KR20190047239A - Combination formulation prepared by wet granulation method, comprising Bazedoxifene or its pharmaceutically acceptable salt, and Cholecalciferol or its pharmaceutically acceptable salt - Google Patents

Abstract

The present invention relates to a composite formulation having an excellent content uniformity, dissolution rate, and stability, which contains bazedoxifene or a pharmaceutically acceptable salt thereof, and cholecalciferol or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to the composite formulation exhibiting an improved content uniformity, dissolution rate, and stability, which contains bazedoxifene acetate wet granules and cholecalciferol concentration powder.

Description

The present invention relates to a combination preparation prepared by a wet granulation method, comprising a bar-cleansing cine or a pharmaceutically acceptable salt thereof and a cholecalciferol or a pharmaceutically acceptable salt thereof. or its pharmaceutically acceptable salt, and Cholecalciferol or its pharmaceutically acceptable salt}

The present invention relates to a combination preparation comprising a bar-cleansing cine or a pharmaceutically acceptable salt thereof and cholecalciferol or a pharmaceutically acceptable salt thereof and having excellent content uniformity, dissolution rate and stability. More specifically, the present invention relates to a combination preparation containing Bazedoxifene acetate wet granules and cholecalciferol concentrated powder, which exhibits improved content uniformity, dissolution rate and stability.

Benzoxepine acetate was prepared from (1-4- [2- (hexahydro-1H-azepin- 1 -yl) ethoxy] benzyl-2- (4- hydroxyphenyl) 5-ol monoacetic acid salt) having the following formula.

Bar Adoxifene is a very poorly soluble solid drug with a solubility of 0.5464 μg / mL and is known to be soluble in organic solvents. In addition, U.S. Patent Nos. 7683051 and 7683052 disclose that the barbiturates have a crystalline form of Form A and Form B.

Piperazine acetate is one of the selective estrogen receptor modulators (SERMs), and Pfizer Korea Co., Ltd. is a product that contains phenylacetate as the active ingredient in bar sterols, It is marketed with permission. It is a tablet formulated once a day for the purpose of treating or preventing osteoporosis in postmenopausal women.

Unlike female hormones, SERM acts tissue-selective. In other words, it acts as a female hormone agonist in the bones, while it acts as a female hormone antagonist in the heart, uterus, breast and brain, thus eliminating the risk factors and side effects of general female hormone agents.

SERM drugs can be taken once a day regardless of diet, and have good stability for the treatment of osteoporosis, which is important for long-term use, in the treatment of gastrointestinal adverse events, endometrial hyperplasia and breast diseases.

It also has an excellent vertebral fracture prevention effect that reduces the risk of vertebral fracture by 42% when compared to raloxifene (60 mg / day). However, if the patient has insufficient calcium and vitamin D intake from the diet, supplementation with a dietary supplement should be used.

Baracetin, phenacetate, also has a low compliance with medication compliance, which is a problem that the patient has to take separately if the patient does not have enough vitamin D from food. Therefore, it is necessary to develop a combination preparation of bar-cleansing ciphen and cholecalciferol.

Accordingly, the present inventors have developed a combination preparation which exhibits improved content uniformity, dissolution rate, and stability while containing baracetate penacetate and cholecalciferol together.

Tablets can be prepared by direct tabletting, dry granulation or wet granulation in a typical formulation process. However, it is not suitable for the preparation of tablets because they have a high repose angle because they have a binding property when they are directly tableted.

Also, when the compacting process, which is another dry method, is used, the angle of repose is too large to cause a mass deviation. It is predicted that not only the content and content uniformity of the bar during the bar removal due to the mass deviation of the bar aside from the bar, but also the content and content uniformity of the cholecalciferol added at the post mixing are expected to be influenced.

However, the present inventors have succeeded in producing wet granules having a particle size distribution similar to that of cholecalciferol at the time of post-mixing when producing wet granules of penacetic acid salt by using a high-speed mixer, It has been found that the disintegration is not disturbed because the content uniformity and the productivity are improved and the stickiness property of the pen is dispersed in other excipients at the time of disinfection, thereby exhibiting excellent dissolution rate and stability.

Also, Korean Patent No. 10-1584674 discloses that when the granule is granulated with water, the agar-phenacetic acid salt is changed from a crystalline form to a B crystalline form.

However, the present inventors found that when the wet granules of penacetic acid were prepared by using a high-speed mixer, there was no change in the crystal form even when water was used. In contrast, dry granules Thereby increasing the production of the flexible material.

The present inventors have also found that the productivity of wet granules is superior to that of dry granules by measurement of angle of repose and particle size.

The present invention relates to a pharmaceutical combination comprising a barzicide ciphen or a pharmaceutically acceptable salt thereof and cholecalciferol or a pharmaceutically acceptable salt thereof and having excellent content uniformity, dissolution rate and stability.

In order to achieve this effect, the pharmaceutical combination preparation of the present invention comprises a granule comprising a bar or a pharmaceutically acceptable salt thereof and a cholecalciferol or a pharmaceutically acceptable salt thereof.

Here, the granules containing the granulocytopenic acid or a pharmaceutically acceptable salt thereof may have a particle size of not less than 150 μm and not more than 50% by weight, and the granules having a granular size of 150 μm to 250 μm may be not less than 40% have.

Preferably, the cholecalciferol or pharmaceutically acceptable salt thereof has 50% by weight or more of particles having a particle size of 150 μm to 250 μm, and the cholecalciferol or pharmaceutically acceptable salt thereof is contained in the form of a concentrated powder .

In addition, in the combination preparation of the present invention, the bar-cleansing cine or a pharmaceutically acceptable salt thereof may preferably be a penic acid acetic acid salt.

The combination preparation of the present invention may further comprise at least one additive selected from the group consisting of lactose, microcrystalline cellulose, sodium starch glycolate, povidone, sodium lauryl sulfate, propyl gallate, and magnesium stearate.

The combined preparation of the present invention can be produced by a wet granulation method using a high speed mixer. At this time, since the loss of raw materials in the manufacturing process is small and the adhesive property of the pen is dispersed in other excipients when the bar is removed, the disintegration is not disturbed and excellent elution is exhibited.

The present invention also relates to a method for preparing a wet granule comprising the steps of: preparing a wet granule in a high-speed mixer, comprising a bar or a pharmaceutically acceptable salt thereof and at least one first additive;

Drying the wet granules; And

The method comprising the steps of uniformly mixing the wet granule, cholecalciferol or a pharmaceutically acceptable salt thereof, and at least one second additive.

The first additive may be selected from the group consisting of lactose, microcrystalline cellulose, sodium starch glycolate, povidone and sodium lauryl sulfate, and the second additive may be selected from the group consisting of lactose, propyl gallate, and magnesium stearate, Can be selected.

In the present invention, the agitation speed of the process of preparing wet granules using a high-speed mixer may be 200 to 400 rpm, preferably 250 to 350 rpm.

In addition, the combination preparation of the present invention can be produced such that the bar-cleansing cine or a pharmaceutically acceptable salt thereof does not change in crystal form before and after the wet granule is produced.

The present invention relates to a process for preparing a granule of the present invention having excellent productivity, dissolution rate and stability by using a wet granulation method and producing a granule with a particle distribution similar to that of a cholecalciferol-concentrated powder in combination with cholecalciferol, It is possible to provide a combination preparation excellent in content uniformity.

The present invention provides a combination preparation comprising a bar-cleansing cine or a pharmaceutically acceptable salt thereof and cholecalciferol or a pharmaceutically acceptable salt thereof and having excellent content uniformity, dissolution rate and stability.

Fig. 1 shows the results of measurement of particle size distribution in the cholecalciferol-concentrated powder of Comparative Example 1 and tablets of Production Examples 1 to 4. Fig.
Fig. 2 shows dissolution rates with time in the control preparation of Comparative Example 2 and the tablets of Production Examples 1 to 4.
FIG. 3 shows the results of measurement of the amount of a substance to be produced under severe conditions for the tablets of Production Examples 1 to 4.
Fig. 4 shows the X-ray powder test results of raw materials of bar acetic acid.
Fig. 5 shows X-ray powder test results of the granules of Production Example 3. Fig.

The present invention relates to a pharmaceutical combination preparation comprising a bar-cleansing cine or a pharmaceutically acceptable salt thereof, and cholecalciferol or a pharmaceutically acceptable salt thereof.

The combined preparation of the present invention may further comprise at least one pharmaceutically acceptable additive selected from the group consisting of a diluent, a disintegrant, a binder, and a glidant.

The combined preparation of the present invention may be formulated into pharmaceutical preparations for oral administration, and the preparations may be tablets, pellets, powders, granules, dry syrups, or capsules, and preferably tablets.

Hereinafter, the present invention will be described more specifically by way of examples. However, these examples are provided for the purpose of helping understanding the present invention, and the scope of the present invention is not limited by the following examples.

Preparation of Combination Preparations Comprising Bar Adoxifene Acetate and Cholecalciferol

According to the methods of Preparations 1 to 4 below, according to the composition of Table 1 and the conditions of preparation of Table 2, tablets containing barmacytial penacetate and cholecalciferol were prepared.

≪ Preparation Example 1 &

The tablets were prepared by the direct tableting method as described below, and the granular water was maintained at the theoretical water content of 2.5%.

1) Barcysteine penacetate was mixed with lactose and microcrystalline cellulose.

2) The mixture was sieved through a 20 mesh sieve.

3) Sodium starch glycolate, sodium lauryl sulfate, copovidone, cholecalciferol and propyl gallate were added and mixed homogeneously.

4) Magnesium stearate was added to the secondary mixture and mixed homogeneously for 5 minutes.

5) The mixture was tabletted using a tablet machine.

≪ Preparation Example 2 &

The tablets were prepared by the dry granulation method as described below, and the granular water was maintained at 2.5% in the theoretical water content.

1) The antimicrobial penacetate was mixed with lactose, microcrystalline cellulose and starch sodium glycolate.

2) Sodium starch glycolate and sodium lauryl sulfate, copovidone were added and dry-granulated using the roller compactor under the conditions of Table 2.

3) The granules were formulated using a 20 Mesh oscillator.

4) The baracetate-penacetate dry granules obtained were mixed with cholecalciferol, lactose and propyl gallate and mixed homogeneously.

5) Magnesium stearate was added to the second mixture and mixed homogeneously for 5 minutes.

6) Purify the mixture using a tablet machine.

≪ Preparation Example 3 &

The tablets were prepared by a wet granulation method using a high speed mixer (HSM) as described below, and the granules were dried in the same manner as the theoretical water of 2.5%.

1) The antimicrobial penacetate was mixed with lactose, microcrystalline cellulose and starch sodium glycolate.

2) The mixed powder was put into a high speed mixer, and wet granulation was carried out under the conditions shown in Table 2 using an aqueous solution containing povidone and sodium lauryl sulfate (binding solution).

3) The wet granulation mixture was dried using a fluid bed dryer or a drying oven.

4) After the obtained bar sterilized penacetate wet granules were sieved using 20 Mesh, cholecalciferol, lactose and propyl gallate were added and mixed homogeneously.

5) Magnesium stearate was added to the second mixture and mixed homogeneously for 5 minutes.

6) The resulting mixture was tableted using a tablet machine.

≪ Preparation Example 4 &

The tablets were prepared by a wet granulation method using a Fluid Bed Granulator (FBG) as follows, and the granules were dried in the same manner as the theoretical water of 2.5%.

1) The antimicrobial penacetate was mixed with lactose, microcrystalline cellulose and starch sodium glycolate.

2) The mixed powder was placed in a fluid bed granulator and wet granulated using an aqueous solution containing povidone and sodium laurylsulfate (binding solution) under the conditions shown in Table 2.

3) The wet granules were sieved using 20 Mesh, and then cholecalciferol, lactose and propyl gallate were added and mixed uniformly.

4) Magnesium stearate was added to the second mixture and mixed homogeneously for 5 minutes.

5) The mixture was tabletted using a tablet machine.

Table 1 shows the compositions and contents of tablets finally obtained in Production Examples 1 to 4. For wet granules, 70.2 mg of purified water was used.

[Experimental Example 1]

Particle size distribution and angle of repose

Table 3 shows the results of measurement of particle size distribution and angle of repose after direct tableting, dry granulation, wet granulation using HSM and FBG according to the methods of Production Examples 1 to 4. Comparative Example 1 shows the particle size distribution of the cholecalciferol-concentrated powder. The particle size profile for each case is shown in FIG.

In the case of a combination formulation with cholecalciferol, cholecalciferol was mixed with penicacetic acid salt and other excipients in the form of cholecalciferol concentrate powder.

It is important to prepare granules having a particle distribution similar to that of the cholacillipelol concentrated powder in order to ensure the uniformity of content of cholecalciferol.

In the case of the cholecalciferol-concentrated powder of Comparative Example 1, almost all of the granules were present at 150 to 250 .mu.m to 69.6% by weight, and there existed 19.0% by weight at 250 to 500 .mu.m and 11.1% by weight at 75 to 150. , And particle sizes of 0 to 75 μm and 500 to 800 μm were almost not present at 0.2 wt% and 0.1 wt%, respectively.

In the case of simple mixing according to Preparation Example 1, the proportion of particles having a very fine particle size, that is, a particle size of 0 to 75 μm, accounted for more than half of 58.8% by weight, and the angle of repose was also high as 52.2 °, It is judged that the flowability is deteriorated due to the presence of the fine particles present in the solution. Based on the above results, it was confirmed that the preparation of the combination without the granulation process was impossible.

In the case of the dry granulation method according to Production Example 2, flake is produced by using pure water pressure without using particle water, thereby producing granules. At this time, since the fine particles were generated during the process of milling the flake, the particle size of 75 탆 to 150 탆, which is a relatively fine particle, accounted for more than half of 54.0 wt%. The angle of repose was 38.4 °, which showed stable flow during production.

In the wet granulation method, HSM method and FBG method were used. In the case of HSM granules, it is a method of granulating with a physical force by adding a binding liquid. In case of FBG, it is a method of granulating granules by spraying a binder and flowing powders.

In the case of HSM, the granules generated by the pressure are formed by using a certain sieve, so that granular particles having a desired size can be produced. Thus, particles having a particle size of 53.0 wt% at 150 mu m to 250 mu m were produced to be similar to the cholecalciferol-concentrated powder, with an angle of repose of 35.6 DEG.

FBG can be dried at the same time as the granulation process, which is advantageous in the process. However, since granules having small size particles are already formed in spite of the granulation of the granulated particles, it is difficult to form the granules in a certain size. As a result, the maximum particle size was found at 75 .mu.m to 150 .mu.m at 46.3% by weight, and it was 31.7% by weight at 150 .mu.m to 250 .mu.m. Therefore, it was confirmed that the mixing with the cholecalciferol concentrated powder was more advantageous in the case of HSM granules.

As a result, it was confirmed that the granules having the most similar particle size to the cholecalciferol concentrated powder were the HSM granules, and the HSM granule Preparation Example 3 is most advantageous in the tablet preparation.

[Experimental Example 2]

According to the manufacturing method, the elution test

The dissolution test was carried out for the tablets of Production Examples 1 to 4 under the following dissolution test conditions and sample analysis conditions. The vivienchol solution was used as a control.

≪ Dissolution test conditions >

1) Elution method: Elution of Korean Pharmacopoeia Method 2 (paddle method)

2) Eluent: pH 4.0 solution: 0.05 mol / L sodium acetate buffer solution (0.05 mol / L acetic acid solution, 0.05 mol / L sodium acetate solution (16.4: 3.6) mixture solution) is used.

3) Amount of eluate: 900 mL

4) Elution temperature: 37.5 DEG C

5) Paddle speed: 50 rpm

6) Test number: 6

7) Sample collection time: 5 minutes, 10 minutes, 15 minutes, 30 minutes and 45 minutes

≪ Specimen analysis condition >

Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 220 nm)

Column: A stainless steel tube having an inner diameter of about 4.6 mm and a length of 150 mm was loaded with 3.0 μm of C8 for liquid chromatography, a column filled with silica gel

Flow rate: 0.8 ml / min

Column temperature: 30 ° C

Analysis time: 10 minutes

The dissolution test results of Production Examples 1 to 4 are shown in Table 4, and the dissolution profiles with time are shown in Fig.

In the case of Preparation Examples 1 and 2, since tablets were prepared without adding water, since the sticky nature of the raw material itself kept the particles together, they did not disintegrate due to agglomeration of the drugs during elution Compared with the control drug.

In the case of Preparation Examples 3 and 4, since the tablets were prepared by wet granulation using water, disintegration of the pen was dispersed into other excipients at the time of disinfection, so that disintegration was not disturbed and elution similar to that of the reference drug was exhibited. However, the FBG granules showed lower elution than the HSM granules and the control drug, which is confirmed to be due to the content of bar sterilized pen as shown in Experimental Example 3.

[Experimental Example 3]

Concentration of phenylacetate and content uniformity test

Tests were carried out on the content and content uniformity of phenylacetate salt in the bar administration under the following test conditions. The experimental results are shown in Table 5.

<Content uniformity test conditions>

Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 220 nm)

Column: A stainless steel tube having an inner diameter of about 4.6 mm and a length of 150 mm was loaded with 3 μm of a C18 for liquid chromatography, a column filled with silica gel

Flow rate: 0.8 ml / min

Column temperature: 30 ° C

Analysis time: 10 minutes

Diluent: 90% methanol

The mean concentrations of bar acetic acid in preparations 1 to 3 were 101.4, 101.3 and 100.1%, respectively. This indicates that the pen did not disappear during the course of the process, which is the main component of small size.

However, in the case of Production Example 4 (FBG granule), the granule is produced by allowing the main component to float in the flow of air. At this time, when the bar having small particles is removed, .

Therefore, it is confirmed that the granulation of FBG granules is most advantageous by using the HSM granulation method, which is less in loss of the main component than the HSM granules.

[Experimental Example 4]

Content and content uniformity test of cholecalciferol

In order to confirm the mixing uniformity of the tablets of Production Examples 1 to 4 and the cholecalciferol concentrated powders, the content and content uniformity of cholecystorpellol were tested under the following test conditions. The experimental results are shown in Table 6.

<Content uniformity test conditions>

Detector: ultraviolet absorption spectrophotometer (measuring wavelength: 265 nm)

Column: A stainless steel tube having an inner diameter of about 4.6 mm and a length of 150 mm was loaded with 3 μm of a C18 for liquid chromatography, a column filled with silica gel

Flow rate: 1.5 ml / min

Column temperature: 30 ° C

Analysis time: 70 minutes

Diluent: 90% methanol

In the cholecalciferol concentrated powders, more than half of the particles have a particle size distribution of 150 mu m to 250 mu m. On the other hand, in Production Example 1, half or more particles exhibited a particle size distribution of 0 mu m to 75 mu m, and in Production Examples 2 and 4, half or more particles exhibited a particle size distribution of 75 mu m to 150 mu m.

In the case of Production Example 1, the result of the content uniformity is 18.6, which is not suitable because it has 15 or more. In Production Examples 2 and 4, 12.9 and 12.1, respectively, .

In the case of Production Example 3, it was confirmed that half or more of the particles exhibited a particle size distribution of 150 μm to 250 μm similar to the cholecalciferol-concentrated powder, and that the determination result of the content uniformity was very stable at 4.1

[Experimental Example 5]

Flexible material test

Flexible test for the tablets of Preparation Examples 1 to 4 was carried out under the following conditions.

&Lt; Conditions for testing a flexible substance &

Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 220 nm)

Column: A stainless steel tube having an inner diameter of about 4.6 mm and a length of 150 mm was charged with C18 for a liquid chromatograph of 2.6 μm, a column filled with silica gel

Flow rate: 0.8 ml / min

Column temperature: 30 ° C

Analysis time: 70 minutes

The tablets of Production Examples 1 to 4 were stored in HDPE bottles under harsh conditions (60 ° C) for 2 weeks and 4 weeks, and the amount of the produced substances was measured. The measurement results are shown in Table 7 and FIG.

As shown in the above table, in the case of Preparation Examples 1 and 2, a high amount of the flexible substance was produced from the beginning, and the pressurization due to the direct tableting process or compacting affects the physical properties of the phenylacetate at the time of bar cleansing, Increase.

In the case of Production Examples 3 and 4, it was confirmed that the increase range of the total flexible substances was very small as compared with the direct tableting method or the dry granulation method. That is, it was confirmed that it is possible to produce tablets having the stability of the active ingredient when they are produced by the wet granulation method.

[Experimental Example 6]

Confirmation of change of crystal form due to HSM granulation method

In order to confirm the change of the crystal form of phenacetate at the time of bar removal due to the HSM granulation method, an X-ray powder test was conducted with the tablet of Preparation Example 3.

FIG. 4 shows X-ray powder test results of raw materials of bar acetic acid and FIG. 5 shows X-ray powder test results of granules of Preparation Example 3. FIG.

As shown in FIG. 4, the erythropoietin acetic acid salt exhibits a crystalline form, and the crystalline form has an A form. The specific 2Θ values are 12.7 °, 16.0 °, 18.5 °, 20.7 ° and 22.3 °. In the case of FIG. 5, 2? Values were 12.7 degrees, 16.0 degrees, 18.5 degrees, 20.7 degrees, and 22.3 degrees.

Therefore, it was confirmed that there was no crystal form change according to the HSM granulation method.

Claims (15)

A pharmaceutical composition comprising a granule comprising a bar-cleansing cine or a pharmaceutically acceptable salt thereof, and a granule comprising cholecalciferol or a pharmaceutically acceptable salt thereof, wherein the granule comprises a bar or a pharmaceutically acceptable salt thereof, Characterized in that the particles having a particle size of not less than 150 [mu] m are not less than 50% by weight.
2. The pharmaceutical combination preparation according to claim 1, wherein the granules containing the bar-cleansing cine or a pharmaceutically acceptable salt thereof have a particle size of 150 mu m to 250 mu m of at least 40 wt%.
The pharmaceutical composition according to claim 1, wherein the cholecalciferol or pharmaceutically acceptable salt thereof is at least 50% by weight of particles having a particle size of 150 to 250 탆 and is contained in the form of a concentrated powder .
The pharmaceutical composition according to claim 1, further comprising at least one additive selected from the group consisting of lactose, microcrystalline cellulose, sodium starch glycolate, povidone, sodium lauryl sulfate, propyl gallate and magnesium stearate. .
The pharmaceutical combination preparation according to claim 1, which is in the form of a tablet.
2. The pharmaceutical combination according to claim 1, wherein the bar or the pharmaceutically acceptable salt thereof is a penic acid acetic acid salt.
A granule comprising a bar-cleansing cine or a pharmaceutically acceptable salt thereof, and cholecalciferol or a pharmaceutically acceptable salt thereof, which is produced by a wet granulation method using a high-speed mixer Or a pharmaceutically acceptable salt thereof.
The pharmaceutical combination preparation according to claim 7, wherein the granules containing the bar-cleansing cine or a pharmaceutically acceptable salt thereof have a particle size of not less than 150 mu m of not less than 50% by weight.
The pharmaceutical combination according to claim 7, wherein the granules containing the bar-cleansing cine or a pharmaceutically acceptable salt thereof have a particle size of 150 μm to 250 μm in an amount of 40% by weight or more.
The pharmaceutical composition according to claim 7, wherein the cholecalciferol or pharmaceutically acceptable salt thereof is at least 50% by weight of particles having a particle size of 150 to 250 탆 and is contained in the form of a concentrated powder .
8. The pharmaceutical combination preparation according to claim 7, wherein the bar-cleansing cine or its pharmaceutically acceptable salt has no change in the crystal form before and after the wet granule is produced.
Preparing a wet granule using a high-speed mixer comprising a bar-cleansing cine or a pharmaceutically acceptable salt thereof and at least one first additive;
Drying the wet granules; And
Uniformly mixing said wet granulate, cholecalciferol or a pharmaceutically acceptable salt thereof, and at least one second additive,
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
13. The method according to claim 12, wherein the first additive is selected from the group consisting of lactose, microcrystalline cellulose, sodium starch glycolate, povidone, and sodium lauryl sulfate.
13. The method according to claim 12, wherein the second additive is at least one selected from the group consisting of lactose and propyl gallate.
13. The process according to claim 12, wherein the stirring speed of the step of producing the wet granules by using the high-speed mixer is 250 to 350 rpm.

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