Solifenacin composition or its salts for use in solid preparation

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medical products and concerns the method of obtaining of a Solifenacin composition or its salts for use in a solid preparation which includes at least one stage chosen of the group consisting of (i) stage of wet granulation with use of a dissolvent for Solifenacin or its salts, thereat quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent makes less than 0.1 mg, (ii) stage of dicrease of quantity or rate of addition of a dissolvent if the dissolvent moves Solifenacin or its salt in an amorphous condition, and quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent 10 mg or more and (iii) stage of activisation of process of crystallisation of a composition of the wet granulation received by means of a usual way. Also the pharmaceutical composition for use in the solid preparation, showing selective opposing action against muscarinic M3 receptors is revealed.

EFFECT: rising of stability of the compositions containing Solifenacin or its salt.

12 cl, 3 tbl, 10 ex

 

The technical field to which the invention relates

This invention relates to compositions with solifenacin or its salt for use in the solid dosage form, the composition comprises a crystalline substance of solifenacin or its salt content of amorphous material in the interval, without affecting the stability of the resulting product, and the manner of its reception. In addition, the present invention relates to pharmaceutical compositions containing solifenacin or its salt and inhibitor formation of amorphous drug.

The level of technology

Solifenacin represents the following formula (I):

[Chemical formula]

and it has the chemical name: (1R,3'R)-3'-hinokitiol-1-phenyl-1,2,3,4-tetrahydro-2-ethanolammonium.

Report that series hinoksalinovym derivatives, including solifenacin or salts thereof have excellent selective antagonistic activity against muscarinic M3receptors and are useful as preventive or therapeutic agents for diseases of the urinary system such as the nervous pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder contracture of the bladder and chronic cystitis, and respiratory diseases such as khron the ical obstructive lung disease, chronic bronchitis, asthma and rhinitis (see patent document 1).

The production process of the hydrochloride of solifenacin described in example 8 of the patent document 1, where crystalline substance, obtained by crystallization in a mixed solvent of acetonitrile and diethyl ether, has a melting point 212-214°C. and has a specific rotation ([α]25D=98,1 (=to 1.00, EtOH).

However, patent document 1 does not include descriptions or assumptions about the significant decay over time of the amorphous solifenacin or amorphous salt, or succinate of solifenacin as the active pharmaceutical ingredient in the product, when the product of solifenacin succinate processed into dosage form according to the usual process of pharmaceutical production.

Non-patent document 1, published by the Japanese Ministry of Health, Labour and Welfare in June 2003, includes a description of the specification of the medicinal product, namely a General idea of the degradation products (impurities in new drug products that observed when testing for stability. In accordance with this document, the threshold for the products of decomposition (degradation), the desired limiting condition for the safety of the medicinal product, lower in any case of 1.0%, as a percentage of product decomposition (degrad the tion), contained in the drug substance or equal to 50 mcg, in the form of a total daily intake of the product of decomposition, when the amount of medicinal substance, which should be entered in the day, is less than 10 mg When the amount of medicinal substance, which should be entered in the day, is 10 mg or more to 100 mg or less, the threshold decomposition product, the desired limiting condition of safety for medicinal products, in any case, below 0.5%, a percentage decomposition product contained in the drug substance or equal to 200 mcg, in the form of a total daily intake of the product of decomposition. Therefore, the technical requirements for product decomposition, which can be determined without the terms of any security restrictions decomposition product, are usually of 1.0% or less in percent decomposition product contained in the drug substance, when the drug is presented, for example, 5-mg content of drug substance. When the drug is presented, for example, with 10-mg content of medicinal substance, the percentage decomposition product contained in the medicinal substance is 0.5% or less.

Drugs with solifenacin, currently planned for release in the market according to the results of clinical trials are tablets containing 2.5 mg, 5 mg and 10 mg What is asaeda these drugs, have a stability that is described in non-patent document 1, consider that the quantity of the main product of decomposition (hereinafter abbreviated as F1) succinate of solifenacin to the total number of succinate solifenacin and products of its decomposition should be limited to 0.5% or less, and that this number must be maintained at a level of 0.4% or less, taking into account variations from batch to batch and error tests.

Patent document 1: description of the EP 801067.

Non-patent document 1: communication No. 0624001, published by the Japanese Committee for pharmacy (Japanese Committee of Pharmaceutical Affairs), "revised guidance on impurities in new drug products containing new active pharmaceutical ingredients" ("Revision of Guideline about Impurities in New Drug Products containing Novel Active Pharmaceutical Ingredients).

Description of the invention

Problems that the invention should allow

This invention succinate of solifenacin was granulated by the method of granulation in the fluidized bed under normal conditions, known to specialists in this field, and producing tablets for the development of succinate solifenacin as an excellent therapeutic agent for pollakiuria, and urinary incontinence. Then conducted preliminary tests of the stability of the obtained tablets for 6 months when tested with accelerated article is rhenium (at 40°C and 75% RH (relative humidity) using the conditions of the hermetically sealed vessel) as one of the common tests for stability. In the observed decrease of the residual relationship succinate of solifenacin, so that the number of the resulting F1 in relation to the total number of succinate solifenacin and its decomposition products exceed 0,4% (see table 2, below, for more details). It became clear that it was difficult to get his product with a pharmaceutically sufficient stability with such a conventional method of pharmaceutical production.

When producing solid drug of solifenacin or its salt as an excellent therapeutic agent for pollakiuria and urinary incontinence, in other words, it is very desirable to develop formulations of solid preparation of solifenacin or its salts, stable over time, which can suppress formed by a number of F1 with respect to the total number of solifenacin or its salts and the products of their decomposition, up to 0.4% or less.

Resolving problems

The decomposition of the drug substance in the drug typically includes, for example, redox reaction, hydrolysis, racemization, fotorazlozheniya and polimerizuet destruction. It has been described that these reactions correlate with heating, the presence of oxygen, lighting, presence of water and interactions with other components. As described above, it is necessary to consider many reasons due to decomposition of lcars the governmental funds, to obtain a stable medicinal products. In this condition prior art, the inventors conducted research on the stabilization of the products of solifenacin. Unexpectedly, it was found that amorphous succinate of solifenacin formed in the manufacturing process of medicinal products, was the main cause decomposition of the active pharmaceutical ingredient over time.

In addition, the authors found that the content of amorphous substances in medicinal products can be suppressed by adjusting the moisture content of the medicinal product during the manufacturing process, when medicinal products were obtained using the process of wet granulation using water solutions of ordinary binders or by heating and/or humidification of the resulting composition after the production process of obtaining. Discovered that a stable solid preparation of solifenacin or its salt, in which its decomposition over time can be suppressed, can be obtained when the ratio of amorphous solifenacin to crystalline and amorphous solifenacin had this or a smaller value.

In addition, the authors found that the drug of solifenacin, in which the decomposition of solifenacin over time can be suppressed, can be obtained when ispolzovaniem of polyethylene glycol (under a different name Macrogol; hereinafter, abbreviated PEG) as binders, regardless of its production process, although PEG is a substance that can be used usually in order to obtain drugs in the amorphous state. Thus was created the invention, which differs from the methods of stabilization described above.

In other words, this invention relates to a described below.

1) Composition solifenacin or its salt for use in a solid preparation, the composition comprises crystalline solifenacin or its salt, where the content of amorphous material is in the range of not affecting the stability of the drug product.

2) Composition with solifenacin or its salt for use in the solid preparation described in paragraph (1), in which the content of amorphous material is 77% or less.

3) the Composition for use in the solid preparation described above in paragraphs 1) or 2), which is obtained by a production method comprising a stage of mixing solifenacin or its salt with fillers without using a solvent, followed by molding by means of pressing.

4) the Composition for use in a solid preparation, as described above in paragraphs 1) and 2), which is obtained by the production method, enabling the m stage of adding solvent to solifenacin or its salt, moreover, the number of solifenacin or its salt that can be dissolved in 1 ml of solvent is less than 0.1 mg.

5) the Composition for use in the solid preparation described above in paragraph 4), in which the solvent is added to solifenacin or its salt is acetone or hexane, or mixtures thereof.

6) the Composition for use in the solid preparation described above in paragraph 1) or 2), which is obtained by a production method comprising a stage of addition of solvent to obtain solifenacin or its salt in an amorphous state, where the number of solifenacin or its salt, which should be dissolved in 1 ml of solvent, is 10 mg or more.

7) the Composition for use in the solid preparation described above in paragraph 6), in which the solvent to obtain solifenacin or its salt in an amorphous state is water, methanol or ethanol, or a mixture.

8) the Composition for use in the solid preparation described above in paragraphs 1 through 7), which is obtained by a production method comprising a stage of stimulation crystallization of amorphous solifenacin or amorphous salt.

9) a Mixture of solifenacin or its salt, the mixture contains amorphous and crystalline solifenacin or amorphous or crystalline salt, where the content of the amorphous solifenacin is or its salt is in the range, without affecting the stability of the product.

10) the Pharmaceutical composition for use in solid drug, where the composition comprises crystalline and amorphous, solifenacin or crystalline and amorphous salt together with an inhibitor of the formation of the amorphous form of the drug.

11) the Pharmaceutical composition described above in paragraph 10), in which the inhibitor amorphous formation is a substance with ethylenoxide chain.

12) the Pharmaceutical composition described above in paragraph 11), where the substance with ethylenoxide chain is polyethylene glycol.

When pressing in accordance with the manufacturing of the drug in a mixture with additives known methods, including the method of stabilization of (E)-1-[4-(2-dimethylamino)ethoxy]phenyl-2-(4-isopropylphenyl)-1-(4-phosphonooxy)phenyl-1-butene, which has such a property that the products of its decay accelerating increase over time under the influence of conditions such as moisture contained in such addition, improvement of communication within the tablets with the addition, when forming the pressing, and the reduction of crystallinity when squeezed and with effectiveness as a therapeutic agent against breast cancer, while reducing humidity (Chemical & Pharmaceutical Bulletin, 42(12), 2582(1994)), as well as a method of stabilizing a composition containing this is Obedinenie, through the production process of granulation melting (JP-A-Hei 9-110698), such as a stabilization technique (JP-A-Hei 10-007547) by essentially anhydrous process for the production of solid drug aniline compounds in tablet form for use in multiple sclerosis, which is associated with great difficulties in precision injection aniline compounds as the main component, due to the fact that during storage in solid drug forms from 6 to 9% of other compounds, in addition to the main connection.

However, these documents of the prior art never included any description of solifenacin or its salt with the structure, completely different from the structures described compounds with physicochemical or pharmacological properties, and is completely different from the properties of the described compounds, and never included any descriptions or assumptions about the problem of decomposition of solid preparation containing an amorphous form over time or its stabilization by regulating the content of amorphous material below the corresponding number in the resulting solid product.

JP-A-Hei-194218, published in the official Gazette discloses a method of stabilizing the nitrogen-containing heterocyclic alkylphenyl derivatives with activity against angiotensin II, in which the reduction of the content of a file sharing which is by deformation of crystals due to mixing during manufacture, pressure, rubbing, heat, etc. that occur during granulation or molding pressing, and the method includes a step of mixing an oily substance with a low melting point, such as PEG, such alkylphenyl derivatives to stabilize received oral drug, when alkylphenyl derivatives are processed in accordance with the formulation mixed with other components. In this case, the stabilizing mechanism using a substance with a low melting point is carried out by suppressing thermal decomposition of the active pharmaceutical ingredient when mixing the oily substance with a low melting point until smooth with an active pharmaceutical ingredient. No descriptions of the assistance of a substance with a low melting point of crystallinity of the active pharmaceutical ingredient. This stabilizing mechanism is completely different from the stabilizing mechanism according to this invention.

In addition, in International Journal of Pharmaceutics, 216 (2001) 43-49, it is reported that when the joint dissolution and crystallization of lactose from PEG precipitated lactose is in the crystalline state. As an alternative, International Journal of Pharmaceutics, 127(1996) 261-272 and International Journal of Pharmaceutics, 262(2003) 125-137, it is reported that when the joint dissolution, crystallizatio the medicinal substance with PEG, the medicinal substance is in an amorphous state. In the case of joint dissolution and crystallization of active pharmaceutical ingredient with a polymer, such as PEG, get active pharmaceutical ingredient is often found in amorphous state, although this depends on the properties of the active pharmaceutical ingredient. Research work on mixing in order to obtain amorphous drug by solubilization nizkorazmernyh medicinal substances and the like, most of the known. All compounds described in these technical patents, have a chemical structure different from the structure of solifenacin. These sources do not include any description of solifenacin or its salts with different physico-chemical and pharmacological properties or any assumption about the data, based on which we can expect crystallization or obtaining amorphous drug of solifenacin by blending with PEG. Even in stabilization in the known documents not described such a composition, or not suggested such a composition, in which the decomposition of the active pharmaceutical ingredient over time can be suppressed by using crystallization using polymers such as PEG.

The composition according to this invention are described in detail below.

"Sol is solifenacin" for use in this invention include acid additive salts of solifenacin with mineral acids, such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid, phosphoric acid, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonate acid, econsultancy acid and glutamic acid and its salts Quaternary ammonium compounds, which are described in the patent document 1. In particular, it is preferable to obtain a pharmaceutical product is the succinate of solifenacin. When using it achieved a significant stabilization effect in accordance with this invention. Thus, succinate salt is especially preferred choice.

"Solifenacin or its salt to be used according to this invention can easily be obtained by the methods described in patent document 1, or by conventional methods. The number of solifenacin or its salt, which is mixed in the composition for use in solid preparation in accordance with this invention, is satisfactory if it contains the active amount per unit dosage. Yes the number is preferably from 0.001% by mass to 97% by weight, more preferably from about 0.05% by weight to 50% by weight, more preferably from 0.05% by mass to 20% by weight, most preferably from 0.05% by mass to 10% by weight. If the pharmaceutical composition according to this invention represents particles, such as pellets, quantity of medicinal substance contained in a pharmaceutical composition consisting of particles is chosen accordingly, usually depending on types of a drug and its pharmaceutical use (indication). Therapeutically active amount or prophylactically active amount is satisfactory without specific limitations.

In addition, the daily dose of solifenacin or its salt is preferably from 0.01 mg to 100 mg, more preferably from 0.5 mg to 50 mg, more preferably from 0.5 mg to 20 mg, most preferably from 0.5 mg to 10 mg

"The crystals or crystalline substance of solifenacin or its salts" refers to the substance of solifenacin or its salt with a crystalline structure and the meaning of this term corresponds to the value used in the field of crystallography. In accordance with this invention, the term "crystal" or "crystal" characterize a substance with less decomposition of solifenacin over time. The terms "crystals" or "Chris is allicance" characterize the substance, different from amorphous substances with significant decomposition of solifenacin over time, this substance is present in a quantity that is outside of the interval without affecting the stability of the drug product the drug.

In accordance with this invention, the term "amorphous" solifenacin or its salt, or the amorphous substance of solifenacin or its salt means a substance with crystallographically amorphous structure. In accordance with this invention, the term "amorphous, solifenacin or amorphous salt or amorphous substance of solifenacin or its salt" means a substance with significant decomposition of solifenacin, when it is present in amounts outside the interval, without affecting the stability of the medicinal product and, in addition, means a substance, other than crystals or crystalline substances with less decomposition of solifenacin over time.

Additionally, in accordance with this invention, the content of amorphous substances" means the ratio of the amorphous material to the total amount of amorphous and crystalline solifenacin or its amorphous and crystalline salts in General.

In accordance with this invention, the phrase "in the interval, without affecting the stability of the medicament is i.i.d. product" means that the product of solifenacin or its salt is stable in harsh conditions in the process to sell a commercial product. In particular, the number of primary formed product decomposition of solifenacin towards solifenacin or its salts and the products of their decomposition in General can be reduced to 0.4% or less in the preliminary test for stability using the conditions of the hermetically closed vessel at 40°C and 75% RH for 6 months.

Thus, in accordance with this invention, the specific content of the amorphous form of a substance in the interval, without affecting the stability of the product is 77% or less, preferably 73% or less, more preferably 71% or less, most preferably 63% or less relative to the total number of amorphous and crystalline solifenacin, or its amorphous and crystalline salts in the case of measurement using near infrared spectrometry. In addition, solifenacin or its salt with an initial content of amorphous substances in excess of the interval, which does not affect the stability of the product, immediately upon receipt, but developing crystallization over time so that the content of amorphous material is reduced to within a given interval without affecting the stability of the product, also includes the trading in the scope of this invention. Thus, the time measurement of the content of amorphous material has no specific limitations. Taking into account that the content of amorphous material must guarantee the stability of the product during its sales, preferably, when the content of amorphous substance, determine at the beginning of sales of a product or in a suitable time thereafter.

In General, the method of evaluation of the content of the amorphous form of solifenacin or its salts in accordance with this invention, may be any method to identify the crystal structure of solifenacin or salts thereof in the composition, including, for example, a method of powder x-ray diffraction method DSC, NMR in the solid state and near-infrared spectrometry. For the crystal structure determination of drug substances at low concentrations in the composition in a mixture with other components crystal structure is preferably determined by NMR in the solid state or near-infrared spectrometry. A simpler way to define the structure is near-infrared spectrometry.

As a method of determining the content of amorphous material succinate of solifenacin used, for example, the method of near infrared spectrometry by determining the spectrum using a spectrometer for near infrared SPECT is hometree Fourier transform (Vector 22/N Bruker Optik GmbH, Germany) (interval definition: 10000 cm-1to 4000 cm-1, resolution: 2 cm-1number of scans: 126) and secondary differentiation of the obtained spectrum (convolutional method of Savitzky-Gollay) for analysis using software designed for the analysis of the near infrared spectrum (e.g., OPUS, Bruker Optik GmbH, Germany). Before spectral determination of substances in the tablet were analyzed spectra of the products obtained by mixing different ratios of crystalline and amorphous succinate of solifenacin, pre-fabricated by the method of spray drying an aqueous solution of succinate solifenacin, using regression analysis partial least squares method to obtain a standard curve. By blending range tablets on the standard curve, you can determine the content of the amorphous form of succinate solifenacin.

As a method of measuring the content of the amorphous form of succinate solifenacin NMR in the solid state, for example, the spectrum of the tablets was determined by using a device for NMR in the solid state (for example, CMX-300, produced by Chemagnetics, USA) (for example, used a sample: made of ceramic, 7.5 mm sample, contact time: 9 msec, repetition time pulse: 38 sec, the number of treatment sample: 5 kHz). The spectrum represent the processing data (for example, functional window indicator, the broadening factor: 30 Hz, trapezoidal window, t1=0, t2=0, t3=0.5, and t4=0,6). In addition, crystalline and amorphous succinate of solifenacin previously obtained by the method of spray drying an aqueous solution of succinate solifenacin, mixed together in different proportions. Then, using lactose as an internal standard, determine the ratio of the peak height crystalline succinate of solifenacin to plot a standard curve. Placing ratio peak/height crystalline succinate of solifenacin received from the tablet spectrum, on the standard curve, it is possible to determine the content of crystalline succinate of solifenacin and the content of its amorphous form.

"Composition for use in solid preparation in accordance with this invention is a pharmaceutical composition for use in solid drug without particular limitation, and the decomposition of solifenacin or its salts over time may be delayed, because the content of the amorphous form is in the interval, without affecting the stability of the product. This term refers to compositions for oral and parenteral administration, such as tablets, pills, powders, granules and capsules.

The phrase "a mixture of solifenacin or its salt containing amorphous and crystal is practical, solifenacin or its amorphous and crystalline salt, and the content of the amorphous form is in the interval, without affecting the stability of the product" means a mixture of amorphous and crystalline solifenacin or its amorphous and crystalline salts and decomposition of solifenacin or its salt is suppressed over time, and the mixture essentially contains the amorphous solifenacin or amorphous salt content of the amorphous form in such a range that does not affect the stability of the product.

In terms of the number of solifenacin or its salt, which is mixed in the composition for use in solid preparation in accordance with this invention, satisfactory, when the composition contains the active number of solifenacin or its salt at a standard dose of the drug.

Method of production "songs with solifenacin or its salt for use in a solid preparation, the composition comprises crystalline solifenacin or crystalline salt, in which the content of the amorphous substance of solifenacin or its salt is in the range of not affecting the stability of the product is in any way using any solvent to obtain solifenacin or its salt in an amorphous state; or a method comprising a stage of reduction of contact solifenacin or its salt with the solvent in the course of RA is the creation of solifenacin or its salts in a solvent, to obtain solifenacin or its salt in an amorphous condition for the formation of amorphous material, and the content of amorphous material is in the range without affecting the stability of the product; or a method comprising a stage of heating and/or humidification of the composition with a content of amorphous material outside of the interval, without affecting the stability of the product during production or after receipt, to bring the content of amorphous material in the frame interval, without affecting the stability of the product, without specific limitations of the equipment or the means of production.

As the production conditions to bring the content of the amorphous form of solifenacin or its salt in the frame interval, which does not affect the stability of the product, you can offer different conditions. In particular, one of the variants of the production conditions is a typical production process without using any solvent to obtain solifenacin or its salt in an amorphous state. Regarding the phrase "the production process without using any solvent to obtain solifenacin or its salt in an amorphous state, the process of production includes direct tableting, which involves mixing of solifenacin or its salt with the corresponding vspomogatelnymi substances without using any solvent and forming pressing the resulting mixture, if you want to get a tablet. In the case where the method involves the step of adding a solvent, this method involves the use of a solvent, almost turning solifenacin or its salt in an amorphous state, and the number of solifenacin or its salt, which should be dissolved in 1 ml of solvent is less than 0.1 mg, for example, acetone, hexane, or mixtures thereof, for wet granulation.

In the case of the production method for obtaining solifenacin or its salt in an amorphous state, at the stage of adding a solvent in the production process of obtaining solifenacin or its salt in an amorphous state, a stable composition with solifenacin or its salt for use in the solid preparation can be obtained in the conditions of production to reduce the amount and rate of addition of the appropriate solvent, such as water, to be used at this stage of production, and the production conditions for reliable achievement of specified quality obtained granules with bringing the content of the amorphous form in a frame interval, without affecting the stability of the product. The solvent to obtain solifenacin or its salt in an amorphous state, as mentioned herein, means a solvent, for which the number of solifenacin or its salt that can be dissolved B1 ml solvent, is 10 mg or more, for example, water, methanol or ethanol, or a mixture, which preferably is water. Specifically, at the stage of spraying an aqueous solution dissolved therein as a binder solution on the powder containing solifenacin or its salt, in the manufacture of a composition for use in a solid preparation, the product is satisfactorily performed by obtaining pellets with a moisture content brought to a preset value or less when spraying binder solution. The moisture content in the granules during and after spraying the binder solution was adjusted to preferably 9% or less, more preferably 6% or less, particularly preferably 5% or less, most preferably 4% or less.

Even when the composition with a content of amorphous form of solifenacin or its salts, equal to 77% or more, receive a production method described above, and conventional wet granulation, there is activation of crystallization of the composition to obtain a composition with a content of amorphous form of solifenacin or its salt in the interval, without affecting the stability of the product. Activation of the crystallization process, referenced herein may be implemented in accordance with any production process activation crystallization is isomorphous of solifenacin or its salt without specific limitations. The production method includes, for example, heating and/or humidification, the microwave irradiation process, the process of low-frequency radiation, ultrasonic radiation and the process of thermionic emission of radiation. The process of heating and/or humidification includes the production process keeping one substance in thermostat at a constant humidity, for example, under conditions of 25°C and 75% RH for one week, followed by re-drying. Satisfactory can be any industrial process heating and/or humidification of the composition until smooth without any specific limitations on the apparatus and the means of production. As for the process of microwave irradiation can be used, for example, the wave length range from 10 MHz to 25 GHz. In addition, the processing time depends on the initial degree of crystallization and the selected substrate. Wavelengths described above, is used for irradiation, for example, in a period of from 10 seconds to 60 minutes. Irradiation can be performed continuously or intermittently. The duration of the implementation of these processes enhance the crystallization may be any, provided that get a stable composition with solifenacin or its salt for use in solid drug without specific limitations, the production of pellets of solifenacin or its salts, or after receipt whom is osili for use in solid drug.

This production process includes, for example, the process of direct tabletting, consisting of a mix of solifenacin or its salt with an appropriate additive and forming extrusion of the mixture, if you want to get a tablet, the process of wet granulation, consisting of a mix of solifenacin or its salt with an appropriate additive, and then spraying the binder solution into the resulting mixture to obtain granules, and the process of granulation of the melt, consisting of a mix of solifenacin or its salt with an appropriate substance with a low melting point and heat and granulation of the mixture. As solifenacin or its salt are strong aggregation, it is difficult to reliably maintain the uniformity of content, the mixture sticks to the punch during the pressing process direct tabletting, and it is very difficult to adjust the amount of a substance with a low melting point, which should be dissolved in the granulation process by melting, so the process of wet granulation is preferred as the production process in accordance with this invention.

The process of wet granulation includes, for example, the spraying of solifenacin or its salt spraying mechanism, and then mixing the obtained powder with a pharmaceutically acceptable doba is kami, such as fillers and baking powder, spraying the binder solution to the mixture to obtain granules, mixing improves the sliding of a substance with granules and pressing mixes in tablets. In accordance with this process it is clear that the crystalline solifenacin or crystalline salt is dissolved in the sprayed binder solution at the stage of spraying the binder solution during granulation and then drying the obtained granules for formation of an amorphous product. By reducing the flow rate of the binder solution during granulation, which reduces the total amount of binder solution, or increase the temperature of the supplied air and the like, to reduce the dissolution of solifenacin or its salt in a binder solution, followed by reduction of the formed amorphous form may be represented pharmaceutical composition in the form of solid preparation.

The preferred flow rate of the binder solution depends on the manufacturing process and scale. The flow rate is preferably from 40 to 100 g/min, more preferably 50-80 g/min in the production of a 5-kg scale in the process of granulation in the fluidized bed. The preferred total amount of binder solution depends on the production process or scale of production. For production of 5-kg scale through a process pseudouridines layer of its total number is preferably from 1000 kg to 2500 kg, more preferably from 1500 kg to 2200 kg Preferred temperature of the air varies depending on the manufacturing process and scale. For the production of 5-kg scale by the process of fluidized bed, however, the temperature is preferably from 50 to 80°C., more preferably from 60 to 80°C.

The mechanism that turns into powder includes, for example, hammer mill, ball mill, jet mill and a colloid mill. Basically, any way pharmaceutical turning into powder can be satisfactory without specific limitations of the equipment or the means of production.

Apparatus for mixing the individual components, which are continuously used to produce powders include, for example, a V type mixer, a ribbon mixer, a container mixer and device for high speed mixing. Basically, may be any satisfactory process for the mixing of the individual components to pharmaceutically smooth without any specific limitations in the equipment or the means of implementation.

Apparatus for granulation (process) includes, for example, high-speed granulation process with mixing, granulation in the fluidized bed, extrusion granulation and granulation in what adenium. Can be any satisfactory granulation technique using a binder solution, without specific limitations of the equipment and means of implementation.

Apparatus for tabletting includes, for example, rotary tabletiruemuju car and tabletiruemuju machine with one punch. Basically, it may be satisfactory way in which it is possible to obtain products forming pressing (preferably pill) without specific limitations of the equipment and means of implementation.

The binder for use in wet granulation include, for example, hypromellose and polyvinylpyrrolidone. Basically, it may be satisfactory any binding substance with a pharmaceutically acceptable binder powder capacity, without specific limitations.

Usually the number of such binders that you want to use, can be his number to obtain a pharmaceutically acceptable product granulation, without specific limitations. Generally this amount is from 0.5 to 50% by weight per unit dose, preferably from 0.5 to 10% by weight per unit dose, more preferably from 2 to 5 mass% on the standard dose.

In such pharmaceutical compositions intended for use in the solid preparation according to this image is Itanium, in addition, the formulations can respectively use different pharmaceutical excipients. Such pharmaceutical excipients may be any pharmaceutically acceptable and pharmacologically acceptable auxiliary substances without specific limitations. For example, you can use binders, loosening, acidifying substances, foaming agents, artificial sweeteners, taste-aromatic additives, lubricants, dyes, stabilizers, buffering agents, antioxidants, and surfactants. For example, the binder include hypromellose and Arabian gum. Loosening tools include, for example, corn starch, potato starch, calcixerollic and nutricology. Acidifying substances include, for example, citric acid, tartaric acid and malic acid. Foaming agents include, for example, sodium bicarbonate. Artificial sweeteners include, for example, saccharin sodium, dvuhkamernyi taliglucerase, aspartame, stevia and sometin. Aromatic additives include, for example, lemon, lime-lemon, orange and menthol. Lubricants include, for example, magnesium stearate, calcium stearate, esters of sucrose and fatty key is lots the polyethylene glycol, talc and stearic acid. Tinted substance include, for example, yellow sesquioxide iron, red sesquioxide iron, food yellow No. 4 and 5, food red No. 3 and 102, and food blue No. 3. Buffers include, for example, citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or their salts, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or their salts, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or their salts. The antioxidants include, for example, ascorbic acid, dibutylaminoethanol, propylgallate. Surfactants include, for example, Polysorbate 80, sodium lauryl sulfate and utverjdenie a polyoxyethylene castor oil. One kind or two kinds or more of these excipients can respectively be added in combination in an appropriate quantity.

In addition, the inhibitor of amorphous formation" (an inhibitor of the formation of amorphous forms) means a substance suppressing the formation of amorphous solifenacin or amorphous salts, when solifenacin or its salt is dissolved in the solvent, and then transformed into a solid state by drying and the like in the manufacture of compositions with solifenacin or its salt for use in the solid preparation is solvent.

Inhibitor of amorphous formation is preferably a substance with ethylenoxide chain. This substance with ethylenoxide chain, which is mentioned here, is any substance with ethylenoxide chain without specific limitations. Since the task of suppressing the formation of amorphous solifenacin or its salts in accordance with this invention is achieved by adding a substance, and this substance can be any substance with any form of molecules or may be of any molecular weight or any degree of polymerization without specific limitations. Molecular weight is preferably in the range of the average molecular weight of from 400 to 1,000,000, more preferably in the range of the average molecular weight of from 2,000 to 200,000. As substances with ethylenoxide chain in the mixture, you can use two or more kinds of substances. In accordance with this invention, in particular, a substance with ethylenoxide circuit includes, for example, PEG, polyethylene oxide, block copolymers of polyoxyethylene and polyoxypropylene, utverjdenie a polyoxyethylene castor oil (hereinafter abbreviated as TCM) and ester of polyethylene glycol and fatty acids. Which one is preferable, in particular, a PEG, a block copolymer of polyoxyethylene and polyoxypropylene or TCM. Preferred PEG.

The block copolymer is of polyoxyethylene and polyoxypropylene in accordance with this invention may be a copolymer of propylene oxide and ethylene oxide. Depending on the ratio in the composition, there are a variety of such copolymers. Can be any suitable such copolymer with a property to suppress the formation of amorphous solifenacin or its salts in the composition. In particular, for example, you can use the polyoxyethylene-(105)-polyoxypropylene-(5)-glycol and polyoxyethylene-(160)-polyoxypropylene-(30)-glycol (under a different name, Pluronic F68).

Inhibitor of amorphous drug is used in a quantity of preferably from 0.1 to 90% by weight, more preferably from 1 to 60% by weight relative to the total weight of the preparation. When PEG is used as a binder for use in the process of wet granulation by dissolving PEG in distilled water, its amount is preferably from 3 to 20% by weight, more preferably from 4 to 10% by weight of the total weight of the powder, which need to pelletize. When the amount of inhibitor amorphous formation was determined at a single mass fraction of crystalline and amorphous solifenacin or its salts, and this number is preferably provided in respect of 0.001-100000% by weight, more preferably from 0.1 to 1000% by weight, even more preferably from 10 to 600% by mass.

In accordance with this invention, the phrase "containing" means solifenacin or it is salt as the active pharmaceutical ingredient is mixed with an inhibitor of amorphous formation. Preferably solifenacin or its salt is in contact with the inhibitor of amorphous formation, so that solifenacin or its salt is distributed in the structure of the mixture. As in the case of using the pharmaceutical composition as a covering means for the drug solifenacin, where the active pharmaceutical ingredient, which is solifenacin or its salt, is not in contact with or in a mixture with the same inhibitor amorphous formation, so that it exists in a localized state (e.g., inhibitor of amorphous formation in accordance with this invention (PEG)), pharmaceutical preparations, for example, with such a structure that solifenacin or its salt are not in physical contact with the inhibitor of amorphous formation in the intermediate layer with the use of other additives and the like are not allowed.

The pharmaceutical composition of solifenacin or its salts for use in the solid preparation in accordance with this invention is described below in detail. In the following examples and comparative examples of the invention are described in more detail. However, this invention should not be construed as limited to these examples.

[Reference example 1]

60 parts of succinate solifenacin was dissolved in 140 parts of water for spray drying the drug in the spray dryer (DL-41, produced by Yamato Science) to obtain the spray dried product.

The crystallinity of the resulting spray dried product of succinate solifenacin was determined using the apparatus for x-ray diffraction (RINT 1400 manufactured by Rigaku Denki). Watched a picture of halo, indicating that the product was amorphous.

<a storage Stability of crystalline and amorphous product>

Results on the stability of the crystalline product before spray drying and amorphous product are presented in table 1. The amount of degradation products over time during storage was determined by high-performance liquid chromatography. Shows the maximum number of decomposition products. After a short period of time after the start of storage of the formed products of the decomposition of the amorphous product of succinate solifenacin, and its stability was worse than the stability of the crystalline product. Therefore, the main cause decomposition of the active pharmaceutical ingredient over time was mainly amorphous succinate of solifenacin formed in the manufacturing process of the drug.

Results the stability of the crystal and the amorphous product of succinate solifenacin

Storage conditions: 40°C and 75% RH

Packing: glass jar

The object of the test: related substances (individual maximum values)

Table 1
Storage conditionsCrystalline productAmorphous
product
SourceBUTBUT
Hermetically
closed
glass vessel
after one weekBUT0,03%
in two weeksBUT0,05%
Outdoor
glass vessel
after one weekBUT0,16%
in two weeksBUT0,16%
BUT: not defined

Example 1

204 part hydroxypropylmethylcellulose 2910 was dissolved and stirred in 1836 parts of water using a mixer with pneumatic motor (AM-GC-1 manufactured by Chuo-Rika Machine), with a binder solution (with a concentration of 10.0/about %). Then mixed 340 h the values of succinate solifenacin and

1360 parts of lactose. Then the mixture was made into powder using a hammer mill (mill samples AR-S using a 1-mm sieve manufactured by Hosokawa Micron). Mixed and converted into a powder product was added 2125 parts of lactose and 1020 parts of corn starch and then loaded into the granulator in the fluidized bed (WSG-5 produced Powlec) for spraying binder solution at a temperature of supplied air, equal to 65°C, air flow rate of 4 m3/min, the flow rate of the binder solution of 75 g/min, air pressure for atomization equal to 1.5 kg/cm2and the cycle of spraying/mixing in 30 seconds/10 seconds during granulation. The moisture content in the granules after spraying the entire volume of the binder solution was 3.9%. After granulation, the granules were dried at a temperature of supplied air 50°C for 10 minutes to obtain pellets of the present invention. Added 12 parts of magnesium stearate to 1188 parts of the dried granulated product when mixed by using a mixer (type DC produced by Yamanouchi). Then the resulting mixture was extruded using a rotary teletrauma machine (HT R-22 manufactured by Hata Tekkosho) with the punches with a diameter of 7.5 mm at tabletirujut pressure of 700 kgf/punch to the weight of the tablets 150 mg in Addition, 800 parts of the obtained tablets were covered with spray solution made the first dissolution/dispersion of 84.3 parts of hydroxypropylmethylcellulose, 15.8 parts of macrogol 6000, with 25.3 parts of talc, and 10.5 parts of titanium oxide and 0.03 part of the red sesquioxide iron in 1223 parts using a vented machine for coating (machine for applying high performance coatings HCT-30, manufactured by Freund Industry Corporation) at a temperature of supplied air 60°C, the speed of rotation of the bowl 13 rpm and the flow rate of the liquid coating of 5 g/min to the proportions of 2.7% covering means against the weight of the tablet with obtaining film-coated tablets of the present invention.

Example 2

Granulation produced by spraying a binder solution to the following conditions of granulation using the machine for granulation in the fluidized bed: when the temperature of the air was increased to 65°C.; air flow rate was 4 m3/min; the flow rate of the binder solution was 75 g/min; the pressure was 0.7 kg/cm2; and the cycle of spraying/mixing was 30 seconds/10 seconds. The moisture content of the granules was 5.5% after spraying the entire binder solution. After granulation was obtained film-coated tablets of the present invention by the method described in example 1.

Example 3

Granulation produced by spraying a binder solution to the following conditions of granulation using the machine for granulation in the fluidized bed temperature filing is imago air was 65°C; the air flow rate was 4 m3/min; the flow rate of the binder solution was 95 g/min; the pressure was 1.5 kg/cm2; and the cycle of spraying/mixing was 30 seconds/10 seconds. The moisture content of the granules was 5.7% after spraying the entire binder solution. After granulation was obtained film-coated tablets of the present invention by the method described in example 1.

Example 4

Granulation produced by spraying a binder solution to the following conditions of granulation using the machine for granulation in the fluidized bed temperature of supplied air was 55°C; the air flow rate was 4 m3/min; the flow rate of the binder solution was 75 g/min; the pressure was 1.5 kg/cm2; and the cycle of spraying/mixing was 30 seconds/10 seconds. The moisture content of the granules was up 8.4% after spraying the entire binder solution. After granulation was obtained film-coated tablets of the present invention by the method described in example 1.

[Comparative example 1]

Granulation produced by spraying a binder solution to the following conditions of granulation using the machine for granulation in the fluidized bed temperature of supplied air was 65°C.; air flow rate was 4 m3/min; the flow rate of the binder R is the cross-section was 115 g/min; the pressure was 1.5 kg/cm2; and the cycle of spraying/mixing was 30 seconds/10 seconds. The moisture content of the granules was 10.6% after spraying the entire binder solution. After granulation was obtained film-coated tablets of the present invention by the method described in example 1.

[Comparative example 2]

Granulation produced by spraying a binder solution to the following conditions of granulation using the machine for granulation in the fluidized bed temperature of supplied air was 65°C.; air flow rate was 3 m3/min; the flow rate of the binder solution was 75 g/min; the pressure was 1.5 kg/cm2; and the cycle of spraying/mixing was 30 seconds/10 seconds. The moisture content of the granules was 10.6% after spraying the entire binder solution. After granulation was obtained film-coated tablets of the present invention by the method described in example 1.

[Comparative example 3]

Granulation produced by spraying a binder solution to the following conditions of granulation using the machine for granulation in the fluidized bed temperature of supplied air was 45°C; the air flow rate was 4 m3/min; the flow rate of the binder solution was 75 g/min; the pressure was 1.5 kg/sup> 2; and the cycle of spraying/mixing was 30 seconds/10 seconds. The moisture content of the granules was 10.8% after spraying the entire binder solution. After granulation was obtained film-coated tablets of the present invention by the method described in example 1.

<Determination of moisture content in the granules during granulation, the content of amorphous succinate of solifenacin in the tablet and quantity of the decomposition products after storage over time>

The results of the moisture content of the granules after spraying the binder solution, the content of amorphous succinate of solifenacin and preliminary results on stability when using the terms in a tightly closed container at 40°C and 75% RH for 6 months are presented in table 2 in the modification of conditions of production during granulation. The moisture content in the granules after spraying the binder solution is shown as the value determined by the loss on drying method (80°C, 2 hours), whereas the content of amorphous succinate of solifenacin shown as the value determined by spectroscopy in the near infrared. Spectrometry near infrared radiation was performed by determining the spectrum of the spectrometer in the near-infrared Fourier transform (Vector 22/N, Bruker Optik GmbH, Germany) (measurement interval 10000 cm-1- 000 cm -1, resolution: 2 cm-1the number of scan: 126). The obtained spectrum was secondary derivative (convolutional method of Savitzky-Gollay) and analyzed using software for spectrum analysis in the near infrared region (OPUS, Bruker Optik GmbH, Germany). Before defining the scope of pills spectra of the products obtained by mixing the crystalline and amorphous succinate of solifenacin at different ratios, pre-fabricated by spray drying an aqueous solution of succinate solifenacin, were subjected to regression analysis partial least squares method to obtain the standard curve. Range of tablets was placed on a standard curve to determine the amount of amorphous succinate of solifenacin. Additionally determined the amount of degradation products by high-performance liquid chromatography after storage for 6 months, applying the conditions in a tightly closed container at 40°C and 75% RH. Additional amounts of the decomposition products, certain, therefore, shows the number formed by the main decomposition product (F1), in relation to the total number of succinate solifenacin and products of its decomposition. Using the ratio formed by F1 as an indicator that assessed the stability of succinate solifenacin.

<the moisture Content of the granules in viagraonli 10 mg tablet succinate of solifenacin, the content of amorphous succinate of solifenacin in the tablet and a preliminary test for stability (within 6 months)>

Table 2
Objects
tests
Example
1
Example
2
Example
3
Example
4
Comparative
example 1
Comparative
example 2
Comparative
example 3
The moisture content in the granules after spraying3,9%5,5%5,7%8,4%10,6%10,6%10,8%
The content of amorphous succinate of solifenacin in the tablet (at the beginning of storage)*163%73%71%77%92%90%92%
Proporcionaremos F1 *2 0,31%0,29%0,35%0,38%0,48%0,44%0,43%
*1: determined by spectrometry infrared radiation in the near-field
*2: the proportion of the main decomposition product of succinate solifenacin in relation to the total number of succinate solifenacin and products of its decomposition

As shown in table 2, 10-mg tablets obtained under particular conditions of production have different moisture content during granulation. As the moisture content of the granules was lower, usually the content of the amorphous form of tablets below.

In comparative examples 1 to 3, in the main production processes, the moisture content in the granules after spraying a binder solution was greater than in the examples. Therefore, the content of amorphous solifenacin was as large as 90% or more. In addition, the quantity of the main product of decomposition of F1 with respect to succinate of solifenacin and products of its decomposition in General exceeds 0.4%. This shows that there is a serious problem in obtaining compositions with solifenacin or its salt, which is stable over time for clinical practice is.

In the case of holding the moisture content of the pellets at the lowest possible level, as in the examples 1 through 4, an alternative content of amorphous substances under the control of the moisture content of 77% or less, while the number of main product of the decomposition of F1 with respect to succinate of solifenacin and products of its decomposition, in General, were of 0.4% or less.

Thus, a drug with solifenacin, stable over time, could be obtained by holding the content of the amorphous form to 77% or less in the product containing solifenacin or its salt.

Example 5

270 parts of PEG (under the trade name Macrogol 6000, produced by Sanyo Chemical) was dissolved in 1080 parts of water and stirred with a stirrer pneumatic motor (AM-GC-1 manufactured by Chuo Rika) to obtain a binder solution (at a concentration of 20.0 in/about %). Then was mixed with 90 parts of succinate solifenacin and 360 parts of lactose (under the trade name lactose 200M manufactured by DMV). Then the mixture was made into powder using a hammer mill (mill sample AR-S using a 1 mm sieve manufactured by Hosokawa Micron). Mixed and converted into a powder product was added 3906 parts of lactose and crystalline cellulose (under the trade name Avicel PH 102, produced by Asahi Chemical), and then loaded into the machine for granulation in the fluidized bed WSG-5, produced Powlec) for spraying binder solution at a temperature of supplied air 70°C, the flow rate of the binder solution 100 g/min, spraying air pressure of 1.5 kg/cm2and the cycle of spraying/mixing 30 seconds/10 seconds for granulation. After granulation, the granules were dried at a temperature of supplied air 70°C for 10 minutes to obtain pellets of the present invention. To 1188 parts of the dried granular product was added 12 parts of magnesium stearate (produced by NOF) for mixing using a mixer (type DC produced by Yamanouchi). Then the resulting mixture was extruded using a rotary teletrauma machine (HT R-22 manufactured by Hata Tekkosho) with the punches with a diameter of 5.5 mm at a pressure of about 500 kgf/punch to obtain tablets with a weight of 60 mg Next 900 parts of the obtained tablets were sprayed solution obtained by dissolving/dispersing 18.6 parts HPMC 2910 (under the trade name TC-5R, produced by Shin-estu Chemical), 3.5 parts of PEG (under the trade name Macrogol 6000, produced by Sanyo Chemical), and 5.6 parts of talc (manufactured Kihara Chemical), and 2.3 parts of titanium oxide (manufactured Freund Industry Corporation) and 0.05 part of the red sesquioxide iron in 270 parts of water, and created a cover using a vented machine for coating (a device for applying high performance coatings HCT-30, manufactured Feund Industry Corporation) at a temperature of supplied air 60°C, when the speed of rotation of the bowl 13 rpm, and the flow of covering liquid 5 g/min to 3.3%proportions covering component in weight tablet with reception of tablets of the present invention is coated.

[Comparative example 4]

Was dissolved in 180 parts HPMC 2910 (under the trade name TC-5R, produced by Shin-estu Chemical) in 1620 parts of water and stirred using a stirrer pneumatic motor (S-GC-1 manufactured by Chuo Rika) to obtain the solution of the binder (at a concentration of 10.0/about%). Then mixed 75 parts of succinate solifenacin and 300 parts of lactose. Then the mixture was made into powder using a hammer mill (mill sample AR-S using a 1 mm sieve manufactured by Hosokawa Micron). Mixed and converted into a powder product was added 2700 parts of lactose and 900 parts of corn starch (manufactured by Nihon Shokuhin) and then loaded into the machine for granulation in the fluidized bed (WSG-5 produced Powlec) for spraying binder solution at a temperature of supplied air 60°C, the degree of atomization of the binder solution of 75 g/min, spraying air pressure of 1.5 kg/cm2and the cycle of spraying/mixing 30 seconds/10 seconds for granulation. After granulation, the granules were dried at a temperature of supplied air 60°C for 10 minutes to obtain pellets of the present invention. To 1188 parts visus is the R granules were added 12 parts of magnesium stearate (produced by NOF) for mixing using a mixer (type DC, produced by Yamanouchi). Then the resulting mixture was extruded using a rotary teletrauma machine (HT R-22 manufactured by Hata Tekkosho) c punches with a diameter of 5.5 mm at a pressure of about 500 kgf/punch to obtain tablets with a weight of 60 mg Next 900 parts of the obtained tablets were coated by the method shown in example 5 to obtain film-coated tablets of the present invention.

[Comparative example 5]

108 parts of potato starch (manufactured by Nihon Shokuhin) was added to 2592 parts of water and then dissolved therein by heating to 80°C. Then the resulting solution was cooled to room temperature to obtain a binder solution. Then was mixed with 90 parts of succinate solifenacin and 360 parts of lactose. Then the mixture was made into powder using a hammer mill (mill sample AR-S using a 1 mm sieve manufactured by Hosokawa Micron). Mixed and converted into a powder product was added 3708 parts of lactose and 1080 parts of corn starch and then loaded into the machine for granulation in the fluidized bed (WSG-5 produced Powlec) for spraying binder solution at a temperature of supplied air 70°C, the degree of atomization of the binder solution of 90 g/min, spraying air pressure of 1.5 kg/cm2and the cycle of spraying/mixing 30 seconds/10 seconds for granulation. After the granules is of the granules were dried at a temperature of supplied air 70°C for 10 minutes to obtain pellets of the present invention. To 129 parts of the dried granular product was added 13 parts of magnesium stearate mixing using a mixer (type DC produced by Yamanouchi). Then the resulting mixture was extruded using a rotary teletrauma machine (HT R-22 manufactured by Hata Tekkosho) c punches with a diameter of 5.5 mm at a pressure of about 500 kgf/punch to obtain tablets with a weight of 60 mg Next 800 parts of the obtained tablets were sprayed and covered with a method shown in example 5 to obtain film-coated tablets of the present invention.

<the Results of preliminary tests of the stability of the preparation of solifenacin, which is obtained by the wet granulation>

It was performed a preliminary test of the stability of succinate tablets of solifenacin, made with binder solution different from the solution used in the granulation (under conditions of 25°C and 60% RH). The results are presented in table 3.

Tablets of comparative example 4, which were obtained using GPMC, could not be sufficiently stable. Even when evaluated other types of binders, starch could improve stability, as shown in comparative example 5. As shown in example 5, the use of PEG could improve stability. It was shown that even under more severe conditions of temperature and VL is gnosti, the terms and conditions of 25°C and 60% RH, the stability of the preparation of solifenacin could be saved.

The results of preliminary tests of the stability of succinate tablets of solifenacin

Storage conditions: 25°C and 60% RH

Packing: Packed in bottles of HDPE with a metal lid

The object of the test: related substances (amount of formed the main decomposition product F1)

Table 3
Example 5Comparative example 4Comparative example 5
Source0,07%0,10%0,07%
After 3 months0,11%0,12%0,17%
After 6 months0,11%0,34%0,35%
After 12 months0,17%--

Industrial applicability

The technical essence of this invented the I is to ascertain the cause decomposition of the active pharmaceutical ingredient in the drug, containing solifenacin or its salt, with the passage of time, which was an amorphous, solifenacin or amorphous salt. By manufacturing this drug when adjusting the content of the amorphous form in it to a preset value or less may be first obtained a stable solid preparation with solifenacin or its salt, which has great advantages for industry. In the preparation containing solifenacin or its salt, optionally contains an inhibitor of the formation of amorphous material, in order to make it possible to obtain a stable pharmaceutical composition for use in solid form, which is a big advantage for the industry.

Thus, this invention is suitable as a method that makes possible to obtain stable compositions of solifenacin or its salts for use in the solid product, which was very desirable to develop a pharmaceutical product for use in pollakiuria and incontinence of urine.

1. The method of obtaining the composition of solifenacin or its salts for use in the solid preparation which comprises at least one phase selected from the group consisting of (i) the stage of wet granulation solvent for solifenacin or its salts, and the number of solifenacin or E. what about the salt, which should be dissolved in 1 ml of solvent is less than 0.1 mg, (ii) a stage of reduction of the quantity or rate of addition of solvent, if the solvent transfers solifenacin or its salt in an amorphous state, and the number of solifenacin or its salt, which should be dissolved in 1 ml of solvent, is 10 mg or more, and (iii) the stage of activation of the process of crystallization of the composition obtained by conventional wet granulation.

2. The method of obtaining the composition of solifenacin or its salts for use in the solid preparation according to claim 1, where the content of the amorphous form is 77% or less.

3. The method of obtaining the composition of solifenacin or its salts for use in the solid preparation according to claim 1 or 2, which includes a step of direct pressing with obtaining a granular composition for use in solid drug.

4. The method of obtaining the composition of solifenacin or its salts for use in the solid preparation according to claim 1 or 2, in which the solvent is an acetone, hexane or a mixture thereof, and the number of solifenacin or its salt, which should be dissolved in 1 ml of solvent is less than 0.1 mg.

5. The method of obtaining the composition of solifenacin or its salts for use in the solid preparation according to claim 1 or 2, in which the solvent is a in the y methanol, ethanol or their mixture, and the number of solifenacin or its salt, which should be dissolved in 1 ml of solvent, is 10 mg or more.

6. The method of obtaining the composition of solifenacin or its salts for use in the solid preparation according to claim 1, in which stage of reducing the amount or rate of addition of solvent is intended to bring the moisture content of the granules in a binder solution to the given value.

7. The method of obtaining the composition of solifenacin or its salts for use in the solid preparation according to claim 6, in which the moisture content in the granules is 9% or less.

8. The method of obtaining the composition of solifenacin or its salts for use in the solid preparation according to claim 1, in which stage (iii) intensification of the process of crystallization represents at least one phase selected from the group consisting of heating and/or humidification, process of microwave irradiation, the process of low-frequency radiation, ultrasonic radiation and the process of thermionic emission of radiation.

9. The method of obtaining the composition of solifenacin or its salts for use in the solid preparation of claim 8, in which the processes of heat and/or moisture are carried out under conditions of 25°C and a relative humidity of 75%.

10. Pharmaceutical composition for use in TV is rdom the drug, where the composition exhibits a selective antagonistic activity against muscarinic M3receptors containing crystalline or amorphous, solifenacin or crystalline or amorphous salt together with an inhibitor of amorphous formation, and inhibitor of amorphous formation is a substance with ethylenoxide chain.

11. The pharmaceutical composition of claim 10, in which the substance with ethylenoxide circuit includes, for example, polyethylene glycol, polyethylene oxide, block copolymers of polyoxyethylene and polyoxypropylene, utverjdenie the polyoxyethylene castor oil or ester of polyethylene glycol and fatty acids.

12. The pharmaceutical composition according to claim 11, in which the substance having ethylenoxide chain is a polyethylene glycol.
Priority items:
Items 1-9 on US 60/556025 and US 60638388;
Paragraphs 10 to 12 of US 60/556025.



 

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7 cl, 160 ex, 45 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel quinuclidine derivatives and their using as pharmaceutical agents. Based on their pharmacological pattern proposed compounds can be useful in treatment of different diseases and disorders associated with cholinergic system of the central nervous system, peripheral nervous system, diseases and disorders associated with contraction of smooth muscle, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain and abstinence syndrome caused by ceasing use of chemical substances.

EFFECT: valuable medicinal properties of compounds.

11 cl, 1 tbl, 46 ex

FIELD: organic chemistry, medicine, chemical technology.

SUBSTANCE: invention describes a method for synthesis of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represented by the formula: . Method involves interaction of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane with hydrobromic acid or its inorganic salt (for example, sodium bromide or potassium bromide) in water in the ionic exchange reaction. 1-Hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represents an immunotropic agent that shows versatile effect on human immune status and elicits antitumor, bacteriostatic and anti-aggregate effects. Invention proposes a method for synthesis of a novel synthetic low-molecular preparation possessing the expressed stimulating effect on the antitumor immunity system that is equal or exceeding by effectiveness effect of the modern domestic and foreign preparation - immunomodulators that represent natural high-molecular biologically active substances prepared by methods of genetic engineering.

EFFECT: improved method of synthesis, valuable medicinal and biological properties of substance.

1 cl, 6 tbl, 21 dwg, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds that represent quaternary ammonium salt of the formula (II): wherein R1 means group chosen from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl; R2 means group chosen from (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, saturated or unsaturated (C3-C7)-cycloalkyl, saturated or unsaturated (C3-C7)-cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl and pyridylmethyl; cyclic groups in R1 and R2 are optionally substituted with one, two or three substitutes chosen from halogen atom, linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy group is unsubstituted or substituted with one or more halogen atoms or hydroxy groups; p means 1 or 2, and carbamate group is joined at positions 2, 3 or 4 of azoniabobicyclic ring system; m means a whole number from 1 to 6; n means 0 or 1; A represents -CH2-, -CH=CH-, -C(O)-, -O-, -S- and -NMe-group; B represents hydrogen atom or group chosen from linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy, cyano, nitro, -CH=CR'R'', -C(O)OR', -OC(O)R', (C3-C7)-cycloalkyl, phenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1.3]dioxolyl, 5-10-membered heteroaryl or heterocyclyl group wherein each R' and R'' represents independently hydrogen atom or linear or branched (C1-C8)-alkyl group, and wherein cyclic groups represented as B are substituted optionally with one, two or three substitutes chosen from halogen atom, hydroxy, linear or branched (C1-C8)-alkyl, -OR', -CONR'R'', -CN, and -COOR'; R' and R'' are given above and wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid, and involving all individual stereoisomers of compound of the formula (II) and their mixtures. Also, invention relates to a method for inhibition, pharmaceutical composition, combined product and their using in therapeutic treatment as antagonists of M3 muscarinic receptors. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 187 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 1-(2S,3S)-2-benzhyryl-N-(5-tert.-butyl-2-methoxybenzyl)quinuclidin-3-amine (further named in the claim as "compound of the formula (I)" ) and its pharmaceutically acceptable salts. Invention relates to an improved method of synthesis of citrate monohydrate salt of compound of the formula (Ia):

EFFECT: improved method of synthesis.

10 cl, 2 sch,

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds selected from 3(R)-(2-hedroxy-2,2-dithiene-2yl acetoxy)-1-(3-phenoxypropyl)-1-azoaniabicyclo[2,2,2]octane,X-, and 1-phenerhyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoaniabicyclo[2,2,2]octane,X-, wherein X- represents pharmaceutically acceptable anion of mono- or polyvalen acid having inhibiting activity in relates to muscarinic M3 receptors. Also disclosed are pharmaceutical compositions containing such compounds and method for treatment of respiratory diseases.

EFFECT: new quinuclidine analogs useful in treatment of respiratory diseases.

20 cl, 1 tbl, 184 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carbamate of the formula (I): or to their pharmaceutically acceptable salts wherein R1 represents compounds of formulas: , , , ,

, , , or ; R3 means hydrogen, halogen atom or alkyl; R2 means benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophene-2-ylmethyl, thiophene-3-ylmethyl or alkyl; p = 1 or 2, and substitution in azabicyclic ring can be at position 2, 3 or 4. Compounds of the formula (I) and their salts possess inhibitory activity with respect to muscarinic M3 receptors and can be used in medicine.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

25 cl, 1 tbl, 165 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to an agent eliciting immunomodulating, antitumor, bacteriostatic and anti-aggregation properties and representing 1-hexadecyl-R-(-)-3-oxy-1-azoniabicyclo[2.2.2]octane bromide and a method for its synthesis. Method involves quartenization of R-(-)-azabicyclo[2.2.2]octane-3-ol with hexadecyl bromide at heating in organic solvent medium. Agent shows low toxicity, high effectiveness, it doesn't cause allergic effect and doesn't possess cumulative effect.

EFFECT: valuable medicinal properties of agent.

3 cl, 9 dwg, 6 tbl, 2 ex

FIELD: pharmacology.

SUBSTANCE: described are C-6 modified indazolyl pyrrolotriaxolines of formula I and their pharmaceutically acceptable salts, where R is selected from group consisting of phenylm phenyl substituted with halogen atom, non-substituted oxazolyl, thienyl, thiazolyl, pyridyl, pyrazinyl; R1 is selected from group consisting of methyl, ethyl and isopropyl; R2 is selected from group consisting of benzyl, imidazolylethyl, (methylimidazolyl)-ethyl, pyperidinylethyl, pyridinylpropyl and other, given in item 1 of invention formula, X is selected from group consisting of bond, O, NR3; and N(R3)2; R3 is independently selected from group consisting of hydrogen, methoxyethyl, diethylaminoethyl, pyrrolidinylethyl. Also described are pharmaceutical composition for treatment of proliferative disease, methods of disease treatment. Compounds of formula I inhibit tyrosine kinase activity of growth factor receptors such as HER1, HER2 and HER4, which makes them useful as anti-cancer agents.

EFFECT: compounds are anti-cancer agents and are useful for treatment of other diseases connected with pathways of signal transduction acting through growth factor receptors.

23 cl, 4 tbl, 175 ex

FIELD: medicine.

SUBSTANCE: wastes of confectionery industry production, milled husk of cacao beans, are drawn in water at temperature 20°C for 2 hours with following extraction by hot water (80-90°C) in battery of four extractors, thickening of extract and drying are carried out.

EFFECT: extension of medication activity spectrum and decrease of power consumption.

8 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to balneology. The mode includes the therapy by means of nitrosiliceous thermal water of Annensky spring from bores №2 and №21 Olcha region of the Khabarovsk Territory. It is ensured by mineral baths by exposition 8-15 minutes at temperature 36C°. The course is 10-12 baths daily, or every second day. The therapy also includes daily mineral water douches for 5-10 minutes. The course is 8-12 procedures. Besides it is combined with mineral water inhalations within 5 to 15 minutes. The course of treatment is 10-15 inhalations. Mineral water drinking is prescribed at 3 ml/kg of body weight with single dose no more than 200 ml, 4 times a day. The course of treatment is 18 days.

EFFECT: method improves the rehabilitation therapy due to reduced bacteriuria severity, inhibited inflammatory processes in urinary tracts and stimulated antioxidant activity.

3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, urology, physiotherapy and to be used in the patients suffering from chronic pyelonephritis accompanied with chronic prostatitis and chronic cystitis. The method involves taking the mineral water of the Slavjanovsky source dosed 3 - 5 ml per kg of body weight, combined with carbonic mineral baths 35-37°C for 15 minutes 3 times a day, № 8-10, mud "panties" at 40-42°C within 30 minutes to 1.5 hours, prostate massage № 8-10, additionally 50-60 minutes later followed with electropulse therapy combined with exposure to laser magnetic rays. Electropulse therapy involves low-frequency, low-voltage pulse current with a spherical unipolar electrode. Exposure is contact, labile, clockwise and located at skin projection of ascending, transverse and descending large intestine at frequency 30.2 Hz within 8-10 minutes. The course of treatment is 10-12 procedures.

EFFECT: method improves life quality of the patients both in latent phase of inflammatory process, and in mild and moderate active chronic process.

2 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention concerns medicine and can be used in pharmaceutical industry. The preparation of uricase of funguses, bacteria, invertebrates or plants clear of the units of uricase exceeding the sizes of octamer. The resulting uricase preparation contains not more than 2% of the specified units from total uricase subunits. At linkage of the given preparation with polyethylene oxide conjugates of an active uricase is obtained. The obtained conjugates of an active uricase are used in a pharmaceutical composition for depression of level of urinary acid in liquids and organism tissues.

EFFECT: invention application allows reducing immunogenic action of uricase, not decreasing its uricolytic action.

29 cl, 14 dwg, 18 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, in particular, nephrology, and concerns treatments of a dysmethabolic nephropathy at children. The way includes introduction of the LAMIFAREN gel in a dose of weight of the child of 3 g/kg a day in 2-3 receptions 30 minutes prior to meal within 30-40 days against the background rehabilitational therapy.

EFFECT: given method allows to increase activity of anti crystal formation, to stimulate antioxidatic protection of the organism.

3 ex

FIELD: medicine.

SUBSTANCE: admixture of 10 ml 0.35% Radachlorine solution in 200 ml of 0.9% isotonic sodium chloride solution is prepareed for treatment of bladder inflammation (cystitis). Then the admixture is entered under the ultrasonic control into a bladder cavity through a catheter in a dose by of 50-200 ml on increasing depending on physiological volume of a bladder and sensation of fullness. Empty the bladder in 30-60 minutes. After that irradiate with a monochromatic light of 650-670 nanometers wavelength and density of energy 200 J/cm2. Influence is carried out in a continuous regimen of radiation incutaneous manner with two fields on pubic and sacral areas. An exposition on each area makes 25-30 minutes. Course of treatment makes 5-15 sessions with 1-2 days interval. As an irradiation source it is possible to use the ELAN complex with a wavelength of radiation of a matrix of 650-670 nanometers, density of power of working radiation of a matrix in a focal plane 30-60 mW/cm2 and the area of maculae irradiation in a focal plane of 40 cm2.

EFFECT: reduction of terms of treatment, prevention of allergic reactions and resistance of a microflora to antibiotics and medicinal preparations, the prevention of development of dysplastic and cicatrical changes in a bladder mucous.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention concerns area of medicine and concerns treatments with application of botulinic toxin. The essence of the invention includes application of a solid, semisolid or liquid composition of botulinic toxin for treatment of the disturbance characterised by spastic strictures of a bladder by means of distribution of a composition of toxin on an external wall of a cylinder which is intended for inflation in a bladder, thus, a cylinder enter into a bladder cavity through the urethra so that the cylinder could be filled by air in a bladder.

EFFECT: advantage of the invention consists to use of a liquid or semisolid composition of botulinic toxin for local treatment of urethra diseases.

5 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula (I), in which X1 is phenyl, 9-member bicyclic heteroaryl, containing S or O as heteroatoms, or 5-member heteroaryl, containing S or O as heteroatoms, each of which is optionally substituted with one or more substitutes, chosen from halogen or C1-6alkyl, which is optionally substituted with one or more halogens. X2 is phenyl, which is optionally substituted with one or more substitutes, chosen from halogen, or 5-member heteroaryl, containing S or O as heteroatoms. Ar is phenylene, which is optionally substituted with one or more substitutes, chosen from halogen, or C1-6alkyl, phenyl, C1-6alkoxy, each of which is optionally substituted with one or more halogens. Y1 is O or S, and Y2 represents O, Z represents -(CH2)n-, where n equals 1, 2 or 3. R1 is hydrogen or C1-6alkoxy and R2 is hydrogen, C1-6alkyl. The invention also relates to pharmaceutical salts of these compounds or any of their tautomeric forms, stereoisomers, stereoisomer mixtures, including racemic mixtures.

EFFECT: invention also pertains to use of these compounds as pharmaceutical compositions, with effect on receptors, activated by the peroxisome proliferator PPARδ subtype, and to pharmaceutical compositions, containing these compounds (I).

36 cl, 41 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine drugs, particularly combination for pain mitigation, including synergic dosage of (S,S)-reboxetine or its pharmaceutically acceptable salt or solvate and 5 type phosphodiesterase inhibitor (PDEV), 3-ethyl-5-[5-(4-ethylpiperasine-1-ylsulfonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrasolo[4,3-d]pyrimidine-7-on. In addition, invention concerns composition and kit for pain mitigation, including the claimed compounds, and application of the combination or composition in pain mitigation.

EFFECT: synergic effect of composition.

12 cl, 1 dwg, 1 ex

Organic compounds // 2358716

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutics and concerns a solid pharmaceutical composition applicable for oral introduction and containing: (a) S1P receptor agonist; and (b) sugar alcohol.

EFFECT: invention provides homogeneous distribution of an active component in the solid composition with its high stability.

18 cl, 2 tbl, 39 ex

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