KR101977890B1 - Stable pharmaceutical composition comprising solifenacin, and method for preparing the same - Google Patents

Abstract

The present invention relates to a solifenacin preparation comprising solifenacin or a pharmaceutically acceptable salt thereof, an antioxidant and a binder, and relates to a solifenacin preparation prepared by a direct tablet method. Compared to the conventional wet granulation method, the present invention provides a solifenacin preparation that can simplify the manufacturing process and can significantly improve problems such as uniformity of content and blending even after high-speed tableting by a direct tableting method .

Description

[0001] The present invention relates to a stable pharmaceutical composition comprising solifenacin and a method for preparing the same,

The present invention relates to a stable formulation comprising solifenacin and a process for its preparation.

Solifenacin has been reported to have excellent selective antagonism to the muscarinic M3 receptor, a compound represented by the following formula (1).

[Chemical Formula 1]

On the other hand, the above-mentioned solifenacin or its pharmaceutically acceptable salt has a problem that the drug is decomposed with time due to various factors involved in the preparation of the finished product, even if it is stable in the raw material state. Typically, it has been reported that amorphous solifenacin succinic acid produced during the production of wet granules is easily oxidized in a short period of time, and in particular, the main decomposition product (oxidized form of solifenacin succinate) is the main cause of decomposition of the main drug. That is, depending on various process conditions such as reaction temperature, pH, reaction time, and mixing sequence in the process, and the like, interaction occurs upon contact with the main component depending on the characteristics of excipients, binders, It is not possible to derive a desirable prescription or process.

In addition, the manufacturing process is difficult because of the strong cohesiveness of the solifenacin or its pharmaceutically acceptable salt. Korean Unexamined Patent Publication No. 10-2007-0010132 discloses that solifenacin or a pharmaceutically acceptable salt thereof is difficult to secure uniformity of contents in a direct tableting method, and is also attached to a punch in tableting, It is difficult to prepare a preparation containing solifenacin or a pharmaceutically acceptable salt thereof, it is described that a wet granulation method is preferable.

Commercial preparations such as Vesicare® containing a solifenacin succinate salt are prepared by wet granulation. Various methods for enhancing the stability of a preparation prepared by the wet granulation method have been proposed. For example, Korean Patent Laid-Open No. 10-2007-0010132 discloses a method for inhibiting the decomposition of a drug with time in a formulation containing a solifenacin succinate salt prepared by a wet granulation method, Or by controlling the amount of water contained in the preparation during the manufacturing process, and after heating the composition by heating and / or humidifying treatment, it is possible to suppress the amorphous content. In addition, the above patent discloses a method for producing an agent that inhibits amorphization of solifenacin by using polyethylene glycol (PEG) or the like as a binding agent in the preparation of a preparation containing solifenacin or a salt thereof, thereby inhibiting the degradation of solifenacin over time .

Korean Patent Laid-Open No. 10-2007-0098889 discloses that stability of the main component can be secured by using a binder having a Tg of 174 ° C or lower in the preparation of a particulate composition of solifenacin or a pharmaceutically acceptable salt thereof have.

As described above, the solifenacin or its pharmaceutically acceptable salt has high cohesiveness and high instability of the raw material and high cohesiveness, so that it is very difficult to select a suitable production method. However, since the water content of the granules during the wet granulation process is affected by various process conditions such as the reaction time and mixing order, it is possible to control the moisture content of the granules by controlling the moisture content of the amorphous material To a certain level is likely to be less effective in improving the stability of pharmaceuticals when applied to large-scale processes.

Further, in the case of formulation through the wet granulation method, the main component tends to be decomposed with time due to interaction with water or an organic solvent such as alcohol used in the manufacturing process, heating for removing these solvents, and the like.

In addition, methods for inhibiting the time-dependent decomposition of solifenacin by selecting and using specific binders in the wet granulation method still have limitations in stability by the wet method. Particularly, among the proposed binders, polyethylene oxide is a strong oxidizing agent (4th), and when lactose or mannitol is blended with polyethylene oxide, the elution behavior of the drug (See Korean Patent Publication No. 10-2012-0093500), which was published by DOW at the 2008 CRS Society. Therefore, the combination of polyethylene oxide is not preferable in that it restricts the selectivity of the excipient mainly used.

There is still a high demand for the development of agents that are more easily process controlled in a commercial production environment, but can inhibit the time degradation of solifenacin or its salts.

The present invention is intended to provide a formulation that is more easily process controlled in a commercial production environment and is capable of inhibiting the time degradation of solifenacin or a pharmaceutically acceptable salt thereof. In addition, the present invention is intended to provide a composition and a preparation method of a preparation which can be prepared by a direct tableting method other than a wet granulation method.

In order to solve the above problems, the present invention provides a solifenacin preparation comprising solifenacin or a pharmaceutically acceptable salt thereof, an antioxidant and a binder.

The term " solifenacin " used in the present invention is a chemical name (1R, 3'R) -3'-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro- - < / RTI > isoquinolinecarboxylate.

[Chemical Formula 1]

Solifenacin has excellent selective antagonism to muscarinic M3 receptors and has been shown to be effective in the treatment of urinary or chronic obstructive pulmonary disease such as neurogenic urinary frequency, neurogenic bladder, nocturnal encephalopathy, unstable bladder, bladder or chronic cystitis, chronic bronchitis, asthma or rhinitis As a prophylactic and therapeutic agent for respiratory diseases.

The term "pharmaceutically acceptable salt" used in the present invention refers to salts of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, Means an acid addition salt with an organic acid such as fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or glutamic acid or a quaternary ammonium salt. Of these, succinic acid salts of solifenacin are preferable for providing them as medicines, and they are particularly preferable because they can remarkably attain the stabilizing effect according to the present invention.

The present invention relates to a preparation of solifenacin, and more particularly, to a preparation capable of inhibiting the time-dependent decomposition of solifenacin, while facilitating process control in a commercial production environment. Since solifenacin is highly cohesive, conventional wet granulation methods have been used to ensure uniformity of content, but solifenacin is sensitive to moisture, and thus can not fundamentally solve the decomposition of solifenacin in the wet granulation method. In the present invention, by including an antioxidant and a binder as constituents of the preparation, uniformity of content can be ensured even in a direct tableting method other than the wet granulation method, and the decomposition of water-sensitive solifenacin can be fundamentally solved.

The term " antioxidant " used in the present invention means a substance inhibiting the decomposition of solifenazine in the preparation, and especially butylhydroxytoluene or butylhydroxyanisole may be used. The antioxidant is preferably contained in an amount of 0.01 to 0.04 parts by weight based on 1 part by weight of the solifenacin or a pharmaceutically acceptable salt thereof. When the amount is less than 0.01 weight, the amount of the main decomposition product of solipenacin (hereinafter referred to as F1) relative to the total amount of degraded active ingredient can not be kept at 0.5% or less, and toxic burden may be given to the human body when it is used in excess of 0.04 weight.

According to one embodiment of the present invention (Examples 1 to 7), it was confirmed that when antioxidants for maintaining the stability of solifenacin were included in the direct tablet method, the solifenacin degradation products were remarkably reduced.

The term " binder " as used herein refers to a substance that imparts a binding force in a preparation of solifenacin, and includes, in particular, hydroxypropylcellulose, gum, hydroxpropylmethylcellulose, polyvinylpyrrolidone, Cellulose, starch, lactose and its hydrate, microcrystalline cellulose and ethylcellulose. Particularly preferably, low-substituted hydroxypropylcellulose can be used. The low-substituted hydroxypropylcellulose (L-HPC) used in the present invention refers to hydroxypropylcellulose having a low-level structure composed of 5 to 16% of hydroxypropoxy group. Due to the water-insoluble properties of the low-substituted hydroxypropylcellulose, there is swelling in contact with the aqueous solution, which not only provides a bonding force in the direct tableting method, but also causes an indirect disintegration Can be expected. In addition, since the particle size is different according to the substitution level, it is possible to select the desired particle size in the direct tableting method and to provide a binding force.

The binding agent is preferably contained in an amount of 0.4 to 10 parts by weight based on 1 part by weight of the solifenacin or a pharmaceutically acceptable salt thereof. If the weight is less than 0.4 wt.%, The binding force of the preparation decreases during tableting, so that compression molding can not be performed or the hardness of the product is low. In addition, when the binder is used in an amount exceeding 20 parts by weight, the drug release pattern in vivo does not satisfy the bioequivalence with commercially available tablets, so that practicality as a solifenacin-containing tablet may be impaired. It is preferable that the binder is included in an amount of 25 to 300 parts by weight based on 1 part by weight of the antioxidant. More preferably, the binder is contained in an amount of 50 to 200 parts by weight based on 1 part by weight of the antioxidant. When the content ratio of the binder and the antioxidant is out of the above range, the stability of the solifenacin can not be guaranteed, or the problem caused by the direct tableting method, such as the uniformity of the content, can not be solved.

As described above, the antioxidant and binding agent are included as a component of the preparation of solifenacin, thereby suppressing the generation of a flexible substance and preparing the preparation by a direct tableting method. Also, a dissolution pattern of solipenacin equivalent to that of a commercial formulation can be obtained Do.

According to one embodiment of the present invention (Examples 8 to 11), it was confirmed that the mass deviation is significantly reduced even when a solifenacin preparation containing an antioxidant and a binder is prepared by a direct tableting method. In addition, according to one embodiment of the present invention (Example 12), a solifenacin preparation containing an antioxidant and a binder exhibited a content uniformity corresponding to that of a preparation prepared by a wet granulation method. From this, it can be confirmed that the problem of the conventional solifenacin preparation, which was produced by the wet granulation method, can be solved by including the antioxidant and the binder as a component of the solifenacin preparation.

In addition, the solipenacin preparation may further include a pharmaceutically acceptable disintegrant, a lubricant or a coating agent to the extent that the effects of the present invention are not impaired. As the coating agent, a film layer may be formed on the outer surface of the solifenacin preparation, for example, a light shielding film layer, a moisture-proofing film layer, or a sugar film layer. Preferably, the outer film layer is formed of a water-soluble material. The water-soluble film layer-forming material may be at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, ethylcellulose, methylcellulose, Polyvinyl alcohol (Opadry® (Colorcon, USA), and mixtures thereof, may be used, but are not limited thereto.

Also, taking into consideration the daily dosage of solifenacin or a pharmaceutically acceptable salt thereof, the soliphenacin preparation may contain 0.01 mg to 100 mg, preferably 0.5 mg to 100 mg, of solifenacin or a pharmaceutically acceptable salt thereof, 50 mg, more preferably 0.5 mg to 20 mg, most preferably 0.5 mg to 10 mg.

The present invention also provides a process for preparing a solifenacin preparation comprising the steps of:

Mixing step (1) of solifenacin or a pharmaceutically acceptable salt thereof, an antioxidant and a binder; And

(Step 2).

Generally, when a preparation having a small ratio of main components is directly prepared by a tabletting method, there is a high possibility that a problem of weight variation and uniformity in tablets is likely to occur. Especially, in the case of a main component weak in stability such as solifenacin, It is not easy to find an optimal formulation method suited to the nature of the main ingredient, solifenacin.

In the present invention, by including the antioxidant and the binder, even if the direct tabletting method is adopted, the revision of the examination standard of the standard and test method examination reference of the medicine etc. (2007.7.2 2007-02) and the Korean Pharmacopoeia (10th revision) And at the same time, it provides a stable composition in which the degradation products and the content of the drug are not reduced. The preparation of the preparation by the direct tableting method according to the present invention is advantageous for mass production because the production process is simpler than the preparation of the preparation by the wet granulation method. Accordingly, the method for producing a solifenacin preparation is characterized in that it does not contain a solvent.

In the present invention, the pulverizer used in the manufacturing process for constituting the composition of the stable medicine including solifenacin or its salt is, for example, a hammer mill, a ball mill, a jet mill, a colloid mill, an electric mesh, an oscillator, However, the apparatus and the means are not particularly limited as long as they are capable of pharmaceutical crushing in general.

Examples of a mixing apparatus for continuously mixing the components include a V-type mixer, a ribbon-type mixer, a container mixer, a high-speed stirring mixer, and the like. The device and the means are not particularly limited.

As the tableting apparatus, for example, a rotary tabletting machine, a single-shot tableting machine and the like can be mentioned. However, the apparatus and the means are not particularly limited as long as they are usually produced by pharmaceutical compression molding (preferably tablet).

According to the present invention, a solifenacin preparation containing solifenacin or a pharmaceutically acceptable salt thereof can be rapidly prepared through a simplified manufacturing process of a direct tableting method, and the stability of the solifenacin preparation is also excellent. In addition, although the coagulation power of the main component is high and the specific gravity of the main component is small and the antioxidant and the binder are used in spite of being manufactured by the direct tableting method, the uniformity of the preparation phase is excellent and there is no problem of weight deviation.

Figs. 1A and 1B show the dissolution test results of Examples 8 to 11 and Example 12 and Comparative Example 3 according to the present invention in comparison with the dissolution test results of the control drug (Bicycare® tablet).
2 shows the dissolution test result of Example 13 according to the present invention in comparison with the dissolution test result of the control drug (Betica 占 10 mg).

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are provided for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example  One

For the preparation of the tablets, 16.65 g of solifenacin succinate, 0.5 g of butylhydroxytoluene and 100.0 g of lactose were blended and blended in a 30 mesh sieve. Subsequently, 50.0 g of microcrystalline cellulose and 325.35 g of lactose hydrate were mixed and then sieved in a 30-mesh sieve (mixed solution-2).

The diphasic mixture 1 and 2 were mixed in a 1 Kg mixer (erweka AR 402 / cubemixer) at 200 rpm for 15 minutes, and then the mixture was mixed with 7.5 g of magnesium stearate sieved in a 30 mesh sieve to obtain a single-ply tablet machine (erweka AR 401) And tableted with a circular tablet. The content of each component in the obtained tablets was as shown in Table 1 below.

Purpose of blending The composition (grade) Weight in one tablet% Excipient Lactose 20.00 chief ingredient Solifenacin succinate 3.33 Disintegration Microcrystalline cellulose 10.00 Excipient Lactose baggage 65.07 Antioxidant Butylhydroxytoluene 0.10 Lubricant Magnesium stearate 1.50 Gross weight (%) 100.00

Example  2 to 7, and Comparative Example  One

Examples 2 to 7 and Comparative Example 1 were prepared in order to evaluate the degree of occurrence of a flexible substance or an impurity or an unknown substance upon addition of an antioxidant in the composition.

For the preparation of Examples 2 to 7 and Comparative Example 1, 16.65 g of solifenacin succinate, 0.2 g of butylhydroxytoluene (0.25-0.5 g according to Examples 2 to 7), 100.0 g of lactose hydrate and 50.0 g of microcrystalline cellulose After blending, the mixture was sieved through a 30-mesh sieve (Baejang Mix-1). Subsequently, 100.0 g of microcrystalline cellulose and lactose hydrate (212.35 to 212.85 g according to Examples 2 to 7 and Comparative Example 1) were mixed and sieved in a 30-mesh sieve (Batch Mixing-2).

The diphtheriae mixture 1 and 2 were mixed in a 1 Kg mixer (erweka AR 402 / cubemixer) at 200 rpm for 15 minutes, then 7.5 g of magnesium stearate sieved with a 30 mesh sieve was mixed by actinic blending, And then tableted with a circular tablet. The finished tumbler was coated with Opadry (yellow, opadry 03B52293). The content of each component in the obtained tablets was as shown in Table 2 below.

Composition Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Comparative Example 1 Lactose 20.00 20.00 20.00 20.00 20.00 20.00 20.00 Solifenacin succinate 3.33 3.33 3.33 3.33 3.33 3.33 3.33 Microcrystalline cellulose (entire mixture) 10.00 10.00 10.00 10.00 10.00 10.00 10.00 Microcrystalline cellulose (post mixture) 20.00 20.00 20.00 20.00 20.00 20.00 20.00 Lactose baggage 42.47 42.52 42.56 42.47 42.52 42.56 42.57 Butylhydroxytoluene 0.10 0.05 0.01 - - - - Butylhydroxyanisole - - - 0.10 0.05 0.01 - Magnesium stearate 1.50 1.50 1.50 1.50 1.50 1.50 1.50 Opa Dry Yellow 2.60 2.60 2.60 2.60 2.60 2.60 2.60 Total weight% 100 100 100 100 100 100 100

Example  8 to 12, and Comparative Example  2 and 3

Tablets having the compositions of Examples 8 to 11 and Comparative Example 2 were prepared in order to evaluate the content uniformity and the dissolution pattern of the preparation according to the present invention.

16.65 g of the solifenacin succinate salt, 0.5 g of butylhydroxytoluene and 95.0 g of isomalt were blended and mixed with a low-substituted hydroxy cellulose (0.0 to 150.0 g according to the compositions of Examples 8 to 11 and Comparative Example 2) After that, the mixture was sieved with 30 mesh sieve (Baejang Mix-1).

10.0 g of hydrophobic colloidal silicon dioxide and lactose hydrate (207.35 to 357.35 g according to Examples 8 to 11 and Comparative Example 2) were continuously mixed and then sieved in a 30-mesh sieve (mixed solution-2).

The diphtheriae mixture 1 and 2 were mixed in a 1 Kg mixer (erweka AR 402 / cubemixer) at 200 rpm for 15 minutes, then 7.5 g of magnesium stearate sieved with a 30 mesh sieve was mixed by actinic blending, And then tableted with a circular tablet. The finished tumbler was coated with Opadry (yellow, opadry 03B52293). The content of each component in the obtained tablets was as shown in Table 3 below.

Composition Example 8 Example 9 Example 10 Example 11 Comparative Example 2 Solifenacin succinate 3.33 3.33 3.33 3.33 3.33 Butylhydroxytoluene 0.10 0.10 0.10 0.10 0.10 Hydrophobic colloidal silicon dioxide 2.00 2.00 2.00 2.00 2.00 Low-substituted hydroxypropylcellulose 5.00 10.00 20.00 30.00 0.00 Isomalt 19.00 19.00 19.00 19.00 19.00 Lactose baggage 66.47 61.47 51.47 41.47 71.47 Magnesium stearate 1.50 1.50 1.50 1.50 1.50 Opa Dry Yellow 2.60 2.60 2.60 2.60 2.60 Gross weight (%) 100 100 100 100 100

In order to prepare tablets according to Example 12 and Comparative Example 3, 16.65 g of solifenacin succinate, 0.5 g of butylhydroxytoluene, and 0.5 g of low-substituted hydroxy cellulose (0.0 to 15.0 according to Example 12 and Comparative Example 3 g), lactose hydrate (18.35 to 33.35 g according to Example 12 and Comparative Example 3) and 33.35 g of isomalt were mixed and mixed in a 30-mesh sieve.

After continuously mixing 5.0 g of hydrophobic colloidal silicon dioxide and 388.15 g of lactose, the mixture was sieved through a 30 mesh sieve.

The diphtheria mixture 1 and 2 were mixed in a 1 kg mixer (erweka AR 402 / cubemixer) at 200 rpm for 15 minutes, and then the mixture was reactively mixed with 10.0 g of sodium stearyl fumaric acid applicated in a 30-mesh sieve, ). ≪ / RTI > The finished tumbler was coated with Opadry (yellow, opadry 03B52293). The content of each component in the obtained tablets was as shown in Table 4 below.

Composition Example 12 Comparative Example 3 Lactose baggage 3.67 6.67 Hydrophobic colloidal silicon dioxide 1.0 1.0 Solifenacin succinate 3.33 3.33 Low-substituted hydroxypropylcellulose 3.00 - Butylhydroxytoluene 0.10 0.10 Isomalt 6.67 6.67 Lactose 77.63 77.63 Sodium stearyl fumarate 2.0 2.0 Opa Dry Yellow 2.60 2.60 Gross weight (%) 100 100

Example  13

Example 13 was prepared in order to evaluate the dissolution of a preparation containing a solifenacin succinate salt having a different composition ratio of solifenacin succinate. The preparation process was the same as that of Example 12, and the content of each component in the obtained tablets was as shown in Table 5 below.

Composition Example 13 Solifenacin succinate 6.49 Butylhydroxytoluene 0.10 Hydrophobic colloidal silicon dioxide 2.92 Low-substituted hydroxypropylcellulose 2.92 Isomalt 19.48 Lactose baggage 64.03 Magnesium stearate 1.46 Opa dry pink 2.60 Gross weight (%) 100

Experimental Example  1: Evaluation of stability according to composition of formulation

(Example 8) prepared in Examples 1 to 7 and binder were packaged in PVC, PVDC, and HDPE containers commonly used in the industry, and then subjected to a severe stability condition (60 DEG C / Relative humidity 80%) and analyzed for initial and 1 week storage, 2 week storage, and 4 week flexible material changes. The stability test was carried out for the control drug under the same conditions using a commercially available Bicycare® 5 mg coated tablet as a control.

In this embodiment, the raw material standard derived from the solifenacin succinate was applied, and the criteria and items were as shown in Table 6 below.

Based on flexible substances standard YM-64250
(+) - (1S, 3'R) -1'-oxidoquinuclidin-3'-yl1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate) Less than 1.1% YM 217880
(+) - (R) -quinuclidin-3-yl [2- (2-benzoylphenyl) ethyl] carbamate 0.5% or less Unknown flexible substance 0.2% or less Sum of flexible materials 2.0% or less

The supernatant was analyzed by high performance liquid chromatography (Agilent). HPLC analysis conditions were as follows.

Detector: Ultraviolet absorptiometer (measuring wavelength: 215 nm)

Column: XBridge 占 C18, 150 占 4.6 mm, 5.0 占 퐉 or equivalent column

Flow rate: 1.0 mL / min

Column temperature: constant temperature around 35 캜

Injection volume: 20 μL

Measurement range: 1) After the test solution is injected, 40 minutes 2) After the standard solution is injected, 20 minutes

Mobile phase: buffer solution ^* / methanol = 35/65

Diluent: mobile phase

* Buffer: 3.4 g of potassium dihydrogenphosphate is dissolved in 1000 mL of water, 1.0 mL of trifluoroacetic acid is added, and the pH is adjusted to 7.5 with triethylamine. The solution is filtered through a 0.45 μm filter and degassed.

The results of evaluating the stability are shown in Table 7 below.

In the case of Example 1, the core tablet was used. However, the contents and the flexible materials all met the standard and were stable regardless of the packaging substrate up to the 4 weeks of the severe case. However, in the case of the control product, the YM-64250 soft material was inadequate for PVC packaging (1 to 4 weeks of harsh) and HDPE (4 weeks), YM-217880 for flexible packaging materials, PVC packaging (1 to 4 weeks), HDPE 2,4 weeks) and PVDC (4 weeks).

In the case of Example 2, the flexible material YM-64250 was detected in the HDPE container until 2 weeks and 4 weeks, but it was lower than that of the commercial formulation and showed appropriate results in the standard.

Overall, it was confirmed that the stability of the antioxidant butylhydroxytoluene and butylhydroxyanisole diisoprenesin succinate used in Examples 1 to 7 was improved. Also, in Example 8 in which an antioxidant and a binder were added, it was confirmed that the level of the flexible substance was appropriate to the standard.

However, in Comparative Example 1 in which no antioxidant was added and in the case of the control drug, a very high level of a substance or an impurity or an unknown substance of the solifenacin succinate was produced irrespective of the packaging material. Therefore, it was confirmed that the preparation of the solifenacin succinate salt in the formulation containing the solifenacin succinate salt according to the present invention was not only effectively inhibited but also had a superior stability to the control drug.

Experimental Example  2: Evaluation of dissolution rate according to formulation

The dissolution rate of the formulation containing the solifenacin succinate salt according to the present invention was compared with that of the control drug (Vesicare® 5 mg). The conditions applied to the dissolution evaluation are as follows.

Sample elution and sample preparation: Agilent technologies.

Elution Model: 708-DS. Dissolution apparatus

Specimen sampling Model name: Dissolution sampling station

Sampling method: Automated sample collection by time (auto sampling)

Elution method: Korean Pharmacopoeia 10 revision, 2nd method (paddle speed: 50 rpm)

Time taken to take the test solution: 5, 10, 15, 30 (and 45 minutes)

Number of samples: 4 tablets

Elution media: Purified water and pH 6.8 phosphate buffer

Elution medium temperature: 37.5 ° C ± 0.5

Detector: Ultraviolet absorptiometer (measuring wavelength: 210 nm).

Column: Develosil ODS-UG-5 (150 mm x 4.6 mm ID, Nomura Chemical Co., Ltd.) or equivalent column.

Column temperature: 40 DEG C

Mobile phase: 0.05 mol / L potassium phosphate buffer (pH 6.0) / acetonitrile mixture (65:35)

Flow rate: 1.0 mL per minute (Adjust the solifenacin retention time to 7-11 minutes.)

Test time: about 12 minutes

As a result, the dissolution rate of each preparation in pH 6.8 phosphate buffer was as shown in Table 8 below.

Elution time (min) Example 8 Example 9 Example 10 Example 11 Comparative Example 2 Treaty 5 22.5 ± 5.4 18.4 ± 4.7 15.9 ± 2.4 12.1 ± 6.2 29.8 ± 1.4 26.3 ± 4.0 10 43.8 ± 2.8 39.9 ± 2.3 37.5 ± 2.2 30.4 ± 2.9 56.7 ± 9.8 50.9 ± 5.8 15 64.5 ± 2.1 60.7 ± 2.2 58.5 ± 1.2 49.7 ± 3.8 83.6 ± 8.7 69.6 ± 8.1 30 84.1 ± 1.6 81.1 ± 1.6 77.6 ± 0.8 68.6 ± 4.4 93.8 ± 5.1 89.6 ± 2.5 45 89.4 ± 1.1 87.3 ± 1.5 84.7 ± 1.1 82.8 ± 3.1 107.5 ± 5.0 93.7 ± 2.4

From the results of Examples 8 to 11, the dissolution rate was decreased as the amount of binder used increased. In Example 11, since the dissolution rate at the time point of 30 minutes is less than 80% of the commercial drug, the release profile is inadequate in terms of bioequivalence to be used as a solifenacin-containing preparation requiring rapid release due to drug characteristics When the average dissolution rate of a commercial product reaches 85% between 15 and 30 minutes in accordance with Notification No. 2013-201 of the Pharmaceutical Safety Authority's Equivalence Test Standard, comparison is made at two points where the average dissolution rate of the commercial product is around 60 and 85% It can be judged to be equivalent when the average dissolution rate of the target drug is within ± 15%). In addition, it is also inappropriate in that the deviation of the average dissolution rate is large.

In the case where no binding agent was added at all (Comparative Example 2), the deviation of the average dissolution rate becomes large, and stable in vivo release of the preparation is difficult to expect.

Experimental Example  3: Evaluation of dissolution pattern according to the composition of the preparation

The release patterns of purified tablets prepared by direct tableting method according to Examples 8 to 11 and Comparative Example 2 were observed and compared with the release pattern of the control drug, and the results are shown in FIG. The conditions for evaluating the elution were as shown in Experimental Example 2.

In the case of Examples 8 to 10, the release profile was within the range of 54.8 to 84.8% at the time of 15 minutes to be judged as a commercial product and 74.9 to 104.9% at the time of 30 minutes judgment (Food and Drug Safety Authority Equivalence Test When the average dissolution rate of a commercial product reached 85% between 15 and 30 minutes according to the standard notification 2013-201, the average dissolution rate of the comparative drug at the two points of time when the average dissolution rate of the commercial product was around 60 and 85% If it is within ± 15%, it can be judged to be equivalent).

However, Example 11 was equivalent to 55.9% at 15 minutes but 72.2% at 30 minutes, which is lower than the equivalence range of 15%. Therefore, in terms of bioequivalence, this composition is not suitable for use as a solifenacin-containing preparation.

The elution patterns of Example 12 and Comparative Example 3 were evaluated in comparison with the reference drug, and the results are shown in FIG. The conditions for evaluating the elution were as shown in Experimental Example 2.

As a result of evaluation, Example 12 showed an emission profile equivalent to that of the comparator. However, the dissolution rate of Comparative Example 3 was out of the acceptable range as compared to the control drug.

The elution pattern of the composition containing 10 mg of Solifenacin (Example 13) was evaluated in comparison with the control drug, and the release profile was equivalent to that of the control drug (FIG. 2). The conditions for evaluating the elution were as shown in Experimental Example 2.

As a result of the evaluation, it was confirmed that the dissolution pattern of the product containing 10 mg of solifenacin according to the present invention was comparable to that of the control drug.

Experimental Example  4: Content uniformity and Disintegration  evaluation

The mass deviations and the haze were compared and evaluated between various composition examples, and the results are shown in Table 9 below. Examples 8 to 11 and Comparative Example 2 were all made to have the same hardness.

Evaluation items Example 8 Example 9 Example 10 Example 11 Comparative Example 2 Hardness (KP) 7 ± 1 7 ± 1 7 ± 1 8 ± 3 7 ± 4 Mass deviation (%) 0.59 0.59 1.02 3.34 7.03 Disintegration (min) 4 ± 1 4 ± 1.5 6 ± 1 12 ± 2.5 5 ± 3.8 Disintegration time (min) in pH 6.8 medium 9 ± 1 10 ± 2 11 ± 3 21 ± 4 12 ± 7

In Example 11 in which the binder was added in an amount of 30% or more, the tablet deviations were larger than those in the other examples, and the mass deviations were larger than those of the other examples. Even in the case of Comparative Example 2 in which no binding agent was added at all, the variation with respect to the individual weight at the time of tableting was as large as about 7% in average weight.

The disintegration time of the formulation was evaluated in the disintegration and pH 6.8 phosphate buffer medium. As a result, it was confirmed that a considerable time was required for elution in Example 11. This is inadequate as a release pattern when considering that the main ingredient, solifenacin succinate, should be released for immediate effect.

Table 10 below shows the results of comparative evaluation of the uniformity of the content of solifenacin succinic acid salt contained in one tablet against the commercially available control drug (Betica tablets) for Example 12 and Comparative Example 3. [ For the uniformity of contents, the test was conducted according to the content uniformity test method in preparation uniformity test of KP 10 (General Test Methods).

1) Diluent: water / acetonitrile mixture = 7/3

2) Preparation of test solution: Put about 1 tablet into a 20-mL volumetric flask and fill it with 80% of the diluted solution. Shake the sample occasionally until it disintegrates, then cool it at room temperature. Dilute to make 20 mL, and filter through a PVDF 0.45um membrane filter to give the sample solution.

3) Preparation of standard solution: Take 50 mg of standard product of solifenacin succinate accurately in a 100-mL volumetric flask and use the diluted solution as the standard solution.

4) Operation and calculation: Perform 10 μL each of the test solution and standard solution according to the liquid chromatography method under the same operating conditions as in the content test, and calculate the amount of solifenacin succinate using the following formula.

5) Calculation formula

A _T : Peak area of the solifenacin succinate in the chromatogram of the sample solution

A _S : Peak area of the solifenacin succinate in the chromatogram of the standard solution

W _S : Standard amount of solifenacin succinate salt taken (mg)

C: Quantity of solifenacin succinate in one tablet (mg)

P: Purity (%) of standard product of the solifenacin succinate

D: Dilution factor (5)

Number of tests Example 12 Comparative Example 3 Treaty Test-1 98.80 101.26 100.50 Test-2 100.4 101.17 101.74 Exam-3 100.8 95.95 98.63 Test-4 100.6 99.42 100.90 Exam -5 101.9 98.10 99.66 Test -6 103.9 97.24 97.52 Test-7 104.1 95.31 100.24 Test-8 100.1 96.46 99.69 Exam-9 100.8 95.68 100.01 Test-10 100.0 96.46 101.68 Average 101.1 97.71 100.06 Standard Deviation 1.70 2.21 1.30

As a result of the content uniformity test, the uniformity of the preparation of Example 12 prepared by the direct tableting method with the aid of the binder and the result of the content for the individual tablets were at the same level as that of the comparator, and compared with the composition without the binder (Comparative Example 3) (Recommendation criteria for the content range of solifenacin succinate in the commercial product range is 93.0 ~ 105.0%).

From the above results, it can be seen that when the direct tableting method is simply applied, the tablet is not sufficiently filled in the die, or there is a large amount of mass deviation due to the layering or polarization phenomenon in the mixed granules, , Capping, and the like.

However, when the composition of the present invention is applied, it can be confirmed that a formulation can be prepared which can be expected to release in vivo at the same level as the reference drug without causing any problems such as a tableting disorder and a mass deviation even by a direct tableting method of the solifenacin succinate have.

In order to evaluate whether the content of the main component was affected by the high-speed tablet machine, the composition of Example 12 was prepared by high-speed tableting and then the content of solifenacin succinate was measured according to the tableting time. The high-speed tablet machine was a piccolo rotary tablet press (manufactured by RIVA) using an eight-punch tableting machine and rotated at 25 rpm at a rate of 25 rpm to randomly obtain a sample to be tableted at the measurement time, The content test was carried out. The time for obtaining the tablets was as early as 5, 10, 15, 30, 45 and 60 minutes and then terminated. The experimental results are shown in Table 11 below. In the case of the high-speed tabletting method, there was no change in the content as in the case of the single-screw tableting machine.

Time to obtain testicular sample Test-1 Test-2 Exam-3 Average Standard Deviation Early 100.6 100.7 99.7 100.3 0.5 After 5 minutes of high-speed puncture 100.3 101.0 99.8 100.4 0.6 After 10 minutes of high-speed punching 101.6 99.9 97.5 99.7 2.1 15 minutes after high-speed tableting 98.2 99.2 100.7 99.4 1.3 Fast 30 minutes after tableting 99.4 100.3 97.9 99.2 1.2 45 minutes after high-speed punch 102.7 104.0 101.3 103.3 0.9 60 minutes of high-speed punctuation (end) 102.2 97.5 98.3 99.3 2.5

Claims (9)

A solifenacin tablet comprising solifenacin or a pharmaceutically acceptable salt thereof, an antioxidant and a binder and being prepared by a direct tableting method without a granulation process,
Wherein said antioxidant is butylhydroxytoluene or butylhydroxyanisole,
The binder is a low-substituted hydroxypropyl cellulose,
Wherein the antioxidant is contained in an amount of 0.01 to 0.04 part by weight based on 1 part by weight of the solifenacin or a pharmaceutically acceptable salt thereof,
The binder is contained in an amount of 0.4 to 10 parts by weight based on 1 part by weight of the solifenacin or a pharmaceutically acceptable salt thereof and is contained in an amount of 25 to 200 parts by weight based on 1 part by weight of the antioxidant, ≪ / RTI > by weight of the soliphenacin tablet.
delete delete delete The tablet of claim 1, wherein the binder is included in an amount of 50 to 200 parts by weight based on 1 part by weight of the antioxidant.
delete The tablet of claim 1, wherein the solipenacin tablet further comprises a disintegrant, a glidant, or a coating.
Solipenacin or a pharmaceutically acceptable salt thereof, butylhydroxytoluene or butylhydroxyanisole as an antioxidant and low-substituted hydroxypropylcellulose as a binder to obtain a mixture; And
7. A process for preparing the solipenacin tablets of any one of claims 1, 5, and 7, comprising directly titrating the mixture.

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