KR20200078121A - Composite formulation for oral administration comprising Tamsulosin and Solifenacin and a process for the preparation thereof - Google Patents

Abstract

The present invention relates to: a complex formulation for oral administration containing tamsulosin or a pharmaceutically acceptable salt thereof, solifenacin or a pharmaceutically acceptable salt thereof, and a stabilizer; and a manufacturing method thereof. More specifically, the present invention relates to: a complex formulation for oral administration having excellent pharmaceutical properties capable of securing content uniformity while improving the stability of the complex formulation containing tamsulosin and solifenacin by containing the stabilizer; and a manufacturing method thereof.

Description

Composite formulation for oral administration comprising Tamsulosin and Solifenacin and a process for the preparation thereof

The present invention relates to an oral combination preparation comprising tamsulosin or a pharmaceutically acceptable salt thereof, solifenacin or a pharmaceutically acceptable salt thereof, and a stabilizing agent, and a method for preparing the same, more specifically, the present invention The present invention relates to an oral composite formulation having excellent pharmaceutical properties capable of securing ?t amount uniformity while improving stability of a composite formulation containing tamsulosin and solifenacin by including a silver stabilizer and a method for manufacturing the same.

Tamsulosin has the structure of Formula 1 below and its general name is (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-2-methoxy -It is a compound that is benzenesulfonamide.

[Formula 1]

Tamsulosin or a pharmaceutically acceptable salt thereof is known to have α-sympathetic blocking activity useful in the treatment of heart failure and benign prostatic hyperplasia. Among them, Tamsulosin hydrochloride selectively inhibits α-adrenoceptor and selectively acts on the genitourinary system, thereby improving the excretion rate of urine by relaxing the smooth muscles surrounding the bladder and the prostate gland. It has been known to have excellent pharmacological effects to improve the symptoms of benign prostatic hyperplasia (BPH) and to have fewer side effects. Tamsulosin having the above characteristics was developed by Yamanouchi Pharmaceuticals in 1996, and various products using tamsulosin hydrochloride are known.

Solifenacin is a quinoline derivative and has the structure of Formula 2 below, and its chemical name is (1R,3'R)-3'-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-iso Quinoline carboxylate.

[Formula 2]

The solifenacin or a pharmaceutically acceptable salt thereof has excellent selective antagonistic action against muscarinic M ₃ receptors, such as neurogenic urinary frequency, neurogenic bladder, enuresis, unstable bladder, bladder spasm or chronic cystitis. It has been reported that it is useful as a preventive treatment for respiratory diseases such as urinary diseases, chronic obstructive pulmonary diseases, chronic bronchitis, asthma and rhinitis.

When tamsulosin and solifenacin having such useful properties are included in one formulation to form a complex formulation, the effect of treating diseases such as better erectile dysfunction and benign prostatic hyperplasia may be promoted, and the use of a single drug By reducing, it can be expected to reduce the side effects that can be caused by long-term drug use.

However, in the case of preparing tamsulosin and solifenacin complex tablets, although each is stable in the raw material state, in the process of preparing the complex tablets in the process of preparing the complex tablets, when the active substance is mixed or contacted with excipients, etc. Stability problems occur in the process of preparing a formulation, such as N-oxide. Accordingly, there is a need for an improvement plan for the stability of tablets that may occur when preparing a complex tablet containing tamsulosin and solifenacin.

1.10-2017-0055211 A 2. 10-2018-0018 450 A

One aspect is to provide an oral combination preparation comprising tamsulosin or a pharmaceutically acceptable salt thereof, solifenacin or a pharmaceutically acceptable salt thereof, and a stabilizer.

Another aspect includes mixing tamsulosin or a pharmaceutically acceptable salt thereof, solifenacin or a pharmaceutically acceptable salt thereof and a stabilizer; And it is to provide a method for producing an oral composite formulation comprising the step of formulating the mixture.

In order to achieve the above object, it is to provide an oral combination preparation comprising tamsulosin or a pharmaceutically acceptable salt thereof, solifenacin or a pharmaceutically acceptable salt thereof, and a stabilizer.

Another aspect includes mixing tamsulosin or a pharmaceutically acceptable salt thereof, solifenacin or a pharmaceutically acceptable salt thereof and a stabilizer; And it is to provide a method for producing an oral composite formulation comprising the step of formulating the mixture.

Oral combination preparations according to one aspect use specific stabilizing agents to suppress the generation of flexible substances that may occur through contact of solifenacin with additives such as excipients during the manufacture of a formulation containing tamsulosin and solifenacin. It can significantly improve the stability over time of the composite formulation. In addition, when the stabilizer is included in a specific weight ratio, content uniformity of the tablet may also be secured. Therefore, according to one aspect, it is possible to provide a complex tablet comprising tamsulosin and solifenacin or a pharmaceutically acceptable salt thereof having excellent quality with a uniform content while having stability for a related substance.

1 is a comparative example, Examples 1 to 3 and Comparative Examples 1 to 3 according to the type of stabilizing agent included in the composite tablet containing tamsulosin hydrochloride pellets and solifenacin succinic acid accelerated stability It is a diagram showing the results confirmed in.
2 is a view showing the results of confirming the stability of the composite tablets according to Comparative Examples, Examples 1 to 3 and Comparative Examples 1 to 3 under severe exposure conditions.
3 is a view showing the results of confirming the stability of the composite formulation under accelerated and severe conditions when fumaric acid is added as a stabilizer.
4 is a view showing the results of confirming the stability of the composite formulation under accelerated and severe conditions when citric acid is added as a stabilizer.
5 is a diagram showing the results of the stability of the composite preparation under accelerated and severe conditions when tartaric acid is added as a stabilizer.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless defined otherwise, are used in the sense as commonly understood by those skilled in the art in the relevant field of the present invention. In addition, although a preferred method or sample is described herein, similar or equivalent ones are included in the scope of the present invention. The contents of all publications described by reference herein are incorporated herein by reference in their entirety.

The present inventors are a combination preparation comprising two drugs, tamsulosin or a pharmaceutically acceptable salt thereof and solifenacin or a pharmaceutically acceptable salt thereof, in one unit dosage form. As a degradation product of solifenacin, a related substance may be generated, and thus the stability of the formulation may be inhibited. As a result, by introducing a specific stabilizing agent into the composite preparation, it is confirmed that it is possible to secure stability over time by inhibiting related substances that may occur in the manufacturing process, and at the same time to ensure uniformity of the content, and of the formulation containing the stabilizing agent. An oral complex formulation with excellent stability has been developed.

Accordingly, an aspect of the present invention provides an oral combination preparation comprising iii) tamsulosin or a pharmaceutically acceptable salt thereof, ii) solifenacin or a pharmaceutically acceptable salt thereof, and iii) a stabilizer. do.

The pharmaceutically acceptable salt of tamsulosin may be, for example, hydrobromide, phosphate, sulfate, hydrochloride, malate, fumarate, lactate, tartrate, citrate, besylate, camsylate or gluconate, but In embodiments, it may be tamsulosin hydrochloride. In addition, the pharmaceutically acceptable salt of solifenacin may be, for example, hydrobromide, phosphate, sulfate, hydrochloride, malate, fumarate, lactate, tartrate, citrate, besylate, camsylate, gluconate or succinic acid. In one embodiment, it may be solifenacin succinic acid.

In the present specification, "stabilization" refers to suppressing any change in the active ingredient by increasing the stability of the active ingredient, and includes inhibiting the production of related substances that may occur during the preparation of the preparation.

The term "stabilizer" refers to any pharmaceutically acceptable additive that can increase the stability of the active ingredient, and inhibits the production of a related substance that can be generated when the active ingredient is mixed with and added to an additive such as an excipient. It means any additive that is pharmaceutically acceptable that can exhibit an effect.

The stabilizer may be in the range of 0.1 to 10% by weight, specifically 0.5 to 10% by weight, based on the weight of the filling in the oral combination preparation, and more specifically, may be used in an amount of 1 to 10% by weight. When the stabilizer is included in the above range, stability can be improved and excellent content uniformity can be secured.

When the content of the stabilizer is less than the above range, the formation of sufficient flexible substances is not effectively suppressed, so the stability of the formulation may be lowered. When the content of the stabilizer exceeds the above range, the content uniformity is based on the determination value. Non-uniform formulations can result.

The stabilizer may be interpreted to be used without limitation if any of the pharmaceutically acceptable additives capable of exhibiting the effect of inhibiting the production of a related substance that can be produced when the solifenacin is mixed with and additives such as excipients. And may be, for example, an acid stabilizer. The acid stabilizer is, for example, fumaric acid, citric acid, tartaric acid, alginic acid, acetic acid, lactic acid, maleic acid, Organic acids such as succinic acid, malic acid, adipic acid, glutamic acid and aspartic acid (phosphoric acid), phosphoric acid , Sulfuric acid, hydrochloride, boric acid, hydrogen bromide, nitric acid, etc. In one specific embodiment, at least one of fumaric acid, citric acid, and tartaric acid may be used. Can be used.

The fumaric acid that may be included in the oral combination preparation is, for example, about 0.1 to 30% by weight, about 0.2 to 25% by weight, about 0.3 to 20% by weight, about 0.4 to 15% by weight, or It may be about 0.5 to 10% by weight. In addition, citric acid that may be included in the oral combination preparation is, for example, about 0.1 to 30 wt%, about 0.2 to 25 wt%, about 0.3 to 20 wt%, about 0.4 to 15 wt%, about 0.5 to 10% by weight, or about 1.0 to 10% by weight. In addition, the tartaric acid that may be included in the oral combination preparation is, for example, about 0.1 to 30% by weight, about 0.2 to 25% by weight, about 0.3 to 20% by weight, about 0.4 to 15% by weight, It may be about 0.5 to 10% by weight, about 1.0 to 10% by weight, 1.5 to 10% by weight, or 2.0 to 10% by weight. The formulation is preferably 0.5 to 10% by weight based on the weight of the combined preparation of fumaric acid as a stabilizer; Citric acid is preferably from 1.0 to 10% by weight based on the weight of the combined preparation; Alternatively, the tartaric acid may be preferably included in an amount of 2.0 to 10% by weight, based on the weight of the combined preparation, but is not limited thereto.

In one aspect, the oral complex formulation may further include one or more pharmaceutically acceptable additives selected from the group consisting of fillers, disintegrants, lubricants and binders.

The filler, disintegrant, lubricant or binder may be any additive known to be commonly used in the art. The filler may be used in an amount of about 1 to 95% by weight, about 5 to 95% by weight, about 10 to 80% by weight, or about 15 to 75% based on the total weight of the combination preparation. The disintegrant may be used in an amount ranging from about 0.1 to 70% by weight, 1 to 67% by weight, or about 5 to 65% by weight based on the total weight of the composite preparation. The binder may be used in an amount in the range of about 0.1 to 30% by weight, or about 2 to 20% by weight based on the total weight of the combination preparation. The lubricant may be used in an amount in the range of about 0.1 to 10% by weight, about 0.3 to 5% by weight, or about 0.5 to 4% by weight based on the total weight of the combination preparation.

For example, the filler may be selected from the group consisting of lactose monohydrate, lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, sorbitol, and combinations thereof; The disintegrant may be selected from the group consisting of, for example, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, F-melt, and combinations thereof; The lubricant may be selected from the group consisting of magnesium stearate, silicon dioxide, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof, and the binder may be, for example, hydroxypropylcellulose, hydroxypropyl methylcellulose, Hypromellose, polyvinyl acetic acid, polyvinylpyrrolidone, copovidone, macrogol, sodium lauryl sulfate, light anhydrous silicic acid, silicate derivatives such as synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate, calcium hydrogen phosphate and The same may be selected from the group consisting of phosphate, carbonate such as calcium carbonate, pregelatinized starch, gums such as acacia gum, cellulose derivatives such as gelatin, ethyl cellulose, and mixtures thereof, but is not limited thereto.

In one aspect, the stabilizer may be included in an amount of about 1mg to 30mg, about 1.5mg to 25mg, or 2mg to 20mg per unit dosage form. When the content of the stabilizer is less than the above range, the formation of a sufficient flexible substance is not effectively suppressed, so the stability of the tablet may be lowered. When the content of the stabilizer exceeds the above range, the content uniformity is based on the determination value. A non-uniform tablet may result.

In one embodiment, the oral combination preparation is tamsulosin hydrochloride; Solifenacin succinic acid; One or more stabilizers selected from the group consisting of fumaric acid, citric acid and tartaric acid; And lactose monohydrate SD 200, low-substituted hydroxypropyl cellulose, F-melt, magnesium stearate, and silicon dioxide.

In one embodiment, tamsulosin hydrochloride in the oral combination preparation may be included in the form of pellets. In one embodiment, the tamsulosin hydrochloride pellets can be prepared by a method for preparing pellets that can be used normally.

In one embodiment, the tamsulosin hydrochloride pellets were dispersed by adding hydroxypropyl methylcellulose (HPMC) and tamsulosin hydrochloride to ethanol, followed by dissolution by adding purified water and dispersing with talc. The prepared drug coating solution may be sprayed onto microcrystalline cellulose (MCC) through a fluid bed granulator to manufacture pellets, but is not limited thereto.

The oral composite preparation may be formulated into oral preparations such as pellets, capsules, tablets (including monolayer tablets, bilayer tablets, inner core tablets, etc.), powders, and granules, but is not limited thereto. More specifically, the oral composite preparation may be in the form of a capsule, a monolayer tablet, or a bilayer tablet. When the composite preparation of the present invention is a capsule, the capsule may have a form including a powder, granules, tablets, syrups, pellets, etc. therein.

In addition, when the oral combination preparations were subjected to a flexible test under the harsh conditions of 60°C, after 4 weeks, the generation of N-oxide, a related substance of solifenacin, compared to the combination preparation without a stabilizer was reduced by 80% to 99%, and the time of tablets was reduced. It was confirmed that the stability was excellent (Test Example 1).

The oral combination preparation may be administered once a day, and may be taken daily.

Another aspect includes mixing tamsulosin or a pharmaceutically acceptable salt thereof, solifenacin or a pharmaceutically acceptable salt thereof and a stabilizer; And it is to provide a method for producing an oral composite formulation comprising the step of formulating the mixture.

The details of the manufacturing method may be applied to the description of the oral combination preparation according to an aspect of the present invention.

When a stabilizer is mixed in a method for preparing an oral composite preparation according to one aspect, when the flexible test is performed under harsh conditions of about 60° C., N-oxide, which is a related substance, is compared to the composite preparation without stabilizer after 4 weeks. The occurrence was significantly reduced by 80% to 99% (Test Example 1).

Preparation of the pellets, capsules, single-layer tablets, double-layer tablets, inner core tablets, powders, or granules is any pellet, capsule, single-layer tablets, double-layer tablets, inner core tablets, powders or granules known in the art It can be prepared according to the method.

[Examples and Test Examples]

Hereinafter, one or more specific examples will be described in more detail through the following examples and test examples. However, these examples are intended to illustrate the specific examples by way of example, and the scope of the present invention is not limited thereto.

Preparation of tamsulosin hydrochloride pellets

Tamsulosin hydrochloride pellets used in the preparation of the composite formulations of Examples 1 to 3 and Comparative Examples 1 to 3 were prepared as follows.

Hydroxypropyl methylcellulose (HPMC) 2910 (P-603) and tamsulosin hydrochloride were added to ethanol to disperse, followed by dissolving with purified water, followed by dispersing with talc. The prepared drug coating solution was sprayed onto microcrystalline cellulose (MCC) through a fluid bed granulator to prepare pellets.

Preparation of tablets of Examples 1-3 and Comparative Examples 1-3

As disclosed in Table 1 below, tamsulosin hydrochloride pellets and solifenacin succinic acid are low-substituted hydroxypropylcellulose (HPC-L), F-melt, lactose monohydrate SD 200, silicon dioxide And one stabilizer consisting of ascorbic acid, butylhydroxytoluene, erythorbic acid, citric acid, fumaric acid and tartaric acid. The above product was mixed with magnesium stearate to prepare granules, and then finally tabletted using a tableting machine to prepare oral composite preparations of Comparative Examples 1 to 3 and Examples 1 to 3.

Contrast Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Example 2 Example 3 ingredient mg/T Tamsulosin hydrochloride pellets 34.58 34.58 34.58 34.58 34.58 34.58 34.58 Solifenacin succinic acid 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Butylhydroxytoluene - 4.00 - - - - - Ascorbic acid - - 4.00 - - - - Erythorbic acid - - 4.00 - - - Citric acid - - - 4.00 - - Fumaric acid - - - - 4.00 - Tartaric acid - - - - - 4.00 HPC-L 10.00 10.00 10.00 10.00 10.00 10.00 10.00 F-melt
(MCC and mannitol mixed) 72.42 70.42 70.42 70.42 70.42 70.42 70.42 Lactose monohydrate SD 200 72.00 70.00 70.00 70.00 70.00 70.00 70.00 Silicon dioxide 4.00 4.00 4.00 4.00 4.00 4.00 4.00 Stearic Acid Masnesium 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Total 200.00 200.00 200.00 200.00 200.00 200.00 200.00

Test Example 1. Confirmation of the stability of the composite preparation by adding a stabilizer

The composite formulations of Examples 1 to 3 and Comparative Examples 1 to 3 were stored under harsh conditions (60°C) and accelerated conditions (40°C 75%RH), respectively, and then initiated, severely for 1 week, 2 weeks, 4 weeks, The amount of N-oxide, a solifenacin analog after 1 week, 1 month, and 3 months after acceleration was measured through the method and process described below.

<Preparation of test solution>

20 tablets of the combined preparation were taken, placed in a 100 mL volumetric flask, and then 20 mL of methanol was added, ultrasonically extracted for 30 minutes, and allowed to cool. After dissolving about 5.44 g of potassium dihydrogen phosphate in 2000 mL of purified water, add 5 mL of triethylamine and adjust solution A to pH 6.6 with phosphoric acid (20 mM potassium dihydrogen phosphate _, 0.25% triethylamine, pH6.6) and ACN. A solution containing 80 ppm of tamsulosin hydrochloride and 1000 ppm of solifenacin succinate filtered as a diluent contained in this 80:20 ratio and then filtered with a 0.45 μm nylon membrane filter was used as a sample solution.

<Preparation of standard amount>

About 4 mg of tamsulosin hydrochloride standard and about 25 mg of solifenacin succinate standard were precisely taken, placed in a 100 mL volumetric flask, and about 30 mL of methanol was added, followed by ultrasonic extraction for about 10 minutes to dissolve completely, followed by aligning the mark with methanol. . 10 mL of the solution was taken, placed in a 100 mL volumetric flask and aligned with methanol. Then, 10 mL of the above solution was placed in a 50 mL volumetric flask, and about 5.44 g of potassium dihydrogen phosphate was dissolved in 2000 mL of purified water, and 5 mL of triethylamine was added and adjusted to pH 6.6 with phosphoric acid solution A (20 mM potassium dihydrogen phosphate _, 0.25 % Triethylamine, pH6.6) and ACN in a dilution containing 80:20 ratio.

<Preparation of placebo solution>

Excipients in an amount corresponding to 20 tablets of excipients excluding the main component were placed in a 100 mL volumetric flask, and 20 mL of methanol was added, followed by ultrasonic extraction for 30 minutes and allowed to cool. After dissolving about 5.44 g of potassium dihydrogen phosphate in 2000 mL of purified water, add 5 mL of triethylamine and adjust solution A to pH 6.6 with phosphoric acid (20 mM potassium dihydrogen phosphate _, 0.25% triethylamine, pH6.6) and ACN. After aligning the mark with the diluted solution contained in the ratio of 80:20, the filtered solution with a 0.45 μm nylon membrane filter was determined as a placebo solution.

<Analysis condition>

50 µl of the test solution and standard solution were injected and tested according to the liquid chromatography method under the following conditions.

It was used as an ultraviolet absorbance photometer as a detector, and the measurement wavelength of the detector was 225 nm. In addition, the column used was a column (CapcellPak MG III) filled with a silica gel with a C18 for liquid chromatograph of 5 μm in a stainless steel tube with a diameter of 4.6 mm and a length of about 150 mm. The flow rate was 1.0 mL/min, the column temperature was 30°C, and the analysis time was 45 minutes. The mobile phase was set to the following solution conditions for each time zone.

A-Solution A (20 mM potassium dihydrogen phosphate _, 0.25% triethylamine, pH6.6)

B-90% acetonitrile

Time (min) A (%) B (%) 0 80 20 10 60 40 15 60 40 22 30 70 37 30 70 38 80 20 45 80 20

Stabilizers to increase the stability of the tablets were added at 2% by weight based on the total weight of the tablets, and the stability of the composite preparations under accelerated and severe conditions for each type of stabilizer was confirmed. The acceleration and harsh measurement results of the related substances of solifenacin succinic acid are shown in Tables 3 to 4 and Figures 1 to 2 below. In FIG. 1, the group not containing the stabilizer is stabilizer X (control), and the group including each stabilizer is butylhydroxytoluene (example 1), ascorbic acid (example 2), erythorbic acid (implementation). Examples 3), citric acid (Comparative Example 1), fumaric acid (Comparative Example 2), and tartaric acid (Comparative Example 3) were shown, and the group containing only active pharmaceutical ingredient (API) was shown as API.

Contrast Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Example 2 Example 3 Stabilizer - Butylhydroxytoluene Ascorbic acid Erythorbic acid Citric acid Fumaric acid Tartaric acid 1 week acceleration 0.413 0.284 0.413 0.529 0.134 0.007 0.081 Acceleration 1 month 1.861 0.816 1.367 1.164 0.294 0.084 0.274 Acceleration 3 months 3.176 0.894 1.814 1.695 0.441 0.114 0.312

As shown in Table 3 and Figure 1, as a result of performing a flexible test under accelerated conditions by simply mixing and tableting the main component and excipients without a stabilizer, the N-oxide related substance is approximately 4 times larger than the conventional 1 week after 1 month of acceleration. It was confirmed that the production amount increased. Even in the tablets of Comparative Examples 1 to 3, after 1 month of acceleration, it was confirmed that the production amount of the related substances was less than the group without the addition of stabilizers. As a result of the 3-month accelerated test test, fumaric acid, tartaric acid, citric acid, butylhydroxytoluene, erythorbic acid, and ascorbic acid were confirmed to increase in amount of related substances, in order to confirm that stability was increased in the reverse order. . Particularly, in the case of accelerated 3 months, the production of a remarkably low level of related substances was confirmed in the citric acid, fumaric acid, and tartaric acid of Examples 1 to 3 compared to the comparative example, and the stability by the stabilizer added to the Example compared to other stabilizers It was confirmed that a remarkably excellent effect was exhibited, and particularly, it was confirmed that fumaric acid exhibited the best stability.

Contrast Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Example 2 Example 3 Harsh 1 week 1.766 0.728 1.139 1.139 0.364 0.061 0.812 Severe 2 weeks 3.994 1.999 2.612 2.612 0.496 0.137 1.224 Severe 4 weeks 7.873 2.812 4.883 3.618 0.817 0.149 1.435

As shown in Table 4 and Figure 2, as a control example, as a result of the simple mixing and tableting of the main component and the excipients without a stabilizer, the softening test was conducted under severe conditions, resulting in a large amount of N-oxide related substances since severely one week later. Therefore, it was confirmed that the production amount was increased by about 4 times compared to the 1st week. As a result of the 4th week of the flexible test confirmation, it was confirmed that the amount of the related substances produced in the order of fumaric acid, tartaric acid, citric acid, butylhydroxytoluene, erythorbic acid, and ascorbic acid increased, and the stability was increased in the reverse order. . Among the stabilizers, in the case of fumaric acid, citric acid, and tartaric acid, stability was significantly higher than that of other stabilizers, and it was confirmed that the generation of N-oxide, a related substance, was inhibited. In particular, in the case of fumaric acid, the result of the severe 4-week softening test showed a stability of about 52 times higher than that of a tablet without a stabilizer, and thus it was confirmed that the production amount of the related substance can be suppressed up to about 99%.

Test Example 2. Confirmation of the stability of the combination preparation by addition of fumaric acid

2-1. Preparation of complex preparations by addition of fumaric acid

In order to confirm the stability according to the amount added in the combined preparation of fumaric acid, which is the stabilizer identified in Test Example 1, fumaric acid was added to 0.1 to 15% by weight based on the total weight of the tablets, and the ingredients of the preparation examples in Table 5 were simply mixed and tableted to prepare them. One control example and Examples 4 to 12 were prepared, and then the stability according to the fumaric acid added in the test example was confirmed.

Contrast Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 ingredient mg/T Tamsulosin hydrochloride pellets 34.58 34.58 34.58 34.58 34.58 34.58 34.58 34.58 34.58 34.58 Solifenacin succinic acid 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Fumaric acid - 0.20 1.00 2.00 4.00 8.00 16.00 20.00 24.00 30.00 HPC-L 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 F-melt (MCC, mannitol mixed) 72.42 72.32 71.92 71.42 70.42 68.42 64.42 62.42 60.42 57.42 Lactose monohydrate SD 200 72.00 71.90 71.50 71.00 70.00 68.00 64.00 62.00 60.00 57.00 Silicon dioxide 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 Stearic Acid Masnesium 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Total 200.00 200.00 200.00 200.00 200.00 200.00 200.00 200.00 200.00 200.00

2-2. Confirmation of the stability of the combination preparation according to the addition of fumaric acid

The stability was the same as the experimental conditions for the stability of Test Example 1, but by varying the amount of fumaric acid, which is an added stabilizer, tablets (Examples 4 to 12) were prepared to carry out an experiment to confirm the stability of the combined preparation. The stability of the resulting formulation was confirmed by measuring the amount of N-oxide that is a solifenacin analog by changing the accelerated condition period to 1 month and the severe exposure period to 4 weeks. It is shown in 6.

Contrast Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Fumarsan Yangbyul 0% 0.1% 0.5% One% 2% 4% 8% 10% 12% 15% Acceleration 1 month 1.861 0.683 0.215 0.092 0.081 0.084 0.077 0.089 0.071 0.062 Severe 4 weeks 7.873 1.293 0.339 0.149 0.130 0.121 0.134 0.127 0.094 0.118

As shown in Table 6 and Figure 3, the stability test results by amount of fumaric acid at 1 month and severely 4 weeks of acceleration, the stability of the oral composite formulation is significantly improved when the fumaric acid containing 0.5% by weight or more compared to the total weight of tablets Was confirmed.

2-3. Confirmation of the uniformity of the content of the combination preparation according to the addition of fumaric acid

According to the content uniformity test in the formulation uniformity test method of the Korean Pharmacopoeia General Test Method, the formulation uniformity test was conducted on the tablets formulated in Test Example 2-1, and liquid chromatography was performed under the following conditions. It was calculated and shown in Table 7 below.

<Preparation of test solution>

1 tablet of the combined preparation was placed in a 50 mL volumetric flask, 10 mL of methanol was added, ultrasonic extraction was performed for 30 minutes, and the mixture was allowed to cool. Thereafter, the target line was aligned with the mobile phase, and then filtered with a 0.45 μm nylon membrane filter to determine the sample solution.

<Preparation of standard amount>

About 20 mg of the standard product of tamsulosin hydrochloride was put in a 250 mL volumetric flask and dissolved in methanol.

About 50 mg of the solifenacin succinate standard was placed in a 50 mL volumetric flask, dissolved in methanol, and aligned with the mark to prepare a solifenacin succinate standard stock solution.

Take 5 mL of the standard stock solution of tamsulosin hydrochloride and 5 mL of standard solution of solifenacin succinate, place them in a 50 mL volumetric flask, align the marks with the mobile phase, and include 8 ppm of tamsulosin hydrochloride and 100 ppm of solifenacin succinate. The solution to be used was used as a standard solution.

<Analysis condition>

The prepared test solution and standard solution were respectively injected at 50 μL, and liquid chromatography was performed under the following conditions.

It was used as an ultraviolet absorbance photometer as a detector, and the measurement wavelength of the detector was 225 nm. In addition, the column used was a column (CapcellPak MG III) filled with a silica gel with a C18 for liquid chromatograph of 5 μm in a stainless steel tube with a diameter of 4.6 mm and a length of about 150 mm. The flow rate was 1.5 mL/min, the column temperature was 40°C, and the analysis time was 15 minutes. As the mobile phase, 12.4 mL of perchloric acid and 3.0 g of sodium hydroxide were dissolved in 1900 mL of purified water, and then pH 2.0 was adjusted with sodium hydroxide.

Contrast Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Fumarsan Yangbyul 0% 0.1% 0.5% One% 2% 4% 8% 10% 12% 15% Content uniformity 101.1 100.1 101.4 100.9 101.5 101.3 102.6 101.4 102.4 101.9 SD 1.4 1.2 2.4 1.6 1.9 2.1 3.8 4.3 6.7 7.8 Judgment 3.96 2.88 5.76 3.84 4.56 5.04 10.22 10.32 16.98 19.12

N=10, criteria: 15 or less

As shown in Table 7, as a result of testing the content uniformity of each amount of fumaric acid, the results showed that the uniformity of the formulation containing 0 to 10% by weight of fumaric acid relative to the total weight of the formulation was suitable, and that 0 to 4% by weight of fumaric acid It was found that the uniformity was better when included in the tablet. However, when the amount of fumaric acid exceeded 10% by weight based on the total weight of the tablet, it was confirmed that 12% by weight and 15% by weight did not meet the criterion.

Therefore, when the amount of fumaric acid relative to the total weight of the formulation is 0.5% by weight or more through the stability test result, and when the amount of fumaric acid relative to the total weight of the formulation is 10% by weight or less through the result of content uniformity, almost all of the salifericin analogs are generated. It was confirmed that it is possible to produce a composite tablet of excellent quality with a uniform content.

Test Example 3. Confirmation of the stability of the combination preparation by addition of citric acid

3-1. Preparation of complex preparations according to the addition of citric acid

To confirm the stability according to the amount added in the combined preparation of citric acid, which is the stabilizer identified in Test Example 1, citric acid was added to 0.1 to 15% by weight based on the total weight of the tablet, and the ingredients of the preparation examples in Table 8 were simply mixed and tableted to prepare them. One control example and Examples 13 to 21 were prepared, and then the stability according to citric acid added in the test example was confirmed.

Contrast Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 ingredient mg/T Tamsulosin hydrochloride pellets 34.58 34.58 34.58 34.58 34.58 34.58 34.58 34.58 34.58 34.58 Solifenacin succinic acid 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Citric acid - 0.20 1.00 2.00 4.00 8.00 16.00 20.00 24.00 30.00 HPC-L 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 F-melt (MCC, mannitol mixed) 72.42 72.32 71.92 71.42 70.42 68.42 64.42 62.42 60.42 57.42 Lactose monohydrate SD 200 72.00 71.90 71.50 71.00 70.00 68.00 64.00 62.00 60.00 57.00 Silicon dioxide 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 Stearic Acid Masnesium 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Total 200.00 200.00 200.00 200.00 200.00 200.00 200.00 200.00 200.00 200.00

3-2. Confirmation of the stability of the combination preparation by the addition of citric acid

The stability was the same as the experimental conditions for the stability of Test Example 1, but by varying the amount of the added stabilizer, citric acid, tablets (Examples 13 to 21) were prepared to carry out an experiment to confirm the stability of the combined preparation. The stability of the resulting formulation was confirmed by measuring the amount of N-oxide that is a solifenacin analog by changing the accelerated condition period to 1 month and the severe exposure period to 4 weeks. It is shown in 9.

Contrast Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 By citric acid 0% 0.1% 0.5% One% 2% 4% 8% 10% 12% 15% Acceleration 1 month 1.861 1.346 0.945 0.438 0.318 0.271 0.303 0.285 0.223 0.214 Severe 4 weeks 7.873 3.229 2.267 0.849 0.774 0.633 0.648 0.558 0.518 0.483

As shown in Table 9 and FIG. 4, as a result of the stability test of citric acid by amount at 1 month and severely for 4 weeks, it was confirmed that stability is greatly improved when citric acid is contained in an amount of 1.0 wt% or more based on the total weight of the tablets.

3-3. Checking the uniformity of the content of the combination preparation according to the addition of citric acid

According to the content uniformity test in the formulation uniformity test method of the Korean Pharmacopoeia General Test Method, the formulation uniformity test was conducted for the tablets formulated in Test Example 2-1. Liquid chromatography was performed by the method described in Test Example 2-3, and the determination was calculated and shown in Table 10 below.

Contrast Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 By citric acid 0% 0.1% 0.5% One% 2% 4% 8% 10% 12% 15% Content uniformity 99.8 101.6 100.7 102.3 99.4 98.7 100.8 101.6 101.8 100.7 SD 0.8 1.8 1.1 1.8 0.7 2.3 3.8 4.6 7.1 8.3 Judgment 1.92 4.42 2.64 5.12 1.68 5.52 8.42 11.14 17.34 19.12

N=10, criteria: 15 or less

As shown in Table 10 above, as a result of confirming the experimental results of content uniformity by amount of citric acid, uniformity was found in the formulation containing 0 to 10% by weight of citric acid, and uniformity was better at 0 to 4% by weight. appear. However, in the case of 12% by weight and 15% by weight, in which the amount of citric acid exceeded 10% by weight based on the total weight of the tablet, it was confirmed that it did not meet the criterion.

Therefore, when the amount of citric acid relative to the total weight of the tablet is 1.0% by weight or more through the stability test result, and the amount of citric acid relative to the total weight of the tablet is 10% by weight or less through the result of content uniformity, almost all of the salifericin analogs are generated. It was confirmed that it is possible to produce a composite tablet of excellent quality with a uniform content.

Test Example 4. Confirmation of the stability of the combination preparation by the addition of tartaric acid

4-1. Preparation of complex preparation according to the addition of tartaric acid

To confirm the stability according to the amount added in the complex formulation of tartaric acid, which is the stabilizer identified in Test Example 1, tartaric acid was added up to 0.1 to 15% by weight based on the total weight of the tablet, and the ingredients of the preparation examples in Table 11 were simply mixed and The prepared and formulated control examples and Examples 22 to 30 were prepared, and then the stability according to the tartaric acid added in the test examples was confirmed.

Contrast Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 ingredient mg/T Tamsulosin hydrochloride pellets 34.58 34.58 34.58 34.58 3 rooms4.58 34.58 34.58 34.58 34.58 34.58 Solifenacin succinic acid 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Tartaric acid - 0.20 1.00 2.00 4.00 8.00 16.00 20.00 24.00 30.00 HPC-L 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 F-melt (MCC, mannitol mixed) 72.42 72.32 71.92 71.42 70.42 68.42 64.42 62.42 60.42 57.42 Lactose monohydrate SD 200 72.00 71.90 71.50 71.00 70.00 68.00 64.00 62.00 60.00 57.00 Silicon dioxide 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 Stearic Acid Masnesium 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Total 200.00 200.00 200.00 200.00 200.00 200.00 200.00 200.00 200.00 200.00

4-2. Confirmation of the stability of the combination preparation according to the addition of tartaric acid

In the same manner as in the stability test conditions of Test Example 1, a tablet (Examples 22 to 30) was prepared by varying the amount of tartaric acid, an added stabilizer, to perform an experiment to confirm the stability of the composite preparation. The stability of the resulting formulation was confirmed by measuring the amount of N-oxide, a solifenacin analog, by changing the period of accelerated conditions to 1 month and the period of severe exposure to 4 weeks. 12.

Contrast Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 By tartaric acid 0% 0.1% 0.5% One% 2% 4% 8% 10% 12% 15% Acceleration 1 month 1.861 1.177 0.749 0.384 0.274 0.242 0.234 0.219 0.183 0.176 Severe 4 weeks 7.873 5.436 3.017 2.668 1.435 1.241 1.111 0.853 0.794 0.667

As shown in Table 12 and FIG. 5, the stability test results by amount of tartaric acid at 1 month and 4 weeks of acceleration accelerated, and stability was improved at 4 weeks of harshness when more than 2.0% by weight of tartaric acid was included compared to the total weight of the tablet. In months, it was confirmed that stability is improved when more than 0.5% by weight of tartaric acid is included.

4-3. Confirmation of the uniformity of the content of the complex preparation according to the addition of tartaric acid

According to the content uniformity test in the formulation uniformity test method of the Korean Pharmacopoeia General Test Method, the formulation uniformity test was conducted for the tablets formulated in Test Example 2-1. Liquid chromatography was performed by the method described in Test Example 2-3, and the determination was calculated and shown in Table 13 below.

Contrast Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 By tartaric acid 0% 0.1% 0.5% One% 2% 4% 8% 10% 12% 15% Content uniformity 100.8 100.1 99.4 101.4 100.6 100.0 101.4 100.7 100.5 101.6 SD 0.8 0.7 0.8 1.3 0.6 2.7 4.3 4.8 7.1 8.3 Judgment 1.92 1.68 1.92 3.12 1.44 6.48 10.32 11.52 17.04 20.02

N=10, criteria: 15 or less

As shown in Table 13, as a result of confirming the experimental results of content uniformity by amount of tartaric acid, uniformity was found in the formulation containing 0 to 10% by weight of tartaric acid, and uniformity was more than 0 to 4% by weight. It turned out to be excellent. However, in the case of 12% by weight and 15% by weight, in which the amount of tartaric acid exceeded 10% by weight based on the total weight of the tablet, it was confirmed that it did not meet the criterion.

Therefore, when the amount of tartaric acid compared to the total weight of the tablet was 2.0% by weight or more, and the amount of tartaric acid compared to the total weight of the tablet was 10% by weight or less through the results of uniformity of content, it was confirmed that the stability of the test result was stable. It has been confirmed that a composite tablet of excellent quality with a uniform content can be produced with little or no material formation.

So far, the present invention has been focused on the preferred embodiments. Those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an explanatory point of view rather than a restrictive point of view. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the equivalent range should be interpreted as being included in the present invention.

Claims (16)

Iv) Tamsulosin or a pharmaceutically acceptable salt thereof, ii) solifenacin or a pharmaceutically acceptable salt thereof, and iii) an oral combination preparation comprising a stabilizer. The method according to claim 1, wherein the stabilizing agent is one or more selected from the group consisting of fumaric acid, citric acid and tartaric acid, oral combination preparations. The method according to claim 1, wherein the pharmaceutically acceptable salt of tamsulosin is an oral combination preparation that is tamsulosin hydrochloride. The method according to claim 1, wherein the pharmaceutically acceptable salt of solifenacin is an oral combination preparation that is solifenacin succinic acid. The method according to claim 1, wherein the stabilizing agent is an oral composite formulation that is included in 0.5 to 10% by weight based on the weight of the composite formulation. The method according to claim 2,
The fumaric acid is 0.5 to 10% by weight based on the filling weight of the composite preparation, the citric acid is 1.0 to 10% by weight based on the filling weight of the complex preparation, or the tartaric acid is 2.0 to 10% by weight based on the filling weight of the combination preparation. Oral combinations that are included in %. The method according to claim 1, wherein the oral composite formulation is an oral composite formulation further comprises at least one pharmaceutically acceptable additive selected from the group consisting of fillers, disintegrants, lubricants and binders. The method according to claim 7,
The filler is an oral composite preparation of at least one selected from the group consisting of lactose monohydrate, lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, sorbitol, and combinations thereof. The method according to claim 7,
The disintegrating agent is a low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, F-melt, and oral combination preparations of one or more selected from the group consisting of a combination thereof. The method according to claim 7,
The lubricant is an oral combination preparation of at least one selected from the group consisting of magnesium stearate, silicon dioxide, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof. The method according to claim 1, wherein the oral combination preparation is tamsulosin hydrochloride; Solifenacin succinic acid; One or more stabilizers selected from the group consisting of fumaric acid, citric acid and tartaric acid; And one or more pharmaceutically acceptable additives selected from the group consisting of fillers, disintegrants and lubricants. The method according to claim 1, wherein the stabilizing agent is an oral combination preparations contained in an amount of 2mg to 20mg per unit dosage form. The method according to claim 1, wherein the composite formulation is an oral composite formulation in the form of pellets, capsules, monolayer tablets, bilayer tablets, inner core tablets, powders, or granules. The method according to claim 1, When the combination formulation is subjected to a flexible test under the harsh conditions of 60 ℃, oral composite formulation for reducing the generation of N- oxide 80% to 99% compared to the combination formulation without stabilizer after 4 weeks. Mixing tamsulosin or a pharmaceutically acceptable salt thereof, solifenacin or a pharmaceutically acceptable salt thereof and a stabilizer; And a method for preparing an oral combination preparation according to any one of claims 1 to 14, comprising formulating the mixture. The method according to claim 15, When the mixing of the stabilizer is carried out in a flexible test under the harsh conditions of 60 ℃, oral composite formulation for reducing the generation of N- oxide 80% to 99% compared to the composite agent without stabilizer after 4 weeks Manufacturing method.

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