalent, cation. Mixed salts may also be formed.
- EP 443983 does not disclose any specific salts of valsartan. Also, it does not mention any special properties of salts. Meanwhile, the active ingredient valsartan has been introduced as an anti-hypertensive agent in a series of countries under the trade name DIOVAN.
- the free acid valsartan has a melting point in a closed crucible of 80 to 95°C and in an open crucible of 105 to 110°C and a melting enthalpy of 12 kJ/mol.
- the density of the valsartan crystals and of the salt hydrates was determined by a helium pycnometer (Accupyc 1330 of Micromeritics, Norcross, GA, USA).
- the density for the crystals of the free acid valsartan is 1.20 ⁇ 0.02.
- the X-ray diffraction diagram consists essentially of a very broad, diffuse Xray reflection; the free acid is therefore characterised as almost amorphous under X-ray.
- the melting point linked with the measured melting enthalpy of 12 kJ/mol unequivocally confirm the existence of a considerable residual arrangement in the particles or structural domains for the free acid valsartan.
- salts of valsartan with the desired advantageous properties has proved to be difficult. In the majority of cases, for example, amorphous salts with little stability are obtained (such as hard foams, waxes or oils). Extensive research has shown that the salts of valsartan according to the invention have proved to be particularly advantageous compared with the free acid valsartan.
- the objects of the present invention are salts of valsartan which are selected from the group consisting of the monosodium salt, the monopotassium salt, the dipotassium salt, the magnesium salt, the calcium salt, the bis-diethylammonium salt, the bis-dipropylammonium salt, the bis-dibutylammonium salt, the mono-L-arginine salt, the bis-L-arginine salt, the mono-L-lysine salt and the bis-L-iysine salt, as well as salt mixtures, or respectively, an amorphous form, a solvate, especially hydrate, as well as a polymorphous form thereof, the respective production and usage, and pharmaceutical preparations containing such salts.
- the objects of the present invention are salts of valsartan which are selected from the group consisting of the monosodium salt, the monopotassium salt, the dipotassium salt, the magnesium salt, the calcium salt, the bis-diethylammonium salt, the bis-dipropylammonium salt, the bis-dibutylammoniumsalt, the mono-L-arginine salt, the bis-L-arginine salt, the mono-L-lysine salt and the bis-L-lysine salt, or respectively, an amorphous form, a solvate, especially hydrate, as well as a polymorphous form thereof.
- Salt mixtures are (i) single salt forms from different cations selected from the above group or (ii) mixtures of those single salt forms which exist for example in the form of conglomerates.
- Preferred salts are for example selected from the mono-sodium salt in amorphous form; di-sodium salt of valsartan in amorphous or crystalline form, especially in hydrate form, thereof.
- the salts according to the invention preferably exist in isolated and essentially pure form, for example in a degree of purity of >95%, preferably >98%, primarily >99%.
- the enantiomer purity of the salts according to the invention is >98%, preferably >99%.
- the salts according to the invention Compared with the free acid, the salts according to the invention, or the amorphous forms, solvates such as salt hydrates, and also the corresponding polymorphous forms thereof, have unexpectedly advantageous properties.
- the crystalline salts and crystalline salt hydrates have a clear melting point which is linked with a marked, endothermic melting enthalpy.
- the crystalline salts according to the invention are stable and are of better quality than valsartan also during storage and distribution.
- the amorphous or partially amorphous salts have limited stability, i.e. as the solid, they have a restricted stability range. To be stabilised, they require certain measures which can be achieved for example by galenic formulations.
- both the crystalline and the amorphous salts according to the invention have a high degree of dissociation in water and thus substantially improved water solubility. These properties are of advantage, since on the one hand the dissolving process is quicker and on the other hand a smaller amount of water is required for such solutions. Furthermore, the higher water solubility can, under certain conditions, also lead to increased biological availability of the salts or salt hydrates in the case of solid dosage forms. Improved properties are beneficial especially to the patients. Furthermore, some of the salts according to the invention have proved to be exceptionally physically stable, particularly the alkaline earth salts.
- the salt hydrates according to the invention show practically no water absorption or water loss over a wide range of humidities and for periods of a few hours, e.g. four hours. Also, for example, the melting point of the salts according to the invention will not be changed by storing under different relative humidities.
- the invention also relates to polymorphous forms of the salts according to the invention.
- Solvates and also hydrates of the salts according to the invention may be present, for example, as hemi-, mono-, di-, tri-, tetra-, penta-, hexa-solvates or hydrates, respectively.
- Solvents used for crystallisation such as alcohols, especially methanol, ethanol, aldehydes, ketones, especially acetone, esters, e.g. ethyl acetate, may be embedded in the crystal grating.
- the extent to which a selected solvent or water leads to a solvate or hydrate in crystallisation and in the subsequent process steps or leads directly to the free acid is generally unpredictable and depends on the combinations of process conditions and the various interactions between valsartan and the selected solvent, especially water.
- the description salt hydrates for corresponding hydrates may be preferred, as water molecules in the crystal structure are bound by strong intermolecular forces and thereby represent an essential element of structure formation of these crystals which, in part, are extraordinarily stable.
- water molecules are also existing in certain crystal lattices which are bound by rather weak intermolecular forces. Such molecules are more or less integrated in the crystal structure forming, but to a lower energetic effect.
- the water content in amorphous solids can, in general, be clearly determined, as in crystalline hydrates, but is heavily dependent on the drying and ambient conditions. In contrast, in the case of stable hydrates, there are clear stoichiometric ratios between the pharmaceutical active substance and the water.
- ratios do not fulfil completely the stoichiometric value, normally it is approached by lower values compared to theory because of certain crystal defects.
- the ratio of organic molecules to water molecules for the weaker bound water may vary to a considerable extend, for example, extending over di-, tri- or tetra-hydrates.
- the molecular structure classification of water is not stoichiometric; the classification may however also be stoichiometric only by chance.
- the different resulting crystal gratings are summarised by the term polymorphism.
- tetrahydrate of the calcium salt of valsartan and the hexahydrate of the magnesium salt of valsartan.
- the X-ray diffraction diagram of powders of these two salt hydrates has a number of discrete X-ray reflections, and practically no signs of non-crystalline or amorphous portions.
- the degree of crystallisation of these defined salt hydrates is therefore surprisingly high.
- relatively large crystals may be cultured from certain salt hydrates, and in the crystallographic sense these are single crystals. Such single crystals allow the structure of the solid to be determined. It is effected by computer-aided evaluation of the reflection intensities measured by an X-ray diffractometer.
- This process for determining the structure of a crystal enables, under normal conditions such as high physical, chemical and enantiomeric purity of the gauged crystals, a clear determination of the structure to be carried out on a molecular or atomic level, namely symmetry and size of the elementary cells, atom positions and temperature factors, and from the ascertained cell volume, the X-ray-photographic density is shown on the basis of a molecular weight.
- the X-ray-photographic structure determination supplies details of its quality.
- the outstanding properties of these two salt hydrates are based on the crystals, which form these salts by incorporating four or six water molecules per valsartan molecule. Thus, practically perfect three-dimensional crystal gratings are produced.
- These two salts have water solubility that is several times better than the free acid of valsartan, and this is especially surprisingly at high melting points and melting enthalpies, which are eight or five times greater than the free acid.
- the extraordinary crystal gratings of these two salt hydrates are the basis for the chemical and physical stability of these two compounds.
- the particularly notable salt hydrate is the tetrahydrate of the calcium salt of valsartan.
- the tetrahydrate of the calcium salt of valsartan is not stable at elevated temperatures both in respect of the hydrate water and in respect of the structure of the molecule.
- the indicated melting point is a hydrate melting point which can only be measured in a closed specimen container.
- Gold containers with a wall thickness of 0.2 mm were used; after weighing in samples of between 2 and 4 mg salt hydrate, they were sealed by cold welding.
- These gold containers have an internal free volume of ca. 22 microlitres.
- the amounts of the sample and the volume of the pressurised containers must be suitably adapted, so that strong dehydration of the salt hydrates cannot take place during measurement of the melting point.
- thermodynamic characteristics illustrate the advantageous physical properties, compared to the free acid, with the two corresponding data, namely a melting point in the closed system of 90°C and a melting enthalpy of 12 kJ • Mol "1 .
- thermodynamic data together with the X-ray data, prove the high stability of this crystal grating. They are the foundation for the special physical and chemical resistance of the tetrahydrate of the calcium salt of valsartan.
- a measurement of the infrared absorption spectrum of the tetrahydrate of the calcium salt of valsartan in a potassium bromide compressed tablet shows the following significant bands expressed in reciprocal wave numbers (cm "1 ): 3750 - 3000 (st); 3400 - 2500 (st);
- the tetrahydrate of the calcium salt of valsartan has the following absorption bands expressed in reciprocal wave numbers (cm "1 ):
- the error margin for all absorption bands of ATR-IR is ⁇ 2 cm '1 .
- the water content is in theory 13.2% for the tetrahydrate of the calcium salt of valsartan.
- thermo-scale TGS-2 Perkin-Elmer Corp. , Norwalk, CT USA .
- a total formula was calculated from this (C 24 H 2 N 5 O 3 ) 2" Ca 2+ » (3.9 ⁇ 0.1) H 2 O.
- the preferred characterisation of the tetrahydrate of the calcium salt of valsartan is obtained from the interlattice plane intervals d of the ascertained X-ray diffraction diagrams, whereby, in the following, average values are indicated with the appropriate error limits, d in [A] : 16.1 ⁇ 0.3, 9.9 ⁇ 0.2, 9.4 ⁇ 0.2, 8.03 ⁇ 0.1 , 7.71 ⁇ 0.1 , 7.03 ⁇ 0.1 , 6.50 ⁇ 0.1 , 6.33 ⁇ 0.1 , 6.20 ⁇ 0.05, 5.87 ⁇ 0.05, 5.74 ⁇ 0.05, 5.67 ⁇ 0.05, 5.20 ⁇ 0.05, 5.05 ⁇ 0.05, 4.95 ⁇ 0.05, 4.73 ⁇ 0.05, 4.55 ⁇ 0.05, 4.33 ⁇ 0.05, 4.15 ⁇ 0.05, 4.12 ⁇ 0.05, 3.95 ⁇ 0.05, 3.91 ⁇ 0.05, 3.87 ⁇ 0.05, 3.35 ⁇ 0.05.
- the most intensive reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A] : 16.1 ⁇ 0.3, 9.9 ⁇ 0.2, 9.4 ⁇ 0.2, 7.03 ⁇ 0.1 , 6.50 ⁇ 0.1, 5.87 ⁇ 0.05, 5.74 ⁇ 0.05, 4.95 ⁇ 0.05, 4.73 ⁇ 0.05, 4.33 ⁇ 0.05, 4.15 ⁇ 0.05, 4.12 ⁇ 0.05, 3.95 ⁇ 0.05.
- a preferred method of checking the above-indicated average values of the interlattice plane intervals and intensities measured by experimentation from X-ray diffraction diagrams with a Guinier camera, for a given substance consists in calculating these intervals and their intensities from the comprehensive single crystal structure determination.
- This structure determination yields cell constants and atom positions, which enable the X-ray diffraction diagram corresponding to the solid to be calculated by means of computer-aided calculation methods (programme CaRine Crystallography, Universite de Compiegne, France).
- the invention relates to the crystalline tetrahydrate of the calcium salt of (S)-N-(1-carboxy-2- methylprop-1 -yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine, a crystalline solid which is clearly characterised by the data and parameters obtained from single crystal X-ray analysis and X-ray powder patterns.
- An in-depth discussion of the theory of the methods of single crystal X-ray diffraction and the definition of the evaluated crystal data and the parameters may be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N.Y. (1968) chapter 3.
- SHELXS 86 Sheldrick, G ⁇ ttingen, 1990
- SHELXL 96 Sheldrick, G ⁇ ttingen, 1996
- SCHAKAL 86 Keller, Freiburg 1986
- PLATON Spek, Acta Cryst., 1990
- the elementary cell is defined by six parameters, namely by the grating constants a, b and c, and by the axial angle, namely by a, ⁇ , und y. In this way, the volume of the elementary cell V c is determined. A differentiated description of these crystal parameters is illustrated in chapter 3 of Stout & Jensen (see above).
- An essential feature for the quality of a pure active substance both for the physical-chemical procedures such as drying, sieving, grinding, and in the galenic processes which are carried out with pharmaceutical excipients, namely in mixing processes, in granulation, in spray- drying, in tabletting, is the water absorption or water loss of this active substance depending on temperature and the relative humidity of the environment in question.
- free and bound water is without doubt introduced with excipients and/or water is added to the process mass for reasons associated with the respective formulation process. In this way, the pharmaceutical active substance is exposed to free water over rather long periods of time, depending on the temperature of the different activity (partial vapour pressure).
- thermogravimetry The measurement error of this sorption method based on thermogravimetry is about 0.1%. Therefore, the tetrahydrate of the calcium salt of valsartan under the conditions employed, which are realistic from a pharmaceutical-galenic point of view, shows no measurable water absorption or loss. This is surprising to a large extent, since the tetrahydrate, which has incorporated about 13% of bound water in the crystal structure, is totally indifferent to water even at extreme values of relative humidity. This property is crucial in the final stages of chemical manufacture and also in practice in all galenic process stages of the different dosage forms. This exceptional stability similarly benefits the patients through the constant availability of the active ingredient.
- this salt is suitable for pressing directly to form corresponding tablet formulations.
- a magnesium salt hydrate of valsartan is preferred, in particular the hexahydrate.
- the thermal behaviour of this salt hydrate in the region of the melting point shows a certain chemical and physical instability. The thermal data are thus dependent on the measurement conditions.
- the melting point of the hexahydrate of the magnesium salt of valsart is 132 ⁇ 1.5° Celsius and the melting enthalpy is 56 ⁇ 3 kJ Mol ' 1 .
- the melting enthalpy which is about 5 times higher than the free acid of valsartan, together with the significantly higher melting point of the hexahydrate of the magnesium salt of valsartan is a measure of the stability of the new-type crystal grating at around room temperature.
- a measurement of the infrared absorption spectrum of the hexahydrate of the magnesium salt of valsartan in a potassium bromide compressed tablet shows the following significant bands expressed in reciprocal wave numbers (cm "1 ): 3800 - 3000 (st); 3000 - 2500 (st); 1800 - 1500 (st); 1500 - 1440 (m); 1440 - 1300 (m); 1280 - 1240 (w); 1240 - 1190 (w); 1190 - 1150 (w); 1120 - 1070 (w); 1050 - 990 (w); 990 - 960 (w); 960 - 920 (w); 920 - 700 (m); 700 - 590 (w); 590 - 550 (w).
- the hexahydrate of the magnesium salt of valsartan has the following absorption bands expressed in reciprocal wave numbers (cm "1 ):
- the error margin for all absorption bands of ATR-IR is ⁇ 2 cm '1 .
- the theoretical water content of the hexahydrate of the magnesium salt of valsartan is 19.1%.
- TG-FTIR thermogravimetry-Fourier transformation- infrared-spectroscopy
- IFS 28 thermogravimetry-Fourier transformation- infrared-spectroscopy 28 from the companies Netzsch Geratebau GmbH, Selb, explanation and Bruker Optik GmbH, Düsseldorf
- the water content was determined at 18.5 %, conforming well with the theoretical value.
- Table 7 illustrates the water loss of the hexahydrate of the magnesium salt of valsartan depending on temperature, using the weight loss measured in an N 2 atmosphere on a thermogravimetric thermal analysis instrument for a heating rate of 10 K°min "1 . From the TG-FTIR measurement, the correlation of the weight loss is assured solely by the release of water.
- the hexahydrate of the magnesium salt of valsartan has a solubility in distilled water at 22°C of 59 g per litre of solution for a pH value of 9.3.
- the crystalline form of the hexahydrate of the magnesium salt of valsartan is clearly characterised by the interlattice plane intervals calculated from the lines in an X-ray powder pattern.
- the measurement and analysis methods used are the same as those used for the tetrahydrate of the calcium salt of valsartan.
- a preferred method of checking the above-indicated average values of the interlattice plane intervals and intensities measured by experimentation from X-ray diffraction diagrams with a Guinier camera, for a given substance consists in calculating these intervals and their intensities from the comprehensive single crystal structure determination.
- This structure determination yields cell constants and atom positions, which enable the X-ray diffraction diagram corresponding to the solid to be calculated by means of computer-aided calculation methods (programme CaRine Crystallography, Universite de Compiegne, France).
- the invention relates in particular to the crystalline hexahydrate of the magnesium salt of (S)-N-(1 -carboxy-2-methylprop-1 -yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)biphenyl-4- ylmethylj-amine, a crystalline solid which is clearly characterised by the data and parameters obtained from single crystal X-ray analysis.
- An in-depth discussion of the theory of the methods of single crystal X-ray diffraction and the definition of the evaluated crystal data and the parameters may be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N.Y. (1968) chapter 3.
- SHELXS 86 (Sheldrick, G ⁇ ttingen, 1990)
- SHELXL 96 (Sheldrick, G ⁇ ttingen, 1996)
- SCHAKAL 86 (Keller, Freiburg 1986)
- PLATON (Spek, Acta Cryst., 1990)
- the elementary cell is defined by six parameters, namely by the grating constants a, b and c, and by the axial angle, namely by a, ⁇ , und y. In this way, the volume of the elementary cell V 0 is determined. A differentiated description of these crystal parameters is illustrated in chapter 3 of Stout & Jensen (see above).
- Table 10 illustrates the mass change, i.e. the water absorption or loss as a function of relative humidity at 25°C for a sample of 9.5 mg of magnesium-valsartan-hexahydrate and for a period of 4 hours (h). The following cycles of changes in relative humidity are shown: 40-90; 90-0; 0-90; 90-0 % relative humidity:
- thermogravimetry The measurement error of this sorption method based on thermogravimetry is about 0.1%. Therefore, the hexahydrate of the magnesium salt of valsartan under the conditions employed, which are realistic from a pharmaceutical-galenic point of view, shows weak, reproducible water absorption or water loss in a range of 20 to 80% relative humidity. This is surprising to a large extent, since the hexahydrate, which has incorporated about 19% bound water in the crystal structure, reversibly absorbs or releases water even at extreme values of relative humidity and is relatively insensitive at an average range of relative humidity. This characteristic enables an uncomplicated physical-chemical process to be developed and allows a choice of the best dosage forms for the patients.
- this salt is suitable for pressing directly to form corresponding tablet formulations.
- magnesium salt of valsartan especially the hexahydrate thereof, shows an advantageous compression hardness profile.
- Calcium/magnesium mixed salts of valsartan also have advantageous properties, for example uniform crystal conglomerates may be produced. These may be advantageously used in the galenic formulation.
- a further object of the invention is the preparation of the salts according to the invention.
- the salts according to the invention including amorphous or crystalline forms thereof, may be prepared as follows:
- the process is carried out in a solvent system, in which the two reactants, namely the acid valsartan and the respective base, are sufficiently soluble. It is expedient to use a solvent or solvent mixture, in which the resulting salt is only slightly soluble or not soluble at all, in order to achieve crystallisation or precipitation.
- One variant for the salt according to the invention would be to use a solvent in which this salt is very soluble, and to subsequently add an anti-solvent to this solution, that is a solvent in which the resulting salt has only poor solubility.
- a further variant for salt crystallisation consists in concentrating the salt solution, for example by heating, if necessary under reduced pressure, or by slowly evaporating the solvent, e.g. at room temperature, or by seeding with the addition of seeding crystals, or by setting up water activity required for hydrate formation.
- the solvents that may be used are for example C C 5 -alkanols, preferably ethanol and isopropanol, as well as CrC 5 -dialkylketones, preferably acetone and mixtures thereof with water.
- the antisolvents for salt crystallisation may be for example C 3 -C 7 -alkylnitriles, especially acetonitrile, esters, especially C 2 -C 7 -alkanecarboxylic acid-C ⁇ -C 5 -alkylester, such as ethyl or isopropyl acetate, di-(C ⁇ -C 5 -alkyl)-ethers, such as tert.-butylmethylether, furthermore tetrahydrofuran, and C 5 -C 8 -alkanes, especially pentane, hexane or heptane.
- C 3 -C 7 -alkylnitriles especially acetonitrile, esters, especially C 2 -C 7 -alkanecarboxylic acid-C ⁇ -C 5 -alkylester, such as ethyl or isopropyl acetate
- a dissolving and crystallising process is used in particular, or a water- equilibrating crystallisation process.
- the dissolving and crystallising process is characterised in that (i) valsartan and the appropriate base are brought to a reaction in a preferably water- containing, organic solvent,
- the solvent system is concentrated, for example by heating, if necessary under reduced pressure and by seeding with seeding crystals or by slowly evaporating, e.g. at room temperature, then crystallisation or precipitation is initiated and (iii) the salt obtained is isolated.
- the water-containing, organic solvent system employed is advantageously a mixtures of alcohols, such as ethanol, and water, or or alkyl- nitrile, especially acetonitrile, and water.
- the equilibrating crystallisation process for producing hydrates is characterised in that (i) valsartan and the appropriate base are added to a water-containing organic solvent, (ii) the solvent is concentrated, for example by heating, if necessary under reduced pressure or by slowly evaporating, e.g. at room temperature, (iii) the residue of evaporation is equilibrated with the required amount of water by (a) suspending the residue of evaporation, which is advantageously still warm, and which still contains some water, in an appropriate solvent or
- the solvent system used as the water-containing organic solvent advantageously comprises mixtures of suitable alcohols, such as C C 7 -alkanols, especially ethanol, and water.
- An appropriate solvent for equilibration is, for example, an ester such as C C 7 -alkane- carboxylic acid-C 1 -C 7 -alkylester, especially ethyl acetate, or a ketone such as di-C- ⁇ -C 5 - alkylketone, especially acetone.
- an ester such as C C 7 -alkane- carboxylic acid-C 1 -C 7 -alkylester, especially ethyl acetate
- a ketone such as di-C- ⁇ -C 5 - alkylketone, especially acetone.
- the equilibration process is notable for example for its high yields and outstanding reproducibility.
- the di-alkali metal salts and alkaline earth metal salts of the present invention may also be obtained in crystalline form and are in the form of hydrates throughout, from appropriate solvents that are conventionally used in production processes, such as esters, e.g. d-C -alkanecarboxylic acid-C r C 7 -alkylesters, especially ethyl acetate, ketones, e.g.
- di-C ⁇ -C 5 -alkylketones especially acetone, C 3 -C 7 -alkylnitriles, especially acetonitrile, or ethers, e.g. di-(d-C 5 -alkyl)- ethers, such as tert.-butylmethylether, also tetrahydrofuran, or mixtures of solvents.
- ethers e.g. di-(d-C 5 -alkyl)- ethers, such as tert.-butylmethylether, also tetrahydrofuran, or mixtures of solvents.
- the preparation of the hydrate-free bis-dialkylammonium salts of the present invention is advantageously effected in one step by using an appropriate solvent which is optionally mixed with an antisolvent. In this way, crystalline salts are obtained. As a rule, the amino acid salts of the present invention are obtained in amorphous form.
- salts or salt hydrates according to the invention are obtained for example by neutralising the acid valsartan with a base corresponding to the respective cation.
- This neutralisation is suitably effected in an aqueous medium, e.g. in water or a mixture of water and a solvent in which valsartan is more soluble than in water.
- Salts with weaker bases may be converted into other salts either by treating with stronger bases or by treating with acids and then neutralising with other bases.
- Crystallisation is effected in water or an aqueous medium, which consists of water and at least one solvent that is miscible or partially miscible with water, i.e. not too non-polar, e.g. an alkanol such as methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, acetonitrile, DMF, DMSO.
- the alkanol portion amounts to about 10 to 90, or 20 to 70, advantageously 30 to 50% by volume.
- the less polar solvent may also be present in lower concentrations. Owing to the restricted water-solubility of valsartan, the process frequently takes place in suspensions, or if valsartan is soluble in the other solvent component, in a solution.
- an aqueous solution of valsartan is neutralised with a calcium hydroxide solution at room temperature and the solution is left to crystallise.
- crystallisation is effected from a solvent mixture of water/ethanol, the ethanol proportion amounting to ca. 30 to 50% by volume.
- crystallisation is effected in a closed system by transporting through a low temperature gradient (especially 1-2°C at 40°C) in 30% by volume of ethanol.
- crystallisation may be optimised, e.g. accelerated, by adding at least one seed crystal.
- the salts according to the invention may be used e.g. in the form of pharmaceutical preparations, which contain the active substance e.g. in a therapeuticaily effective amount of the active substance, optionally together with a pharmaceutically acceptable carrier, for example with an inorganic or organic, solid or optionally also liquid pharmaceutically acceptable carrier, which is suitable for enteral, e.g. oral, or parenteral administration.
- a pharmaceutically acceptable carrier for example with an inorganic or organic, solid or optionally also liquid pharmaceutically acceptable carrier, which is suitable for enteral, e.g. oral, or parenteral administration.
- the invention relates in particular to a pharmaceutical composition, especially in a solid dosage unit, preferably for oral administration, optionally together with a pharmaceutically acceptable carrier.
- compositions of this kind may be used for example for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the A ⁇ receptor for example a disease or condition selected from the group consisting of
- Atherosclerosis atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
- Primary usages are for the treatment of high blood pressure and congestive heart failure, as well as post-myocardial infarction.
- the valuable potential of the salts or combinations of the present invention for the prevention and treatment of myocardial infarction can be found using the following test model.
- CAO coronary artery occlusion
- cardiomyocytes cross-sectional area and length in sections of LV myocardium
- Methodology Infarct size Six ⁇ m-thick transverse histological sections of the left ventricle are stained with nitroblue tetrazolium and acquired by a B/W XC-77CE CCD video camera (Sony). The resulting image is processed on a KS 300 image analysis system (Carl Zeiss Vision) using a software specifically developed (Porzio et al., 1995). A single operator blinded to treatment interactively defines the boundaries of the interventricular septum, and the infarcted area on each section is semiautomatically identified as the area of unstained ventricular tissue. The software automatically calculates for each component of the ventricular section defined as the chamber, septum, infarcted area, infarcted LV wall and viable LV wall, a set of geometric parameters (Porzio et al., 1995).
- Hearts are fixed in situ, by retrograde perfusion with buffered 4% formaldehyde after arrest in diastole by i.v. injection of 0.5 M KCI. After fixation, the left ventricle (LV) and the free wall of the right ventricle are separately weighed; LV longer diameter is measured with a caliper.
- LV histological sections are stained with hematoxylin & eosin for qualitative examination and to quantify cardiomyocytes cross-sectional area with a semi-automated image analysis routine. Interstitial collagen deposition in LV is evaluated on Sirius red stained sections with a semi-automated image analysis routine (Masson et al., 1998).
- Collagen content in LV spared myocardium LV tissue in the spared myocardium is homogenized, subjected to PAGE-SDS electrophoresis and electroblotted onto nitrocellulose membrane. The blots are exposed to primary antibodies, i.e. rabbit anti-rat collagen type I or type III antiserum (Chemicon). The primary antibodies are recognized by secondary antibodies conjugated to alkaline phosphatase (for colagen type I) or peroxidase (collagen type III).
- LV chamber volume is determined in hearts arrested in diastole (KCI) and fixed in formalin under a hydrostatic pressure equivalent to the measured LV end-diastolic pressure.
- a metric rod is inserted into the LV to measure LV inner length.
- the transverse diameters of the LV chamber are measured in two 1 -mm thick transverse sections near to the base and the apex of the ventricle (Jeremic ef al., 1996).
- the chamber volume is computed from an equation integrating transverse diameters and inner length.
- a microtip pressure transducer (Millar SPC-320) connected to a recorder (Windograf, Gould Electronics) is inserted into the right carotid artery to record systolic and diastolic blood pressures.
- the pressure transducer is advanced into the LV to measure LV systolic (LVSP) and end-diastolic (LVEDP) pressures, the first derivative of LV pressure over time (+dP/dt) and heart rate.
- LVSP LV systolic
- LVEDP end-diastolic
- Non-invasive blood pressure Systolic blood pressure and heart rate are measured by the tail-cuff method (Letica LE 5002) in conscious rats.
- Urine electrolytes, hormones Rats are individually housed in metabolic cages and 24-h urine collected on 1 ml HCI 6N. Water intake is measured. Urine catecholamines are extracted on Bondelut Ci 8 columns (Varian), separated by HPLC (Apex-ll C18, 3 ⁇ m, 50x4.5 mm analytical column, Jones Chromatography) and quantified with an electrochemical detector (Coulochem II, ESA) (Goldstein etal., 1981). Plasma and urine aldosterone, and plasma angiotensin II is determined with specific radioimmunoassays (Aldoctk-2, DiaSorin and Angiotensin II, Nichols Diagnostics). Urine sodium and potassium are measured by flamme photometry.
- Endothelial dysfunction is being acknowledged as a critical factor in vascular diseases.
- the endothelium plays a bimodal role as the source of various hormones or by-products with opposing effects: vasodilation and vasoconstriction, inhibition or promotion of growth, fibrinolysis or thrombogenesis, production of anti-oxidants or oxidising agents.
- Genetically predisposed hypertensive animals with endothelial dysfunction constitute a valid model for assessing the efficacy of a cardiovascular therapy.
- Endothelial disfunction is characterized by, for example, increased oxidative stress, causing decreased nitric oxide, increased factors involved in coagulation or fibrinolysis such as plasminogen activating inhibitor-1 (PAI-1 ), tissue factor (TF), tissue plasminogen activator (tPA), increased adhesion molecules such as ICAM and VCAM, increased growth factors such as bFGF, TGFb, PDGF, VEGF, all factors causing cell growth inflammation and fibrosis.
- PAI-1 plasminogen activating inhibitor-1
- TF tissue factor
- tPA tissue plasminogen activator
- ICAM interleukinogen activator
- VCAM increased adhesion molecules
- growth factors such as bFGF, TGFb, PDGF, VEGF, all factors causing cell growth inflammation and fibrosis.
- the treatment e.g. of endothelian dysfunction can be demonstrated in the following pharmacological test:
- the drugs are administered in drinking fluid.
- the pressure effect of Ang II at 1 mg/kg obtained in controls normotensive rats can be reduced after treatment with a salt according to the present invention (Gervais et al. 1999).
- Body weight is measured every week.
- Systolic blood pressure and heart rate are recorded by tail cuff plethysmography 3 and 2 weeks before starting the study and at 2 weeks after drug administration.
- Urine is collected over a 24 hour period from rats kept in individual (metabolic) cages the week before starting treatment and at weeks 4 and 12 for volume measurement and protein, creatinine, sodium and potassium determination using standard laboratory methods.
- blood samples are withdrawn from the retro- orbital plexus (maximum 1 ml) for creatinine, Na + and K + assays.
- salts or combinations according to the present invention can be used for the regression of a cholesterol diet-induced atherosclerosis, can be demonstrated using the test model described, e.g., by C. Jiang et al. in Br. J. Pharmacol. (1991), 104, 1033-1037.
- salts or combinations according to the present invention can be used for the treatment of renal failure, especially chronic renal failure, can be demonstrated using the test model described, e.g., by D. Cohen et al. in Journal of Cardiovascular Pharmacology, 32: 87-95 (1998).
- the present pharmaceutical preparations which, if so desired, may contain further pharmacologically active substances, are prepared in a manner known perse, for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes, and contain from about 0.1% to 100%, especially from about 1% to about 50%, of lyophilisates up to 100% of the active substance.
- the invention similarly relates to compositions containing the salts according to the invention.
- the invention similarly relates to the use of the salts according to the invention preferably for the production of pharmaceutical preparations, especially for the prophylaxis and also for the treatment of diseases or conditions which may be inhibited by blocking the ATi receptor.
- Primary usages are for the treatment of high blood pressure and congestive heart failure, as well as post-myocardial infarction.
- the invention similarly relates to the use for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the A ⁇ receptor, characterised in that a patient, including a human patient, requiring such treatment is administered with a therapeuticaily effective amount of a salt according to the invention, optionally in combination with at least one composition for the treatment of cardiovascular diseases and related conditions and diseases listed hereinbefore or hereinafter.
- the invention similarly relates to combinations, e.g. pharmaceutical combinations, containing a salt of the present invention or in each case a pharmaceutically acceptable salt thereof in combination with at least one composition for the treatment of cardiovascular diseases and related conditions and diseases as listed hereinbefore or hereinafter, or in each case a pharmaceutically acceptable salt thereof.
- Combinations with other compositions for the treatment of cardiovascular diseases and related conditions and diseases as listed hereinbefore or hereinafter, or in each case a pharmaceutically acceptable salt thereof, are likewise objects of the present invention.
- compositions selected from the group consisting of a:
- angiotensin converting enzyme (ACE) Inhibitor or a pharmaceutically acceptable salt thereof
- HMG-Co-A reductase inhibitors also called ⁇ -hydroxy- ⁇ -methylglutaryl-co-enzyme-A reductase inhibitors
- HMG-Co-A reductase inhibitors are understood to be those active agents that may be used to lower the lipid levels including cholesterol in blood.
- the class of HMG-Co-A reductase inhibitors comprises compounds having differing structural features.
- the compounds that are selected from the group consisting of atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin, or, in each case, a pharmaceutically acceptable salt thereof.
- HMG-Co-A reductase inhibitors are those agents which have been marketed, most preferred is fluvastatin and pitavastatin or, in each case, a pharmaceutically acceptable salt thereof.
- ACE-inhibitors also called angiotensin converting enzyme inhibitors
- the class of ACE inhibitors comprises compounds having differing structural features.
- Preferred ACE inhibitors are those agents that have been marketed, most preferred are benazepril and enalapril.
- the class of CCBs essentially comprises dihydropyridines (DHPs) and non-DHPs such as diltiazem-type and verapamil-type CCBs.
- DHPs dihydropyridines
- non-DHPs such as diltiazem-type and verapamil-type CCBs.
- a CCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mi
- CCBs are therapeuticaily used, e.g. as anti-hypertensive, anti-angina pectoris or anti-arrhythmic drugs.
- Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt thereof.
- DHP is amlodipine or a pharmaceutically acceptable salt, especially the besylate, thereof.
- An especially preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt, especially the hydrochloride, thereof.
- Aldosterone synthase inhibitor is an enzyme that converts corticosterone to aldosterone to by hydroxylating cortocosterone to form 18-OH-corticosterone and 18-OH-corticosterone to aldosterone.
- the class of aldosterone synthase inhibitors is known to be applied for the treatment of hypertension and primary aldosteronism comprises both steroidal and non- steroidal aldosterone synthase inhibitors, the later being most preferred.
- the class of aldosterone synthase inhibitors comprises compounds having differing structural features.
- non-steroidal aldosterone synthase inhibitor is the (+)-enantiomer of the hydrochloride of fadrozole (US patents 4617307 and 4889861) of formula
- a preferred steroidal aldosterone antagonist is eplerenone of the formula
- a preferred dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP) inhibitor is, for example, omapatrilate (cf. EP 629627), fasidotril or fasidotrilate, or, if appropriable, a pharmaceutically acceptable salt thereof.
- a preferred endothelin antagonist is, for example, bosentan (cf. EP 526708 A), furthermore, tezosentan (cf. WO 96/19459), or in each case, a pharmaceutically acceptable salt thereof.
- a renin inhibitor is, for example, a non-peptidic renin inhibitor such as the compound of formula
- a diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon. The most preferred is hydrochlorothiazide.
- the jointly therapeuticaily effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, separately or in a fixed combination.
- the structure of the active agents identified by generic or tradenames may be taken from the actual edition of the standard compendium 'The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
- the corresponding active ingredients or a pharmaceutically acceptable salts thereof may also be used in form of a solvate, such as a hydrate or including other solvents, used for crystallization.
- the compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
- the compounds having an acid group (for example COOH) can also form salts with bases.
- the present invention likewise relates to a "kit-of-parts", for example, in the sense that the components to be combined according to the present invention can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. simultaneously or at different time points.
- the parts of the kit of parts can then e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
- the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components.
- the invention furthermore relates to a commercial package comprising the combination according to the present invention together with instructions for simultaneous, separate or sequential use.
- Dosaging may depend on various factors, such as mode of application, species, age and/or individual condition.
- the doses to be administered daily are between ca. 0.25 and 10 mg/kg, and for warm-blooded animals with a body weight of ca. 70 kg, preferably between ca. 20 mg and 500 mg, especially 40mg, 80mg, 160mg and 320mg based on the free acid.
- the invention is illustrated in particular by the examples and also relates to the new compounds named in the examples and to their usage and to methods for the preparation thereof.
- the di-potassium salt of valsartan is formed, especially a hydrate thereof.
- the di-potassium salt is noted in particular for its marked water solubility.
- the crystalline tetrahydrate of the di-potassium salt of valsartan, with a melting point of 135.0°C, may be mentioned in particular. According to elementary analysis, a certain sample of this hydrate has a water content of 3.72 mols of water per mol of di-potassium salt. For high relative humidity at room temperature, the tetrahydrate is formed and for low values of relative humidity, the anhydrate of the di-potassium salt is formed.
- a magnesium salt of valsartan is similarly produced, in this instance as an amorphous solid with 3.4% H 2 O.
- the temperature of glass transition as a mean value of the stage of the specific heat of 0.85 J • [g • ° C] "1 is 167 °C. No melting point is observed.
- the Ca(OH) 2 used contains traces of CaCO 3 ; therefore the added amount includes an excess of 5%.
- the pH is ca. 6, and after adding the excess it rises to 7.
- the solution becomes turbid through the small amount of finely divided CaCO 3 , which is removed through a folded filter.
- the product contained in the solution crystallises continuously upon removal of the alcohol content by allowing to stand at room temperature. The procedure can be accelerated by using a flat dish in a recirculating air drier at 40°C. After concentrating to ca. one half, the alcohol content of the solution drops to ca. 10% by volume and most of the product crystallises.
- the melting point for the tetrahydrate of the calcium salt of valsartan, produced according to example 1 , for a heating rate of 10 K « min "1 and in a closed specimen container with a small internal volume is determined as 205°C and the melting enthalpy as 92 kJ » Mol '1 .
- the density of the crystals of the calcium-valsartan-tetrahydrate produced according to example 1 is 1.297 g » cm "3 . This value conforms to the theoretically calculated value of 1.298 g » cm '3 calculated from the single crystal structure.
- the enantiomer purity of the salt hydrate produced according to example 1 is determined by a stereo-specific HPLC method.
- the stereo-specific separation is achieved by a chiral column (Chiral AGP).
- the pH value hereby rises to ca. 6.
- the process is effected with an excess of 10%, i.e. a further 0.40 g of MgO are added. This excess is not fully dissolved, and the pH value rises to ca. 7.5.
- the small residue is filtered from the solution through a folded filter and washed with 50 ml of 50% ethanol.
- the combined clear solution is carefully concentrated at 40°C whilst stirring with a magnetic stirrer in a large crystallisation dish. Towards the end of this procedure, the solution has a tendency to harden into a glassy gel. Scratching with a glass rod induces the in situ crystallisation in this phase, which may be recognised by the white colour of the crystalline solid thus formed.
- the product is dried at 50°C in a recirculating air drier until reaching a constant weight.
- the yield of magnesium-valsartan-hexahydrate is 53.7 g or 95% based on the valsartan employed as the free acid.
- Crystal data sum formula (C 24 H 27 N 5 O 3 ) 2' 2K + . x H 2 O (x 3.5 ⁇ 1.0) molecular mass 574.78 crystal system orthorhombic space group P2-*2 1 2 a (A) 38.555(2) b (A) 7.577(1) c (A) 10.064(1)
- SHELXS86 (Sheldrick, G ⁇ ttingen), XHELXL93 (Sheldrick, G ⁇ ttingen), SCHAKAL92 (Keller, supra)
- 0.95 g of the salt are heated to reflux in 20 ml of acetonitrile/water (1 :1), whereby the mixture almost dissolves.
- the mixture is allowed to cool to room temperature, mixed with 20 ml of acetonitrile, filtered by suction and washed twice with acetonitrile/water (1:1) and dried over night in a high vacuum at 80°C Melting point: from 300°C (decomposition).
- Example 9 Production of the magnesium salt as the hexahydrate of valsartan by a water-equilibrating process.
- This mixture is transferred through a candle filter to a 35 litre enamel boiler and the glass receptacle and the transfer tube are rinsed with 885 g of isopropanol and 1122 g of deionised water.
- a vacuum is created in the boiler to an initial theoretical value of 89-100 mbar.
- a temperature of the heating medium of 45-50°C and a boiling temperature of the mixture of 37-40°C, a total of 13.66 kg of aqueous isopropanol is distilled.
- the distillation pressure By lowering the distillation pressure to a final value of 10 mbar and simultaneously raising the heating medium temperature to 65°C, the amount of distillate is increased to a total of 17.12 kg.
- the physical data, especially the X-ray powder pattern, correspond to the magnesium hexahydrate salt of example 2.
- the suspension present at the end of distillation is cooled to ca. 5°C whilst stirring, and is stirred for ca. 16 hours at 5°C.
- the suspension is then filtered through B ⁇ chner filters.
- the boiler is rinsed with a mixture of 3600 ml of deionised water and 400 ml of ethanol, the mixture being cooled to 5°C, and the rinsing mixture is used to wash the filter cake. A moist filter cake is thus obtained. Drying of a partial amount on metal sheets in a vacuum drying chamber at 50 mbar pressure and 40°C oven temperature for 24 hours until reaching a constant weight yields a dry substance.
- the physical data especially the X-ray powder pattern, correspond to the calcium tetrahydrate salt of example 1.
- valsartan disodium salt (2.4 ⁇ 1.0 mole H 2 O): 50 ml of 2N sodium hydroxide solution are added dropwise at ca. 25°C to a solution of 21.5 g of valsartan in 200 ml of isopropanol. The clear solution (pH ca. 7.2) is concentrated under vacuum at ca.40°C. The amo ⁇ hous residue of the disodium salt is suspended in 100 ml of isopropanol, and water is removed by concentrating under vacuum once more at ca. 40°C and degassing. The amorphous residue is suspended in 75 ml of acetone and 2 ml of water at ca. 40°C. At ca.
- the easily stirrable crystal suspension is cooled to 10°C, stirred for at least one hour, filtered by suction and washed with 20 ml of tert.butylmethylether.
- the moist filter cake is dried over night at ca. 30 mbar and at 30°C. A colourless, slightly hygroscopic crystal powder is obtained.
- Valsartan calcium/magnesium mixed salt
- the X-ray diffraction diagram corresponds to a conglomerate of calcium tetrahydrate and magnesium hexahydrate from example 1 and 2.
- Valsartan bis-diethylammonium salt
- Valsartan bis-dipropylammonium salt
- a solution of 2.15 g of valsartan in 30 ml of acetone is mixed with 1.4 g of dibutylamine at ca. 25°C. Crystallisation sets in after a short time, and the thick suspension is gradually diluted with 20 ml of isopropyl acetate over ca. 1 hour. After stirring for 4 hours at ca. 25°C, the crystals are removed by suction, washed twice with 10 ml of isopropyl acetate and dried in a vacuum at 50°C. A colourless, slightly hygroscopic crystal powder is obtained.
- Formulation example 1 Directly compressed tablet:
- Ingredient no. 1 is sieved through a 0.5 mm sieve and mixed for 15 minutes in a Turbula with ingredients 1-6. Tablets are compress using a single punch tablet press with punches of a diameter of 8mm.
- Ingredients no. 1 -5 are mixed for 50 minutes and compacted on a Freund roller compactor.
- the band is milled and after admixing ingredient no 6, compressed into tablets using a single punch tablet press with punches of a diameter of 8mm.
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Priority Applications (24)
Application Number | Priority Date | Filing Date | Title |
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AU8967201A AU8967201A (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
PL360737A PL205715B1 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
DK01969407T DK1313714T3 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
EP01969407A EP1313714B1 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
DE60135560T DE60135560D1 (en) | 2000-07-19 | 2001-07-17 | VALSARTAN SALT |
KR10-2003-7000815A KR100529658B1 (en) | 2000-07-19 | 2001-07-17 | Valsartan Salts |
JP2002512157A JP4102664B2 (en) | 2000-07-19 | 2001-07-17 | Valsartan salt |
NZ52355701A NZ523557A (en) | 2000-07-19 | 2001-07-17 | Calcium salt of valsartan |
SK55-2003A SK287558B6 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts, their use, method for their production and pharmaceutical composition comprising said salts |
AU2001289672A AU2001289672B2 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
HU0300731A HU229280B1 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
BR0112665-2A BR0112665A (en) | 2000-07-19 | 2001-07-17 | Salts |
US10/333,100 US20030207930A1 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
CA2415962A CA2415962C (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
IL15388201A IL153882A0 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
MXPA03000525A MXPA03000525A (en) | 2000-07-19 | 2001-07-17 | Valsartan salts. |
SI200130881T SI1313714T1 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
IL153882A IL153882A (en) | 2000-07-19 | 2003-01-09 | Calcium salt of valsartan and a process for its manufacture |
NO20030232A NO326504B1 (en) | 2000-07-19 | 2003-01-17 | Valsartan salts, process for their preparation, use thereof, and pharmaceutical composition containing such a compound |
HK03108267.6A HK1055963A1 (en) | 2000-07-19 | 2003-11-13 | Valsartan salts |
US11/678,284 US20070149587A1 (en) | 2000-07-19 | 2007-02-23 | Valsartan Salts |
US12/186,172 US8278339B2 (en) | 2000-07-19 | 2008-08-05 | Valsartan salts |
US13/599,032 US20120329844A1 (en) | 2000-07-19 | 2012-08-30 | Valsartan salts |
US14/081,441 US9499499B2 (en) | 2000-07-19 | 2013-11-15 | Valsartan salts |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP00115556 | 2000-07-19 | ||
EP00115556.3 | 2000-07-19 |
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US10/333,100 A-371-Of-International US20030207930A1 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
US10333100 A-371-Of-International | 2001-07-17 | ||
US11/678,284 Continuation US20070149587A1 (en) | 2000-07-19 | 2007-02-23 | Valsartan Salts |
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WO2002006253A1 true WO2002006253A1 (en) | 2002-01-24 |
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PCT/EP2001/008253 WO2002006253A1 (en) | 2000-07-19 | 2001-07-17 | Valsartan salts |
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US (5) | US20030207930A1 (en) |
EP (1) | EP1313714B1 (en) |
JP (1) | JP4102664B2 (en) |
KR (1) | KR100529658B1 (en) |
CN (2) | CN100413852C (en) |
AR (2) | AR032758A1 (en) |
AT (1) | ATE406355T1 (en) |
AU (2) | AU2001289672B2 (en) |
BR (1) | BR0112665A (en) |
CA (1) | CA2415962C (en) |
CY (1) | CY1108559T1 (en) |
CZ (1) | CZ303389B6 (en) |
DE (1) | DE60135560D1 (en) |
DK (1) | DK1313714T3 (en) |
EC (1) | ECSP034436A (en) |
ES (1) | ES2309090T3 (en) |
HK (1) | HK1055963A1 (en) |
HU (1) | HU229280B1 (en) |
IL (2) | IL153882A0 (en) |
MX (1) | MXPA03000525A (en) |
MY (2) | MY136446A (en) |
NO (1) | NO326504B1 (en) |
NZ (1) | NZ523557A (en) |
PE (1) | PE20020613A1 (en) |
PL (1) | PL205715B1 (en) |
PT (1) | PT1313714E (en) |
RU (1) | RU2275363C2 (en) |
SI (1) | SI1313714T1 (en) |
SK (1) | SK287558B6 (en) |
WO (1) | WO2002006253A1 (en) |
ZA (1) | ZA200300285B (en) |
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