New crystalline forms of tiotropium bromide

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to crystalline tiotropium bromide anhydrate differing in X-ray diffraction values by the presence of an orthorhombic elementary cell with the parameters a=11.7420 (4) Å, b=17.7960 (7) Å, c=19.6280 (11) Å and the cell volume V=4101.5 (3) Å.

EFFECT: invention refers to method for preparing said form of tiotropium bromide and to a based pharmaceutical composition for treating respiratory diseases, first of all for treating chronic obstructive pulmonary disease and asthma.

5 cl, 15 dwg, 18 tbl, 15 ex

 

The present invention relates to new crystalline forms of Tiotropium, to methods for their preparation and to their use for the preparation of pharmaceutical compositions intended for the treatment of respiratory diseases, primarily for the treatment of chronic obstructive pulmonary disease (COPD) and asthma.

Background of invention

Tetrapyrrolic known from application EP 418716 A1 and has the following chemical structure:

.

Tetrapyrrole is a highly anticholinergic agent with long lasting effect, which can be used for the treatment of diseases of the respiratory tract, primarily for the treatment of chronic obstructive pulmonary disease and asthma. Under Tiotropium means free ammonium cation.

Tetrapyrrolic enter the body mainly by inhalation. This may be relevant inhalation powders, packaged in suitable for this purpose capsules (inhaled). An alternative to this for inhalation of Tiotropium in the body can also be used the corresponding inhalation aerosol composition for aerosol inhalation). Such compositions for aerosol inhalation are also powder compositions for Aero is Olney inhalation, which as a propellant contain, for example, HFA134a, HFA227 or a mixture.

To obtain the above meets the applicable requirements of the composition used for inhalation into the body of a medicinal active substance, technology is used, based on various parameters, which in turn are associated with characteristics of the pharmaceutical active substance. In the case of pharmaceutical compositions that are similar to tetrapyrrolic applied in the form of inhalation powders or preparations for aerosol inhalation, crystalline active ingredient used for the preparation of pharmaceutical compositions in milled (micronized). As for obtaining the pharmaceutical composition required pharmaceutical quality necessary to ensure the presence of crystals of the active substance is always the same morphology, taking into account this aspect to the stability and properties of crystalline active ingredient should be more demanding.

Based on the above the basis of the invention was based on the task of getting Tiotropium in new crystalline forms, which would satisfy the above high requirements applicable to medicinal substance.

Detailed description of the invention

In the claimed invention, it was found that tetrapyrrolic depending on the choice of conditions that can be used for purification obtained on an industrial scale crude product formed in various crystalline modifications.

In the claimed invention was, in particular, it was found that the purposeful receipt of such various modifications is largely determined by the choice used for crystallization solvents, as well as the choice of process conditions during the crystallization process.

With the invention it has been unexpectedly found that on the basis of monohydrate tetrapyrrole, which can be obtained in crystalline form by choosing the particular reaction conditions and which was first described in WO 02/30928, it is possible to obtain tetrapyrrolic in anhydrous crystalline modifications, which fully satisfies specified in the beginning of the description of the high requirements and thus allows us to solve the put in the basis of the present invention the task.

In accordance with this, in the present invention proposes such anhydrous crystalline Tiotropium. Under used in some cases in the description of the present invention the expression "anhydrate of tetrapyrrolic" means proposed in subramaniyaswamiji crystalline Tiotropium.

With this in mind, the invention relates to such crystalline anhydrate of tetrapyrrole, which according to x-ray analysis is distinguished by the presence of his orthorhombic unit cell with parameters a=11,7420(4) Å, b=17,7960(7) Å, C=19,6280(11) Å and cell volume V=4101,5(3) Å3.

The next object of the present invention is proposed in the new crystalline solvate of Tiotropium. In one of the embodiments of the present invention as it relates to the crystalline MES of tetrapyrrolic with 1,4-dioxane. In another embodiment, the present invention proposes a method of obtaining a new crystalline MES of tetrapyrrolic with 1,4-dioxane, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with 1,4-dioxane, which according to x-ray analysis is distinguished by the presence of a monoclinic unit cell with parameters a=13,6650(3) Å, b=12,0420(3) Å, C=13,7090(3) Å, β=103,8150(13)° and the cell volume V=2190,61(9) Å3.

In yet another embodiment of the present invention as it relates to the crystalline MES of tetrapyrrolic with ethanol. In another embodiment, the present invention proposes a method of obtaining a new crystalline solvatochromism with ethanol, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with ethanol, which according to x-ray analysis is distinguished by the presence of a monoclinic unit cell with parameters a=13,5380(2) Å, b=11,9830(2) Å, C=26,9410(5) Å, β=105,1990(6)° and the cell volume V=4217,65(12) Å3.

In yet another embodiment of the present invention as it relates to the crystalline MES of tetrapyrrolic with methanol. In another embodiment, the present invention proposes a method of obtaining a new crystalline MES of tetrapyrrolic with methanol, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with methanol, which according to x-ray analysis is distinguished by the presence of a monoclinic unit cell with parameters a=13,4420(2) Å, b=37,0890(5) Å, C=13,6290(2) Å, β=104,7050(10)° and the cell volume V=6572,18(16) Å3.

In yet another embodiment of the present invention as it relates to the crystalline MES of tetrapyrrolic with anisole. In another embodiment, the present invention proposes a method of obtaining a new crystalline MES of tetrapyrrolic with anisole, just to clarify on when erah in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with anisole, which is characterized in that its x-ray powder diffraction pattern in addition there are characteristic peaks corresponding to values of d equal to 12,99 Å, 8,84 Å, Of 7.96 Å, 6,84 Å, 6,55 Å, 5,76 Å, Of 5.40 Å, 4,88 Å, 4,43 Å, Is 4.21 Å, 4,14 Å, To 3.73 Å, To 3.58 Å, To 3.41 Å, Of 3.27 Å, 3,18 Å, 3,00 Å and 2.95 Å.

In yet another embodiment of the present invention as it relates to the crystalline MES of tetrapyrrolic with n-butanol. In another embodiment, the present invention proposes a method of obtaining a new crystalline MES of tetrapyrrolic with n-butanol, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with n-butanol, which is characterized in that its x-ray powder diffraction pattern in addition there are characteristic peaks corresponding to values of d equal to 9,83 Å, Of 10.93 Å, 13,38 Å, 13,54 Å, 15,34 Å, 17,95 Å, 19,77 Å, 20,83 Å, 21,41 Å, 24,15 Å, 24,56 Å, 25,03 Å, 25,66 Å, 26,03 Å, 26,95 Å and 29,87 Å.

In yet another embodiment of the present invention as it relates to the crystalline MES of tetrapyrrolic with N,N-dimethylacetamide (DMA). In another embodiment, the present invention proposes a method of obtaining novog the crystalline MES of tetrapyrrolic with DMA, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with DMA, which differs from its x-ray powder diffraction pattern in addition there are characteristic peaks corresponding to values of d equal to 8,86 Å, 7,89 Å, 6,50 Å, 5,73 Å, lower than the 5.37 Å, 4,89 Å, Was 4.42 Å, 4,18 Å, 4,10 Å, A 3.83 Å, And 3.72 Å, 3,55 Å, 3,39 Å At 3.25 Å, And 3.16 Å and 2.95 Å.

In yet another embodiment of the present invention as it relates to the crystalline MES of tetrapyrrolic with N,N-dimethylformamide (DMF). In another embodiment, the present invention proposes a method of obtaining a new crystalline MES of tetrapyrrolic with DMF, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with DMF, which differs from its x-ray powder diffraction pattern in addition there are characteristic peaks corresponding to values of d equal to 8,86 Å, Of 7.95 Å, 6,51 Å, 5,73 Å, Are 5.36 Å, 4,89 Å, 4,43 Å, 4,19 Å, 4,12 Å, Is 3.82 Å, 3,68 Å, Of 3.57 Å, 3,40 Å At 3.25 Å, And 3.16 Å and 2,96 Å.

In yet another embodiment of the present invention as it relates to the crystalline MES of tetrapyrrolic with isopropanol. In another embodiment, the present invention affords the fast way to get a new crystalline MES of tetrapyrrolic with isopropanol, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with isopropanol, which differs from its x-ray powder diffraction pattern in addition there are characteristic peaks corresponding to values of d equal to 9,87 Å, 11,00 Å, 13,31 Å, 13,47 Å, Br15.15 Å, 15,35 Å, 16,30 Å, 18,06 Å, 19,80 Å, 19.93 Per Å, 20,26 Å, 20,77 Å, 21,33 Å, 23,54 Å, To 24.02 Å, 24,64 Å, 25,08 Å, 25,85 Å, 27,02 Å, 27,68 Å, 27,93 Å, Å and 29,50 29,86 Å.

In yet another embodiment of the present invention as it relates to the crystalline MES of tetrapyrrolic 1,2-propane diol. In another embodiment, the present invention proposes a method of obtaining a new crystalline MES of tetrapyrrolic 1,2-propane diol, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic 1,2-propane diol, which differs from its x-ray powder diffraction pattern in addition there are characteristic peaks corresponding to values of d equal to 8,89 Å, 7,97 Å, 6,59 Å, 5,77 Å, 5,43 Å, 4,90 Å, Of 4.44 Å, To 4.17 Å, Of 3.85 Å, To 3.73 Å, Of 3.60 Å, 3,55 Å, Of 3.42 Å, 3,30 Å, 3,20 Å and 2,96 Å.

In yet another embodiment of the present invention as it relates to the crystalline MES, Tiotropium is and pyridine. In another embodiment, the present invention proposes a method of obtaining a new crystalline MES of tetrapyrrolic with pyridine, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with pyridine, which differs from its x-ray powder diffraction pattern in addition there are characteristic peaks corresponding to values of d equal to 13,06 Å, 8,89 Å, 7,88 Å, 6,57 Å, 5,76 Å, Of 5.40 Å, 4,89 Å, Of 4.45 Å, 4,16 Å, And 3.72 Å, 3,55 Å, Of 3.43 Å, 3,29 Å, 3,19 and 2.95 Å Å.

In yet another embodiment of the present invention as it relates to the crystalline MES of tetrapyrrolic with tert-butanol. In another embodiment, the present invention proposes a method of obtaining a new crystalline MES of tetrapyrrolic with tert-butanol, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with tert-butanol, which is characterized in that its x-ray powder diffraction pattern in addition there are characteristic peaks corresponding to values of d equal 13,13 Å, 8,81 Å, 7,98 Å, 6,57 Å, 5,76 Å, 5,41 Å, 4,89 Å, Of 4.44 Å, To 4.23 Å, 4,14 Å, To 3.73 Å, Of 3.56 Å, Of 3.42 Å, 3,29 Å, 3,19 and 2.95 Å Å.

In yet another embodiment, altoadige of the invention it relates to the crystalline MES of tetrapyrrolic with tetrahydrofuran (THF). In another embodiment, the present invention proposes a method of obtaining a new crystalline MES of tetrapyrrolic with THF, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with THF, which differs from its x-ray powder diffraction pattern in addition there are characteristic peaks corresponding to values of d equal to 8,69 Å, To 7.84 Å, 6,47 Å, Of 5.92 Å, 5,70 Å, lower than the 5.37 Å, Is 4.85 Å, To 4.41 Å, 4,34 Å, 4,19 Å, Å 4.09 to, 3,81 Å, At 3.69 Å, To 3.58 Å, To 3.52 Å, 3,40 Å, Of 3.27 Å, 3,18 and 2.94 Å Å.

In yet another embodiment of the present invention as it relates to the crystalline MES of tetrapyrrolic with tetrahydropyranol (TBM). In another embodiment, the present invention proposes a method of obtaining a new crystalline MES of tetrapyrrolic with TBM, illustrated by examples in the following experimental part.

With this in mind, the invention relates to such crystalline MES of tetrapyrrolic with TBM, which differs from its x-ray powder diffraction pattern in addition there are characteristic peaks corresponding to values of d, equal to 8.94 Å, 7,97 Å, 6,54 Å, Of 5.75 Å, To 5.35 Å, 4,89 Å, Of 4.44 Å, To 4.23 Å, 4,13 Å, With 3.89 Å, With 3.79 Å, The 3.65 Å, Of 3.60 Å, Of 3.53 Å, Of 3.43 Å, 3,24 Å, 3,17 Å and 2,98 Å.

The present invention relates t is the train to the application of the proposed therein crystalline forms of Tiotropium for the preparation of pharmaceutical compositions intended for the treatment of respiratory diseases, primarily for the treatment of COPD and/or asthma.

The present invention relates further to methods for its proposed crystalline forms of Tiotropium.

Thus, in particular, the present invention relates to a method of obtaining a new offer in the invention is a crystalline form of anhydrous Tiotropium, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) is dissolved in an acceptable solvent, preferably in a solvent mixture containing N,N-dimethylacetamide, more preferably in a solvent mixture containing dimethylacetamide and water, heated for 10-60 min to a temperature in the range of about from 30 to 70°C., preferably from 40 to 60°C., and then cooled to a temperature below 15°C, preferably below 10°With so by crystalline anhydrate, which precipitates from the mixture. The invention relates further to the use of monohydrate tetrapyrrolic as starting material for obtaining the proposed invention in crystalline anhydrate of tetrapyrrolic.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with methanol, characterized in that the crystalline monohydrate Tiotropium the foreign Ministry (known from WO 02/30928) is dried at a temperature in the range from 60 to 90°C, preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, and then dissolved in containing methanol solvent, preferably in a solvent mixture containing methanol and acetone, then cooled to a temperature below 0°C, preferably to a temperature in the range from -30 to -10°C, holding at that temperature for 10 h, preferably 12-20 hours, and the thus obtained crystals of MES with methanol, isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with methanol.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with ethanol, wherein the crystalline monohydrate tetrapyrrole (known from WO 02/30928) is dried at a temperature in the range from 60 to 90°C., preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, and then dissolved in containing ethanol solvent, preferably in a mixture of solvents containing ethanol and acetone, then cooled to a temperature below 0°C, preferably to a temperature in the range from -30 to -10°C, with a dwell time at this temperature for 10 h, preferably 12-20 hours, and thus obtained to Italy is isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with ethanol.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with isopropanol, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) is dried at a temperature in the range from 60 to 90°C., preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, and then dissolved in containing methanol solvent, preferably in pure methanol, thus obtained solution is added to the containing isopropanol solvent, it is preferable to pure isopropanol, then cooled to a temperature below 15°C, preferably to a temperature in the range from 0 to 5°C., holding at that temperature for 8 h, preferably 10-16 hours, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with isopropanol.

The present invention relates also to a process for the preparation of new crystalline MES tetrapyrrole is with n-butanol, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) is dried at a temperature in the range from 60 to 90°C., preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, and then dissolved in containing methanol solvent, preferably in pure methanol, thus obtained solution is added to contain n-butanol solvent, it is preferable to pure n-butanol, then cooled to a temperature below 15°C, preferably to a temperature in the range from 0 to 5°C, with a dwell time at this temperature for 8 h, preferably 10-16 hours, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with n-butanol.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with THF, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) is dried at a temperature in the range from 60 to 90°C., preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, and then dissolved in containing methanol solvent, preferably in pure methanol thus obtained by the process is added to THF containing solvent, it is preferable to pure THF, then cooled to a temperature below 15°C, preferably to a temperature in the range from 0 to 5°C., holding at that temperature for 8 h, preferably 10-16 hours, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with THF.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with dioxane, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) is dried at a temperature in the range from 60 to 90°C., preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, and then dissolved in containing methanol solvent, preferably in pure methanol, thus obtained solution is added to contain dioxane solvent, it is preferable to pure dioxane, then cooled to a temperature below 15°C, preferably to a temperature in the range from 0 to 5°C., holding at that temperature for 8 h, preferably 10-16 hours, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as the original mA is eriala to get proposed in the invention of the crystalline MES of tetrapyrrolic with dioxane.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic 1,2-propane diol, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) is dried at a temperature in the range from 60 to 90°C., preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, and then dissolved in containing 1,2-propandiol solvent, preferably in pure 1,2-propane diol, thus obtained solution is maintained at a temperature in the range from 30 to 70°C., preferably from 40 to 60°C, for about 20-90 min, preferably 30-70 min, if necessary, filtered, then cooled to a temperature below 15°C, preferably to a temperature in the range from 0 to 10°C, with a dwell time at this temperature for 12 h, preferably 18-30 h, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic 1,2-propane diol.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with anisole, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) dried at temperature is in the range from 60 to 90°C, preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, and then dissolved in containing anisole solvent, preferably in pure anisole, thus obtained solution is maintained at a temperature in the range from 30 to 70°C., preferably from 40 to 60°C., for about 20-90 min, preferably 30-70 min, if necessary, filtered, then cooled to a temperature below 15°C, preferably to a temperature in the range from 0 to 10°C, with a dwell time at this temperature for 12 h, preferably 18-30 h, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with anisole.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with TBM, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) is dried at a temperature in the range from 60 to 90°C., preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, and then dissolved in containing Tgp solvent, preferably in a clean Tgp, thus obtained solution is maintained at a temperature in the range from 30 to 70°C., preferably from 40 d is 60°C, for about 20-90 min, preferably 30-70 min, if necessary, filtered, then cooled to a temperature below 15°C, preferably to a temperature in the range from 0 to 10°C, with a dwell time at this temperature for 12 h, preferably 18-30 h, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with Tgp.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with DMF, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) is dried at a temperature in the range from 60 to 90°C., preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, then suspended in DMF containing solvent, preferably in pure DMF, to the thus obtained solution add antibacterial, preferably methylene chloride, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with DMF.

The present invention relates also the way to obtain a new crystalline MES of tetrapyrrolic with DMA, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) is dried at a temperature in the range from 60 to 90°C., preferably from 70 to 85°C. for about 10-60 minutes, preferably 20-40 min, then suspended in containing DMA solvent, preferably in pure DMA, to the thus obtained solution add antibacterial, preferably methylene chloride, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with DMA.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with THF, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) dissolved in containing acetone solvent, preferably in a solvent mixture containing acetone and water, after which the solvent is slowly evaporated, the remaining solid process containing THF solvent, preferably a solvent containing THF and water, thus obtained solution is maintained at a temperature in the range from 30 to 70°C., preferably from 40 to 60°C. for about 10-60 minutes, preferably 20-40 min, C the fact is cooled to a temperature below 15°C, preferably to a temperature in the range from 0 to 10°C, with a dwell time at this temperature for 12 h, preferably 18-30 h, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with THF.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with tert-butanol, wherein the crystalline monohydrate tetrapyrrole (known from WO 02/30928) dissolved in containing acetone solvent, preferably in a solvent mixture containing acetone and water, after which the solvent is slowly evaporated, the remaining solid process containing tert-butanol solvent, preferably a solvent containing tert-butanol and water, thus obtained solution is maintained at a temperature in the range from 30 to 70°C., preferably from 40 to 60°C. for about 10-60 minutes, preferably 20-40 min, then cooled to a temperature below 15°C, preferably to a temperature in the range from 0 to 10°C, with a dwell time at this temperature for 12 h, preferably 18-30 h, and the thus obtained crystals are isolated and dried. The invention relates duleek application monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with tert-butanol.

The present invention relates also to a process for the preparation of new crystalline MES of tetrapyrrolic with pyridine, characterized in that the crystalline monohydrate tetrapyrrole (known from WO 02/30928) dissolved in containing acetone solvent, preferably in a solvent mixture containing acetone and water, after which the solvent is slowly evaporated, the remaining solid process containing a pyridine solvent, preferably a solvent containing pyridine and water, thus obtained solution is maintained at a temperature in the range from 30 to 70°C., preferably from 40 to 60°C. for about 10-60 minutes, preferably 20-40 min, then cooled to a temperature below 15°C, preferably to a temperature in the range from 0 to 10°C, with a dwell time at this temperature for 12 h, preferably 18-30 h, and the thus obtained crystals are isolated and dried. The invention relates further to the use of monohydrate tetrapyrrolic as starting material to obtain the proposed invention the crystalline MES of tetrapyrrolic with pyridine.

Below the invention is described in more detail based on examples, however, the scope of the invention is not considered limited to these examples, specific variants of its implementation.

Examples of the synthesis of accom is utilized in the invention crystalline forms

Example 1: Crystalline anhydrate of tetrapyrrolic

600 mg of the crystalline monohydrate tetrapyrrole (obtained according to WO 02/30928) dissolved in 10 ml of a mixture of N,N-dimethylacetamide and water in the ratio 1:1. Then the resulting solution was stirred at 50°C for 30 minutes then the solvent is slowly evaporated in a vacuum (about 1 kPa) at room temperature. After about 24 hours begins the formation of the first crystals of the crystalline anhydrous Tiotropium, which is separated by filtration and dried at ambient conditions.

Example 2: Crystalline MES of tetrapyrrolic with methanol

1.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) for 30 min, dried in vacuum at 80°C. Then, the thus obtained anhydrous form under stirring dissolved in 10 ml of a mixture of methanol and acetone in a ratio of 2:1. Then, the solution for 16 h and stored in a refrigerator at -20°C. After slow heating of the solution to room temperature with stirring crystallizes MES of tetrapyrrolic with methanol. The resulting crystals are filtered and dried at ambient conditions.

Example 3: Crystalline MES of tetrapyrrolic with ethanol

1.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) for 30 min, dried in vacuum at 80°C. Then received the mayor by anhydrous form under stirring dissolved in 10 ml of a mixture of ethanol and acetone in a ratio of 2:1. Then, the solution for 16 h and stored in a refrigerator at -20°C. After slow heating of the solution to room temperature with stirring crystallizes MES of tetrapyrrolic with ethanol. The resulting crystals are filtered and dried at ambient conditions.

Example 4: Crystalline MES of tetrapyrrolic with isopropanol

2.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) for 30 min, dried in vacuum at 80°C. Then, the thus obtained anhydrous form under stirring dissolved in 50 ml of methanol. This methanol solution tetrapyrrolic then, under stirring and at room temperature is added slowly to 50 ml of isopropanol. Next, the mixture is stirred for 30 min at room temperature and then left to stand overnight in a refrigerator at 4°C. the Resulting crystals are filtered and dried at ambient conditions.

Example 5: the Crystalline MES of tetrapyrrolic with n-butanol

2.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) for 30 min, dried in vacuum at 80°C. Then, the thus obtained anhydrous form under stirring dissolved in 50 ml of methanol. This methanol solution tetrapyrrolic then, under stirring and at room temperature is added slowly to 50 ml of n-butanol. Next, the mixture premesis the Ute for 30 min at room temperature and then left overnight in a refrigerator at 4°C. The resulting crystals are filtered and dried at ambient conditions.

Example 6: Crystalline MES of tetrapyrrolic with THF

2.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) for 30 min, dried in vacuum at 80°C. Then, the thus obtained anhydrous form under stirring dissolved in 50 ml of methanol. This methanol solution tetrapyrrolic then, under stirring and at room temperature is added slowly to 50 ml of tetrahydrofuran. Next, the mixture is stirred for 30 min at room temperature and then left overnight in a refrigerator at 4°C. the Resulting crystals are filtered and dried at ambient conditions.

Example 7: Crystalline MES of tetrapyrrolic with 1,4-dioxane

2.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) for 30 min, dried in vacuum at 80°C. Then, the thus obtained anhydrous form under stirring dissolved in 50 ml of methanol. This methanol solution tetrapyrrolic then, under stirring and at room temperature is added slowly to 50 ml of dioxane. Next, the mixture is stirred for 30 min at room temperature and then left overnight in a refrigerator at 4°C. the Resulting crystals are filtered and dried at ambient conditions.

Example 8: Crystallises the s MES of tetrapyrrolic 1,2-propane diol

2.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) for 30 min, dried in vacuum at 80°C. Then, the thus obtained anhydrous form for 20 min, suspended in 10 ml of 1,2-propane diol at 50°C and then filtered, obtaining a saturated solution of Tiotropium in 1,2-propane diol. Next, through Ehud determine the concentration of tetrapyrroles in 1,2-propane diol, which is about 100 mg/ml After filtration of the suspension at 50°C. a small portion of the filtrate is transferred into a 1.8-ml glass test tube, which is placed in the apparatus for regulating the temperature. Then the solution is incubated for 30 min at 50°C and then cooled at a rate of 30°C/h to a final temperature of 5°C. At this temperature the solid is left in the solution for 24 hours Vegascasinoonline when cooled dry solid is then filtered off and dried at ambient conditions.

Example 9: Crystalline MES of tetrapyrrolic with anisole

1.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) suspended for 20 min at 50°C in 5 ml of a mixture of anisole (methoxybenzene) and water in the ratio of 60:40 and then filtered, obtaining a saturated solution of Tiotropium in a mixture of solvents. Next, through Ehud determine the concentration of Tiotropium in a mixture of anisole and the water in the ratio of 60:40, which is about 90 mg/ml After filtration of the suspension at 50°C. a small portion of the filtrate is transferred into a 1.8-ml glass test tube, which is placed in the apparatus for regulating the temperature. The solution is incubated for 30 min at 50°C and then cooled at a rate of 30°C/h to a final temperature of 5°C. At this temperature the solid is left in the solution for 24 hours Vegascasinoonline when cooled dry solid is then filtered off and dried at ambient conditions.

Example 10: the Crystalline MES of tetrapyrrolic with Tgp

1.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) suspended for 20 min at 50°C in 5 ml of a mixture of TBM and water in the ratio of 60:40 and then filtered, obtaining a saturated solution of tetrapyrroles in this solvent mixture. Next, through Ehud determine the concentration of Tiotropium in a mixture Tgp and water in the ratio of 60:40, which is about 35 mg/ml After filtration of the suspension at 50°C. a small portion of the filtrate is transferred into a 1.8-ml glass test tube, which is placed in the apparatus for regulating the temperature. The solution is incubated for 30 min at 50°C and then cooled at a rate of 30°C/h to a final temperature of 5°C. At this temperature the solid is left in the solution for 2 hours Vegascasinoonline when cooled dry solid is then filtered off and dried at ambient conditions.

Example 11: Crystalline MES of tetrapyrrolic with DMF

1.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) for 30 min, dried in vacuum at 80°C. Then, the thus obtained anhydrous form within 2 hours and suspended in 10 ml of DMF at room temperature and then filtered, obtaining a saturated solution of tetrapyrrolic DMF. Next, through Ehud determine the concentration of tetrapyrroles in DMF, which is about 75 mg/ml After filtration of the suspension at room temperature, a small portion of the filtrate is transferred into a 1.8-ml glass test tube. Next, add dichloromethane as antibacterial when the ratio between the solvent and antibacterial 1:2. Precipitated precipitated solid substance produce by filtration and dried at ambient conditions.

Example 12: Crystalline MES of tetrapyrrolic with DMA

1.0 g of the monohydrate of Tiotropium (obtained according to WO 02/30928) for 30 min, dried in vacuum at 80°C. Then, the thus obtained anhydrous form within 2 hours and suspended in 10 ml of DMA at room temperature and then filtered, obtaining a saturated solution of Tiotropium in DMA. Next, through Ehud definition is given concentration tetrapyrrolic in DMA, which is about 40 mg/ml After filtration of the suspension at room temperature, a small portion of the filtrate is transferred into a 1.8-ml glass test tube. Next, add dichloromethane as antibacterial when the ratio between the solvent and antibacterial 1:2. Precipitated precipitated solid substance produce by filtration and dried at ambient conditions.

Example 13: Crystalline MES of tetrapyrrolic with THF

600 mg of crystalline Tiotropium (obtained according to WO 02/30928) dissolved in 10 ml mixture of acetone and water at a ratio of 80:20. Then 40 µl of this stock solution is transferred into one of the small tubes 96-well plate. Tablet with with mother liquor is placed in a vacuum chamber (1.3 kPa) and incubated at room temperature for 40 hours After evaporating the mother of the solvent in the tube, add 40 ál of a mixture of THF and water in the ratio of 60:40. Then the whole 96-well plate, sealed and heated at 5°C/min to a temperature of 50°C, at which the tablet stand still for 30 minutes Then the tablet is cooled at a speed of 5°C./h to a final temperature of 5°C. At this temperature, the tablet is left for 24 hours Then the tablet open and then by evaporating the solvent at room temperature in a vacuum chamber (13 kPa) receive the solid substance.

Example 14: Crystalline MES of tetrapyrrolic with tert-butanol

600 mg of crystalline Tiotropium (obtained according to WO 02/30928) dissolved in 10 ml of a mixture of tert-butanol and water in the ratio of 80:20. Then 40 µl of this stock solution is transferred into one of the small tubes 96-well plate. Tablet with with mother liquor is placed in a vacuum chamber (1.3 kPa) and incubated at room temperature for 40 hours After evaporating the mother of the solvent in the tube, add 40 ál of a mixture of tert-butanol and water in the ratio 20:80. Then the whole 96-well plate, sealed and heated at 5°C/min to a temperature of 50°C, at which the tablet stand still for 30 minutes Then the tablet is cooled at a speed of 5°C./h to a final temperature of 5°C. At this temperature, the tablet is left for 24 hours Then the tablet open and then by evaporating the solvent at room temperature in a vacuum chamber (13 kPa) get a solid substance.

Example 15: Crystalline MES of tetrapyrrolic with pyridine

600 mg of crystalline Tiotropium (obtained according to WO 02/30928) dissolved in 10 ml mixture of acetone and water in the ratio of 80:20. Then 40 µl of this stock solution is transferred into one of the small tubes 96-well plate. Tablet with with mother liquor is placed in a VA is Oumou camera (1.3 kPa) and incubated at room temperature for 40 hours After evaporating the mother of the solvent in the tube, add 40 ál of a mixture of pyridine and water in the ratio 50:50. Then the whole 96-well plate, sealed and heated at 5°C/min to a temperature of 50°C, at which the tablet stand still for 30 minutes Then the tablet is cooled at a speed of 5°C./h to a final temperature of 5°C. At this temperature, the tablet is left for 24 hours Then the tablet open and then by evaporating the solvent at room temperature in a vacuum chamber (13 kPa) get a solid substance.

The characterization proposed in the invention forms tetrapyrrolic

Methods

X-ray diffraction on single crystal

After crystallization experiments with selected suitable for the analysis of a single crystal, which was glued to the glass, which was secured by x-ray diffractometer goniometer. Such crystals are analyzed by x-ray diffractometry at a temperature of 233 K, using the system KappaCCD and Kαradiation of molybdenum, the generated x-ray machine FR590 (Bruker Nonius, Delft, the Netherlands).

The unit cell parameters and the crystal structure was determined and refined using the software package maXus (Mackay and others, 1997). On the basis of the crystal structure was calculated theoretical x-ray then skovby the diffraction pattern, using the program PowderCell 2.3 version for the Windows operating system (Kraus and others, 1999).

X-ray powder diffractometry

To obtain x-ray powder diffraction was used high-performance installation for x-ray powder diffraction type Avantium's T2. Plate with the analyzed samples were placed in the diffractometer Bruker GADDS, equipped with a two-dimensional detector Hi-Star. For calibration platform for x-ray powder diffraction was used beginat silver for large interplanar distances d and corundum for small interplanar distances d.

Analyses were carried out at room temperature using monochromatic Kαradiation of copper in the range of angles 2θ from 1.5 to 41.5°. The diffraction pattern of each face were obtained by measurements in two ranges of angle 2θ (1,5≤2θ≤19,5° for the first cycle and 21.5≤2θ≤41,5° for the second cycle) with exposure time of from 90 to 180 s for each cycle. X-ray powder diffraction pattern was obtained without subtracting background noise or without application of the procedure of smoothing the curve.

Characterization of crystalline anhydrate of tetrapyrrolic

Crystalline anhydrate of tetrapyrrolic crystallizes in the orthorhombic crystal system (see table 1).

Table 1
Detailed data about the parameters of the crystal and the structure of the form
Empirical formulaC19H22NO4S2+·Br-
Fw472,41
T [K]293(2)
λ [Å]0,71073
Crystallographic symmetryorthorhombic
Space groupPbca
The dimensions of the unit cell
and [Å]a=11,7420(4)
b [Å]b=17,7960(7)
[Å]C=19,6280(11)
β [°]
V [Å3]4101,5(3)
Z 8
Dm[g/cm3]1,530
F(000)1936
The size of the crystal [mm]0,4 x 0,4×0,1
The range of angle θ [°]2→27,5
The number of registered reflexes20542
The number of independent reflections4648 [Rint=0,0442]
The amount of data/restraints/parameters4648/0/350
S1,038
R [I > 2σ(I)]R1=0,0445, wR2=0,0814
The R indices (all data)R1=0,0732, wR2=0,0918
The extinction coefficient0,0006(2)

Anhydrate of tetrapyrrolic obtained as described above is vysokobarotermicheskogo connection. It thoroughly examined the x-ray powder diffractometry. Rent is anouska powder diffraction pattern, obtained for the proposed invention anhydrate of tetrapyrrolic shown in figure 1.

The following table 2 presents the characteristic peaks indicating their intensity.

In the above table and in subsequent tables, the value of 2θ[°]" denotes the angle of diffraction in degrees and the value "d[Å]" signifies specific interplanar distances in angstroms (Å).

Characterization of the crystalline MES of tetrapyrrolic with 1,4-dioxane

Crystalline MES of tetrapyrrolic with 1,4-dioxane crystallizes in the monoclinic crystal system (see table 3).

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic with 1,4-dioxane, shown in figure 2. The following table 4 presents the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic with ethanol

Crystalline MES of tetrapyrrolic with ethanol crystallizes in the monoclinic crystal system (see table 5).

X-ray powder diffraction pattern obtained for the proposed the CSOs in the invention of the crystalline MES of tetrapyrrolic with ethanol, shown in figure 3. The following table 6 presents the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic with methanol

Crystalline MES of tetrapyrrolic with methanol crystallizes in the monoclinic crystal system (see table 7).

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic with methanol, shown in figure 4. The following table 8 presents the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic with anisole

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic with anisole, shown in figure 5. The following table 9 presents the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic with n-butanol

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES Tiotropium the IDA with n-butanol, shown in Fig.6. The following table 10 shows the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic CDMA

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic with DMA shown in Fig.7. The following table 11 presents the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic sdmf

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic with DMF, shown in Fig. The following table 12 presents the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic with isopropanol

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic with isopropanol shown in Fig.9. The following table 13 shows the characteristic peaks indicating their intensity.

The defining characteristic is cteristic crystalline MES of tetrapyrrolic 1,2-propane diol

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic 1,2-propane diol, shown in figure 10. The following table 14 shows the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic with pyridine

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic with pyridine, as shown figure 11. The following table 15 shows the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic with tert-butanol

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic with tert-butanol, shown in Fig. The following table 16 presents the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic with THF

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic with THF,shown in Fig. The following table 17 shows the characteristic peaks indicating their intensity.

Characterization of the crystalline MES of tetrapyrrolic with Tgp

X-ray powder diffraction pattern obtained for the proposed invention the crystalline MES of tetrapyrrolic with Tgp shown in Fig. The following table 18 presents the characteristic peaks indicating their intensity.

Compositions containing the proposed invention in the form of tetrapyrrolic

The proposed invention in crystalline form tetrapyrrolic most suitable for the preparation, on the basis of, for example, introduced into the body by inhalation of pharmaceutical compositions, such as inhalation powders or, for example, compositions with a propellant for aerosol spray, primarily inhalation powders and compositions in the form of a suspension in the propellant for aerosol spray. Such pharmaceutical compositions or formulations in addition to the proposed invention, the crystalline forms of Tiotropium may contain one or several active substances of other types selected from betamimetics, EGFR inhibitors, inhibitors of phosphodiesterase 4 (PDE), steroids and antagonistas LT4, optionally in combination with pharmaceutically acceptable auxiliary substance.

Inhalation powders

The present invention relates to inhalation powders containing from 0.001 to 3% of Tiotropium in the form proposed in the invention, the crystalline forms of Tiotropium mixed with physiologically harmless auxiliary substance. Under Tiotropium this implies ammonium cation.

Preferred according to the invention inhalation powders containing tiotropy in an amount of from 0.01 to 2%. More preferred inhalation powders containing tiotropy in the amount of from about 0.03 to 1%, preferably from 0.05 to 0.6%, most preferably from 0.06 to 0.3%. Of particular importance according to the invention have further inhalation powders containing tiotropy in the amount of approximately from 0.08 to 0.22%. The above values of the relative content of Tiotropium refer to the quantity contained in the powder Tiotropium-cation.

Used in provided by the present invention aims auxiliary substances produced by the respective grinding and/or sieving traditional known from the prior art methods. In some cases, used according to the invention excipients can also be a mixture thereof, a mixture between the FDS is th different fractions of the same excipients with different average size of its particles.

As an example, physiologically harmless adjuvants that can be used for inhalation powders used for the manufacture thereof proposed in the invention capsules (ingleton), can be called monosaccharides (e.g. glucose, fructose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligo - and polysaccharides (e.g. dextrans, dextrins, maltodextrin, starch, cellulose), a polyalcohol (e.g., sorbitol, mannitol, xylitol), cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin, χ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), amino acids (e.g. arginine hydrochloride) or salt (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. It is preferable to apply a mono - or disaccharides, particularly preferably the use of lactose or glucose, primarily, but not exclusively, in the form of their hydrates. Especially preferred according to the invention be used as excipients lactose.

The maximum average size of the particles used in the present invention inhalation powder excipients reaches 250 μm, preferably ranges from 10 to 150 μm, most preferably from 15 to 80 μm. Under certain from the conditions it may be desirable to admix to the above-mentioned auxiliary substances to their faction with a smaller average particle size, components 1 to 9 μm. Such excipients with a smaller particle size is also selected from the above group of auxiliary substances used in inhalation powders. The average particle size can be determined well-known from the prior art methods (see, for example, WO 02/30389, sections a and C). After preparation of the mixture of excipients to it to obtain the proposed invention inhalation powders admixed micronized crystalline anhydrate of tetrapyrrolic with an average particle size of preferably from 0.5 to 10 μm, most preferably from 1 to 5 μm (see, for example, WO 02/30389, section b). Methods of milling and micronization of active substances known from the prior art.

If the excipients are not using a specially prepared mixture of excipients, it is most preferable to apply an excipient in the form of particles, the average size of which is 10 to 50 μm and among which 10% of the fine fraction, in which the particle size is from 0.5 to 6 μm. Under average size (or average size) of the particles in this context refers to the amount of 50% of all particles, the spatial distribution in which the particle size was determined using a laser diffractometer by dry dispersion. Regni particle size can be determined well-known from the prior art methods (see, for example, WO 02/30389, sections a and C). Similarly, under the fine fraction, which accounts for 10%, in this context, refers to the fraction of 10% of the total number of particles, the spatial distribution in which the particle size was determined using a laser diffractometer. In other words, under the fine fraction, which accounts for 10%, according to the present invention refers to the fraction of particles that have no more than 10% of particles with all their quantity (in terms of their spatial distribution by size).

In accordance with the present invention are given in percent of the data in all cases, unless specifically stated otherwise, represent weight percents (wt.%).

In the most preferred inhalation powders used excipient with an average particle size of from 12 to 35 μm, particularly preferably from 13 to 30 μm. The most preferred next especially those of inhalation powders, in which the particle size of the excipient in the fine fraction, which accounts for 10% of the total number of particles of an excipient is from about 1 to 4 μm, preferably from about 1.5 to 3 microns.

One of the distinguishing features of the proposed invention inhalation powders is in accordance with the provision in the core is Wu inventions task in the possibility of their introduction into the organism with consistently high precision single dosage. When variations are introduced at one time quantities inhalation powder is less than 8%, preferably less than 6%, most preferably less than 4% of the nominal amount.

After the measuring weighing the required portions of the source materials of the excipient and active substance using known from the prior art methods is purchasing an inhaled powder. You can refer to, for example, in the publication WO 02/30390. In accordance with this proposed invention inhalation powders can be obtained, for example, the following method. In the below methods to obtain inhalation powders these components are used in mass quantities, which correspond to the amounts specified above in the description of compounds of inhalation powders.

First, in the corresponding mixer load excipient and active substance. The average particle size used active substance is from 0.5 to 10 μm, preferably from 1 to 6 μm, most preferably from 2 to 5 μm. The excipient and active substance preferably be submitted to the mixer through a sieve or sieve granulator with the size of the sieve mesh from 0.1 to 2 mm, more preferably from 0.3 to 1 mm, most preferably from 0.3 to 0.6 mm. in will smeet is l preferably first download excipient, and then feeding into the mixer active substance. When mixed with this technology both components preferably serve individual portions. The most preferred is alternately feeding into a mixer of both components by layer-by-layer sieving it. Excipients can be mixed with the active substance already in the process of filing both of these components in the mixer. More preferably, however, begin mixing of both components only on the completion of their layer-by-layer sieving in the mixer.

The present invention relates also to the use of the proposed therein inhalation powders for the preparation of pharmaceutical compositions intended for the treatment of respiratory diseases, primarily for the treatment of COPD and/or asthma.

Proposed in the invention inhalation powders can be introduced into the body, for example, using inhalers, in which a single dose from a supply vessel is issued with the metering chamber (for example, according to US 4570630), or using other devices (for example, according to DE 3625685). Preferably, however, to sack proposed in the invention inhalation powder in capsules (obtaining the so-called ingleton), which are used in inhalers as described, for example, in WO 94/28958.

For introduction into the body are exposed to the made in the invention inhalation powders containing from their capsules is most preferable to use the inhaler, shown in Fig. This inhaler is characterized by the presence of the housing 1 with two Windows 2, a partition plate 3, which is provided by the inlet air hole and which is provided with a grid 5, held in the assembled state of the respective mounting element 4, which is connected with plate wall 3 of the chamber 6 in which is located the capsule inhalation powder and the side which is provided by the push button 9, provided with two sharpened needle 7 and is moveable against the force of the spring 8, the mouthpiece 12, which is hinged to rotate about an axis 10, connecting it to the housing 1, the partition plate 3 and the cap 11, and through holes 13 for the passage of air serving to regulate the fluidic resistance.

The present invention relates further to the use of inhalation powders containing one or more proposed in the invention, the crystalline forms of Tiotropium, preferably one proposed in the invention is a crystalline form of Tiotropium, for the preparation of pharmaceutical compositions intended for the treatment of respiratory diseases, primarily for the treatment of COPD and/or asthma, characterized in that use is described above and shown in Fig inhaler.

When rasfasovyvanie before agemy in the invention inhalation powders, containing the proposed invention in crystalline form tetrapyrrole, in capsules is most preferable to use capsules, material chosen from the group of synthetic polymers, particularly preferably from the group comprising polyethylene, polycarbonate, polyesters, polypropylene and polyethylene terephthalate. The most preferred synthetic polymer as a material for the manufacture of capsules is polyethylene, polycarbonate or polyethylene terephthalate. In the manufacture of capsules made of polyethylene, which is one of preferred according to the invention materials, it is preferable to use polyethylene with a density of from 900 to 1000 kg/m3more preferably from 940 to 980 kg/m3most preferably from about 960 to 970 kg/m3(high density polyethylene). Such polymeric materials in the manufacture of these capsules according to the invention can process a variety of known from the prior art methods. Preferred according to the invention by a method of processing polymer is injection molding. In the manufacture of capsules by injection molding according to the most preferred option do not use adhesive lubricant to extract capsules out of shape. For such a method of manufacture of capsules typical Ho is Osho proven technology and the very high reproducibility.

Another object of the present invention are described above capsules containing proposed in the invention inhalation powder described above. Contents inhalation powder in these capsules may be about 1 to 20 mg, preferably from about 3 to 15 mg, most preferably from about 4 to 12 mg. Preferred according to the invention the capsules contain from 4 to 6 mg inhalation powder. Equally preferred according to the invention and capsules for inhalation containing the proposed invention in the powder composition in an amount of from 8 to 12 mg.

The present invention relates also to a kit for inhalation, comprising one or more of the above-described capsules containing proposed in the invention inhalation powder inhaler described above and shown in Fig.

The present invention relates further to the use of the above-described capsules containing proposed in the invention inhalation powders for the preparation of pharmaceutical compositions intended for the treatment of respiratory diseases, primarily for the treatment of COPD and/or asthma.

Completed proposed in the invention inhalation powder capsules are made known from the prior art methods by packaging proposed in the invention and galatsion powders in empty capsules.

The examples proposed in the invention inhalation powder

Below the invention is described in more detail based on examples, however, the scope of the invention is not considered limited to these examples, specific variants of its implementation.

The active ingredient

To obtain the proposed invention inhalation powders use proposed in the invention is a crystalline form of Tiotropium. These forms can be ekranizirovat likewise known from the prior art methods (see, for example, WO 03/078429 A1). When referred to in the description of the present invention the average particle size proposed in the invention, the crystalline forms of Tiotropium determine its known from the prior art measurement methods (see, for example, WO 03/078429 A1, section D.2).

Excipient

In the examples below as an auxiliary substance use lactose monohydrate. As such, it is possible to use, for example, a product manufactured by Borculo Domo Ingredients, Borculo, the Netherlands, under the trade name Lactochem Extra Fine Powder. Lactose in this class meets the invention specifications regarding the size of its particles and the specific surface. The specific characteristics of lactose, various parties which were used for the preparation of inhalation powder is s, discussed below are given in the examples.

Obtaining powder compositions

Equipment

To obtain inhalation powders can be used, for example, the following machinery and equipment.

Mixer, respectively mixer for powders: turbomaster volume of 2 l, type 2C, manufacturer: firm Willy A. Bachofen AG, located at the address: CH-4500, Basel.

Manual sieve: the size of the cells is 0.135 mm

To sack containing Tiotropium inhalation powder in empty capsules for inhalation can be either manually or in an automated mode. You can use the following equipment.

Machine for filling capsules: MG2, type G100, manufacturer: firm MG2 S.r.l., located at: I-40065 Plan di Macina di Pianoro (BO), Italy.

Examples of compositions

Example compositions 1

Powder mixture

To obtain a powder mixture used 299,39 g excipients and 0.61 g of micronized crystalline anhydrate of tetrapyrrolic.

In the corresponding mixer through a hand sieve with mesh size 0,315 mm fall asleep for about 40-45 g excipients. Then in the mixer alternately in layers sift crystalline anhydrate of tetrapyrrolic portions of about 90-110 mg and excipients portions approximately 40-45, excipient and active substance is loaded into smesitel the 7th, respectively 6 layers.

Sifted thus the components of the inhalation powder is then mixed in the mixer (mixing at 900 rpm). Thus obtained final mixture twice sift through the hand sieve and after each sifting stirred at 900 rpm

As described in example 1, the methodology can be obtained inhalation powders, after packaging in which the corresponding polymer capsules get, for example, discussed below capsules for inhalation.

Example composition 2
anhydrate of tetrapyrrolic0,0113 mg
the lactose monohydrate5,4887 mg
capsule100.0 mg
Only105,5 mg
An example of the composition 3
anhydrate of tetrapyrrolic0,0225 mg
the lactose monohydrate5,4775 mg
plastic capsules100.0 mg
Everything about 105,5 mg
An example of the composition 4
anhydrate of tetrapyrrolic0,0056 mg
the lactose monohydrate5,4944 mg
plastic capsules100.0 mg
Only105,5 mg
An example of the composition 5
anhydrate of tetrapyrrolic0,0113 mg
monohydrate lactose*)5,4887 mg
capsule100.0 mg
Only105,5 mg
*Lactose contains 5% specially added to it small fraction of micronized lactose monohydrate with an average particle size of about 4 microns.
An example of the composition 6
anhydrate of tetrapyrrolic0,0225 mg
monohydrate lactose *)5,4775 mg
plastic capsules100.0 mg
Only105,5 mg
*Lactose contains 5% specially added to it small fraction of micronized lactose monohydrate with an average particle size of about 4 microns.
An example of the composition 7
anhydrate of tetrapyrrolic0,0056 mg
monohydrate lactose*)5,4944 mg
plastic capsules100.0 mg
Only105,5 mg
*Lactose contains 5% specially added to it small fraction of micronized lactose monohydrate with an average particle size of about 4 microns.

Obviously, in the form of pharmaceutical compositions discussed in the examples above, you can likewise use one of the other above-described crystalline forms of Tiotropium. To obtain products containing one of the other proposed invention solvate, can in a simple way to prepare a powder mixture, a similar description is Noah in example 1, as well as in examples 2-7, instead of using anhydrate of tetrapyrrolic one of the other proposed invention the crystalline solvate.

Suspension with propellant for aerosol inhalation

The proposed invention in crystalline form tetrapyrrolic if necessary, you can also enter the body, containing the propellant formulations for aerosol inhalation. To apply for this purpose the most suitable suspension for aerosol inhalation.

In accordance with this present invention relates to suspensions proposed in the invention, the crystalline forms of Tiotropium in propellant HFA 227 and/or the propellant HFA 134a, optionally in a mixture with one or more other propellant, preferably selected from the group comprising propane, butane, pentane, dimethyl ether, CHClF2CH2F2, CF3CH3, isobutane, isopentane and neopentane.

According to the invention the preferred suspension, which as a propellant contain only HFA 227, a mixture of HFA 227 and HFA 134a either HFA 134a. When used in the proposed invention the compositions in the form of a suspension in a mixture of propellants HFA 227 and HFA 134a ratio by weight between both of these components can vary arbitrarily. When used in the proposed invention the comp is the dispositions in the form of suspensions along with propellant HFA 227 and/or propellant HFA 134a of one or more other propellants, selected from the group comprising propane, butane, pentane, dimethyl ether, CHClF2CH2F2, CF3CH3, isobutane, isopentane and neopentane, the share of these other propellants should preferably be less than 50%, more preferably less than 40%, most preferably less than 30%.

The proposed invention in suspension in the preferred embodiment, must contain Tiotropium in such quantity that corresponds to the content of Tiotropium-cation from 0.001 to 0.8%, more preferably from 0.08 to 0.5%, most preferably from 0.2 to 0.4%.

In accordance with the present invention is given in percentage data, unless otherwise stated, always represent weight percents (wt.%).

In some cases, in the present description, instead of the term "suspension" is also used the notion of "composition in the form of suspension". Both of these concepts are in accordance with the invention are equivalent.

In the proposed composition of the invention containing propellant compositions for aerosol inhalation, respectively compositions in the form of suspensions may also include other components, such as surface-active substances, adjuvants, antioxidants or flavourings.

Include in some cases the composition of the proposed invention suspensions surfactants site is preferably to choose from a group, include Polysorbate 20, Polysorbate 80, levacet (Myvacet) 9-45, levacet 9-08, isopropylmyristate, oleic acid, propylene glycol, polyethylene glycol, bridge (Brij), etiloleat, glyceryltrinitrate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, cetyl alcohol, stearyl alcohol, cetylpyridinium, block copolymers, natural oil, ethanol and isopropanol. From among the above-mentioned auxiliary substances in suspension, it is preferable to use Polysorbate 20, Polysorbate 80, levacet 9-45, levacet 9-08 or isopropylmyristate. Most preferably the use of melazeta 9-45 or isopropylmyristate.

When included in the composition proposed in the invention suspensions of surface-active substances, their content should preferably be from 0.0005 to 1%, most preferably 0.005 to 0.5%.

Include in some cases the composition of the proposed invention suspensions adjuvants are preferably selected from the group comprising alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid and citric acid. It is more preferable to use ascorbic acid, phosphoric acid, hydrochloric acid or citric acid, among which the most preferred hydrochloric acid or citric who Isleta.

When included in the composition proposed in the invention suspensions adjuvants their content preferably should be from 0.0001 to 1.0%, more preferably from 0.0005 to 0.1%, especially preferably from 0.001 to 0.01%, and most preferred according to the invention, the interval of values of the content of the adjuvant is from 0.001 to 0.005%.

Include in some cases the composition of the proposed invention suspensions antioxidants are preferably selected from the group comprising ascorbic acid, citric acid, edetate sodium, againbuy acid, Tocopherols, equivalent, butylhydroxyanisole and ascorbyl palmitate, from which it is most preferable to use Tocopherols, equivalent, butylhydroxyanisole or ascorbyl palmitate.

Include in some cases the composition of the proposed invention suspensions flavorings or additives, preferably selected from the group comprising peppermint, saccharin, Dentomint®, aspartame and essential oils (e.g., cinnamon, anise, menthol, camphor), from which it is most preferable to use peppermint or Dentomint®.

Given that the proposed invention the suspension is introduced into the body by inhalation, contained active substances should be submitted in high quality disperses form. For this proposed invention is a crystalline form of Tiotropium or subjected to fine grinding (micronizer), or directly get in fine form known from the prior art methods. Methods micronization of active substances known from the prior art. The average particle size of the active substance after micronisation should preferably be from 0.5 to 10 μm, more preferably from 1 to 6 μm, most preferably from 1.5 to 5 μm. In a preferred embodiment, the sizes of at least 50%, more preferably at least 60%, most preferably at least 70% of the particles of the active substance must lie in the above range of values. In the most preferred embodiment, the dimensions of at least 80%, especially preferably at least 90%, of the particles of the active substance must lie in the above range of values.

Another object of the invention are suspensions that contain only one of the proposed invention the active ingredients and do not contain any other additives.

Proposed in the invention of the suspension, you can get known from the prior art methods. In accordance with these suspension components are mixed with the propellant or propellants (if necessary at low temperatures) and ZAT is m obtained by the suspension fill in appropriate containers.

For introduction into the body described above is proposed in the invention suspension with propellant can be used are known from the prior art inhalers (pressurized inhalers with dosing scale, DIDs). Accordingly another object of the present invention are pharmaceutical compositions as described above suspensions in combination with one or more suitable to their introduction into the body of the inhaler. Another object of the present invention are inhalers, characterized in that they contain the above-described proposed in the invention suspension with propellant.

The present invention relates to containers (removable cartridges)are being equipped with the appropriate valve can be used in the appropriate inhaler and which contain one of the above-described proposed in the invention suspension with propellant. Such capacity (replaceable cartridges) and how they fill proposed in the invention suspension with propellant known in the prior art.

With regard to the pharmaceutical effectiveness of Tiotropium present invention relates further to the use of its proposed suspensions for the preparation introduced into the body by inhalation or nasal pharmaceutical composition is preferably prepared for what I pharmaceutical composition, intended for inhalation or nasal treatment of diseases in which anticholinergic agents is able to demonstrate a therapeutic effect.

In a particularly preferred embodiment, the present invention relates further to the use of its proposed suspensions for the preparation of pharmaceutical compositions intended for inhalation treatment of respiratory diseases, mainly asthma or COPD.

Below the present invention is illustrated in more detail by examples, which are purely illustrative and do not limit its scope.

Examples of compositions in the form of suspensions for aerosol spray

The suspension, containing, along with the active substance and the propellant other components:

An example of the composition 8

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,04
oleic acid0,005
HFA-22799,955

An example of the composition 9

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,02
oleic acid0,01
HFA-22760,00
HFA-134a39,97

An example of the composition 10

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,02
isopropylmyristate1,00
HFA-22798,98

An example of the composition 11

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,02
levacet 9-450,3
HFA-22799,68

An example of the composition 12

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic 0,02
levacet 9-450,1
HFA-22760,00
HFA-134a39,88

An example of the composition 13

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,04
Polysorbate 800,04
HFA-22799,92

An example of the composition 14

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,01
Polysorbate 200,20
HFA-227efficiency of 99.78

An example of the composition 15

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,04
levacet 9-0801,00
HFA-22798,96

An example of the composition 16

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,02
isopropylmyristate0,30
HFA-22720,00
HFA-134a79,68

The suspension containing only the active substance and propellant

An example of the composition 17

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,02
HFA-22760,00
HFA-134a39,98

An example of the composition 18

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,02
HFA-227of 99.98

An example is oppozitsii 19

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,02
HFA-134aof 99.98

An example of the composition 20

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,02
HFA-227of 99.98

Example composition 21

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,02
HFA-134aof 99.98

An example of the composition 22

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,02
HFA-22720,00
HFA-134a79,98

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,04
HFA-22740,00
HFA-134a59,96

An example of the composition 24

ComponentsConcentration [wt.%]
anhydrate of tetrapyrrolic0,04
HFA-22780,00
HFA-134a19,96

Obviously, in the form of pharmaceutical compositions discussed in the examples above, you can likewise use one of the other above-described crystalline forms of Tiotropium. To obtain products containing one of the other proposed invention solvate, can in a simple way to prepare pharmaceutical compositions similar to those described in examples 8-24 using instead of anhydrate of tetrapyrrolic one of the other proposed invention the crystalline solvate.

1. Crystalline anhydrate of tetrapyrrolic characterized by x-ray analysis the presence of his orthorhombic unit cell with parameters a=11,7420(4) Å, b=17,7960(7) Ǻ, C=19,6280(11) Å and cell volume V=4101,5(3) Ǻ.

2. The pharmaceutical composition intended for the treatment of diseases of the Airways, characterized in that it contains a form of Tiotropium according to claim 1 together with one or more active substances selected from betamimetics, EGFR inhibitors, inhibitors of phosphodiesterase 4 (PDE), steroids and LTD4 antagonist, optionally in combination with pharmaceutically acceptable auxiliary substance.

3. Application forms Tiotropium according to claim 1 for the preparation of pharmaceutical compositions intended for the treatment of respiratory diseases, mainly asthma or chronic obstructive pulmonary disease.

4. The method of obtaining anhydrous crystalline Tiotropium according to claim 1, characterized in that the crystalline monohydrate tetrapyrrolic dissolved in appropriate solvent, preferably in a solvent mixture containing N,N-dimethylacetamide is heated to a temperature in the range of about from 30 to 70°C., then cooled to a temperature below 15°C To produce crystalline anhydrate and the thus obtained crystals are isolated and dried.

5. The use of crystalline monohydrate tetrapyrrolic as starting material to obtain the crystalline form of Tiotropium according to claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: this invention relates to derivatives of cyclopropylthropine of the general formula I wherein X- is a one-charge anion, A and B represent -CH=CH-, R means hydrogen, hydroxygroup, -C1-C4alkyl, R1 and R2 have identical or different values and designate - C1-C5alkyl, R3, R4, R3' and R4' have identical or different values and designate hydrogen or halogen, Rx and Rx' jointly designate a simple bond or bridge group -O-, not obligatorily in the form of their pharmacologically acceptable acid-additive salts. The compounds of formula I are antagonists of muscarine receptor of subtype 3, which allows an assumption that they may be used as anticholinergic preparation. Intermediate compound are also described used in synthesis of the compounds I, pharmaceutical compositions based on the compounds I and the use of the latter for treatment of asthma, chronic obstructive disease of lungs.

EFFECT: new compounds possess useful biological properties.

9 cl, 7 ex

The invention relates to a method for producing the intermediate product to obtain with antiholinergicescuu activity of substances derived tropovoy acid, more specifically to a method of obtaining pure enantiomers esters (+) or (-) tropovoy acid with aminoalcohols

The invention relates to new esters of carboxylic acids with valuable properties, in particular the esters taylorbow acids and aminoalcohols of General formula (I)

< / BR>
where a group

< / BR>
where m and n are independent of each other represent 1 or 2,

Q group of formulae

< / BR>
Q' группаNR, where R denotes hydrogen or alkyl with 1 to 4 carbon atoms, unsubstituted or substituted with halogen or hydroxyl, or a group NRR', where R' is alkyl with 1 to 4 carbon atoms, or R and R' together form alkylene with 4 to 6 carbon atoms, and in the case of the fourth connection to the positive charge of the nitrogen atom is the equivalent of the anion (X),,

R1thienyl, phenyl, furyl, cyclopentyl and cyclohexyl, unsubstituted or substituted stands, and thienyl and phenyl may be substituted by fluorine or chlorine,

R2hydrogen, alkoxy 1 to 4 carbon atoms or alkyl with 1 to 4 carbon atoms,

Rahydrogen, fluorine, chlorine or methyl, provided that when a represents 3-tropanol, R1hydroxyl and R

Novel salt i // 2417220

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which is N-{2-[((2S)-3-{[1-(4-chlorobenzyl)piperidin-4-yl]amino}-2-hydroxy-2-methylpropyl)oxy]-4-hydroxyphenyl}acetamide benzoate or solvate thereof. The invention also relates to a pharmaceutical composition, dry inhalant powder, use of compounds in any of claims 1-6, as well as a method of modulating chemokine receptor 1 (CCR1).

EFFECT: obtaining a novel biologically active compound, having chemokine receptor 1 (CCR1) modulating activity.

13 cl, 6 ex, 2 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel optically active phenylthanolamine compounds of formula (I) having a (-)-configuration, or pharmaceutically acceptable salts thereof, which have β2-receptor agonist effect and can be used to treat asthma or bronchitis. In formula (I) R1 is H or halogen; R2 is CF3, CN or halogen; R3 is a straight or branched alkyl, having 1-6 carbon atoms or a cycloalkyl having 3-6 carbon atoms.

EFFECT: high efficiency of using the agents.

9 cl, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula in which R1 and R2 independently denote C1-6alkyl; R4 denotes phenyl, substituted with trifluoromethyl if necessary; X denotes hydrogen or methyl; and Y denotes -C(O)R, where R denotes C1-6alkyl; or Y denotes -P(O)(OR5)2, where R5 denotes hydrogen or C1-6alkyl; or pharmaceutically acceptable salts thereof. Said compounds are prodrugs of adenosine A2B receptor. The invention also relates to a pharmaceutical composition which is an adenosine A2B receptor antagonist based on the compound of formula I.

EFFECT: formula I compounds and the pharmaceutical composition can be used in treating different diseases in mammals, such as gastrointestinal disorders, immunological disorders, allergic disorders, neurological disorders, cardiovascular disorders and diseases associated with cell hyperproliferation.

13 cl, 1 tbl, 15 ex

FIELD: medicine.

SUBSTANCE: compounds of the invention exhibit properties of β2- adrenoreceptor agonists. In formula (I) , R1 represents hydrogen; each R2, R3, R4, R5, R4' and R5' independently represents hydrogen or C1-C6alkyd; e is equal to 0 or 1; A represents C(O); D represents oxygen or sulphur; m is equal to an integer 0 to 3; n is equal to an integer 0 to 3; R6 represents the group -(X)p-Y-(Z)q-R10; each X and Z independently represents C1-C6akylene group; each p and q is independently equal to 0 or 1; Y represents a bond, oxygen, CH2 or NR9; R7a and R7b independently represent hydrogen or C1-C6alkyl; R9 represents C1-C6alkyl; R10 represents hydrogen or saturated or unsaturated 6-members ring system optionally containing at least one ring heteroatom, chosen of nitrogen. And this ring system is optionally substituted by C1-C6alkoxycarbonyl; R7 represents 6-12-members aromatic ring system which is optionally substituted by halogen, trifluoromethyl, hydroxyl, C1-C6alkyl, C1-C6alkoxy or NH2; provided R6 does not represent hydrogen or unsubsituted C1-C6alkyl group. Also, the invention refers to methods for producing compounds of formula (I), to a pharmaceutical composition exhibiting properties of β2- adrenoreceptor agonists containing the compound of formula (I) as an active ingredient, to application of the compound of formula (I) in preparing a drug, to a combination containing the compound of formula (I) and one or more agents.

EFFECT: improved properties of the composition.

27 cl, 2 tbl, 32 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to application in an effective amount and to new nicotine receptor agonists described by general formula (i) or (ii) for treating inflammatory diseases chosen from a group including asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary tissue fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP), chronic hypersensitivity pneumonitis and bronchiolitis obliterans organising pneumonia (BOOP). The compounds (i) and compounds (ii) relate to formulae (i) (ii) where in formula (i) R1 and R2 independently mean alkyl with 1-10 carbon atoms; Xa means CH or N; Ya means one or more substitutes chosen from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms optionally substituted with one or more halogen atoms, and alkoxy with 1-10 carbon atoms; n means an integer 0 or 2; J means a counterion representing a compound for maintaining electric neutrality, e.g., halogen, sulphate, sulphonate; in formula (ii) R3 is chosen from or Xb means N or N+-R10; R4 means one or more substitutes chosen from hydrogen, halogen; each R10, R11 and R12 independently means alkyl with 1-10 carbon atoms; provided the presence of the counterion when Xb means N+-R10.

EFFECT: use of nicotine receptor agonists in the effective amount for treating inflammatory diseases.

26 cl, 40 dwg, 3 tbl, 38 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical product for treatment of respiratory disease, which contains combinations: a) first active ingredient, representing compound of general formula , where m equals 0, 1 or 2; each R1 independently represents halogen or cyano; R2 represents hydrogen atom or methyl; R3 represents C1-C4alkyl; and R4 represents hydrogen or halogen; or its pharmaceutically acceptable salt; and (b) second active ingredient, which represents glucocorticosteroid. Invention also relates to application of product by any of ii.1-15, to method of respiratory disease treatment, to set, as well as pharmaceutical composition.

EFFECT: obtaining of novel pharmaceutical product for treatment of respiratory disease.

35 cl, 5 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I)

or pharmaceutically acceptable salts thereof, in which: R1, R2, R3, R4, A and E are as described in the claim, and to pharmaceutical composition containing said compounds, and a method of treating and application in order to treat conditions mediated by antagonistic activity towards acid pump, such as gastrointestinal diseases, gastrooesophageal diseases, gastrooesophageal reflux disease (GERD), laryngopharyngeal reflux disease, peptic ulcers, gastric ulcers, duodenal ulcers, NSAID- induced ulcers, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, nonerosive reflux disease (NERD), viscerogenic pain, cancer, heartburn, nausea, oesophagitis, dysphagia, hypersalivation, disorders of the respiratory channel or asthma.

EFFECT: possibility of using compounds to treat different diseases.

9 cl, 1 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to derivatives of 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one of formula (I) where R1 represents CH3 or CH3CH2; R2 represents H, 3-CN, 2-CF3, 2-F, 3-F, 3-CF3, 3-CONH2 or SO2CH3; R3 represents H; R4 represents H or CH3; and R5 represents H; or, when R4 represents CH3, R5 represents H or F; and to its pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition exhibiting properties of CX3CR1 receptor antagonist containing compound (I) of formula or its pharmaceutically acceptable salt mixed with a pharmaceutically acceptable diluent or carrier.

EFFECT: enabled administration of the derivatives of 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one as selective CX3CR1 receptor antagonists.

13 cl, 1 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel anhydrous tetomilast type A crystalline form, having powder X-ray diffraction spectrum essentially the same as the powder X-ray diffraction spectrum having characteristic peaks at 2θ = 10.5°, 13.1°, 18.4°, 21.9° and 25.8°, pharmaceutical compositions based thereon and synthesis methods thereof.

EFFECT: considerable advantages in terms of industrial production owing to significantly better filterability.

8 cl, 14 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to experimental medicine, toxicology and deals with treatment and prevention of poisoning with phosphorus organic insecticides (POI). For this purpose carboxym and atropine are introduced to experimental animals in doses 2-3 time lower than in separate introduction.

EFFECT: method ensures increase of protective preventive efficiency in animals in experiment by 6-11 times, also due to allosteric exponentiation, which serves the base for further development of effective and safe POI antidote for people.

7 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: present invention refers to medicine, more specifically to a method for making a preparation for transdermal nicotine introduction that enables to produce said preparation for transdermal nicotine introduction by convenient and economical way with maintaining high-precision equal nicotine concentration, that enables to produce the preparation being fixedly and softly attached due to reduced skin irritation after removal and excellent adhesiveness. The present invention refers to the preparation for transdermal nicotine introduction characterised by excellent equal nicotine concentration with fixed and soft attachment and reduced skin irritation after removal. There is described the method for making the preparation containing a substrate and a formed adhesive layer which contains nicotine and an adhesive-compatible liquid ingredient; where the method involves: (1) preparing the adhesive layer in which a nicotine wetting angle of the adhesive layer before nicotine coating makes 20-60°, and (2) coating the adhesive layer with nicotine to ensure nicotine absorption in the adhesive layer; as well as to the preparation containing the substrate and the formed adhesive layer containing nicotine and the adhesive-compatible liquid ingredient in which the nicotine wetting angle of the adhesive layer before nicotine coating makes 20-60°.

EFFECT: development of an advantageous process of the preparation for transdermal nicotine introduction.

6 cl, 7 tbl, 14 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel indazole-carboxamide compounds of formula ,

in which radicals and groups are as defined in claim 1 of the formula of invention. Present invention also relates to pharmaceutical compositions containing said compounds, to methods of using such compounds to treat 5-HT4-receptor mediated diseases.

EFFECT: said compounds are 5-HT4-receptor agonists.

16 cl, 10 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula: ,

where R1 is selected from a group consisting of cycloalkyl which is unsubstituted or substituted with hydroxy or lower alkoxy, lower hydroxylalkyl, lower hydroxyhalogenalkyl, -CH2-CR9R10-cycloalkyl; R9 is hydrogen or lower alkyl; R10 is hydrogen, hydroxy or lower alkoxy; R2 is hydrogen; X is O or NR14; R14 is hydrogen or lower alkyl; R3 is selected from a group consisting of lower alkyl, cycloalkyl, lower cycloalkylalkyl, lower alkoxyalkyl, lower halogenalkyl, lower carbamoylalkyl, lower phenylalkyl, lower heterocyclylalkyl, where the heterocyclyl is a saturated 4- or 5-member ring containing one or two oxygen atoms, lower heteroarylalkyl, where the heteroaryl group is unsubstituted or mono- or disubstituted with a halogen, and phenyl which is unsubstituted or mono- or disubstituted with a halogen; or R3 and R14 together with a nitrogen atom to which they are bonded form an N-heterocyclic ring selected from pyrrolidinyl, piperidinyl or azepanyl; R4 and R8 independently denote hydrogen or halogen; R5 and R7 are independently selected from a group consisting of hydrogen, halogen, lower halogenalkyl, lower halogen, alkoxy and cyano; R6 is selected from a group consisting of hydrogen, halogen, lower halogenalkyl, lower halogen alkoxy and cyano; and pharmaceutically acceptable salts thereof, as well as to a pharmaceutical composition based on said compounds, which has CB1 modulating activity.

EFFECT: novel compounds which can be used to treat and prevent diseases associated with modulation of CB1 receptors, such as obesity, are obtained and described.

23 cl, 153 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, more specifically to a method for making a preparation for transdermal nicotine introduction, which involves the stage of formation on a substrate of an adhesive layer containing an adhesive and a liquid component compatible with the adhesive, and the stage of nicotine impregnation of the adhesive layer by continuous coating of the adhesive layer.

EFFECT: invention provides direct application of nicotine on the adhesive layer that is impracticable by conventional methods, and application of the preparation for transdermal nicotine introduction prepared by the method is associated with lesser physical skin irritation when removed and provides a pleasant sensation during gluing on.

5 cl, 4 dwg, 9 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: there is described a nicotine transdermal delivery system containing an adhesive layer containing nicotine in the form of a free base and a liquid component compatible to this adhesive wherein the adhesive layer is cross-linked, and the liquid component is found in a proportion 20-75 weight parts per 100 weight parts of the adhesive layer as a whole.

EFFECT: nicotine transdermal delivery system exhibits good adhesiveness and cohesion, and simultaneously provides low skin irritation during removal and pleasant sensation during adhesion.

7 cl, 2 tbl, 11 dwg, 22 ex

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