KR102463733B1 - Pharmaceutical composition comprising Varenicline Oxalate with improved content uniformity and stability - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for dry granulation tablets comprising varenicline oxalate or a hydrate thereof, a diluent, a filler, a disintegrant, a lubricant and a fluidizing agent, and a method for preparing the dry granulated tablet.

Description

Pharmaceutical composition comprising Varenicline Oxalate with improved content uniformity and stability

The present invention relates to a pharmaceutical composition containing varenicline oxalate having improved content uniformity and stability.

Varenicline having the structure of Formula 1 below is compound name 5,8,14-triazatetracyclo[10.3.1.0 ^{2,11.0 4,9} ]-hexadeca-2(11),3, 5,7,9-pentaene is a compound that binds to the neuronal nicotinic acetylcholine receptor and modulates the function of the choline receptor.

[Formula 1]

Varenicline is used for ulcerative colitis, pyoderma gangrene, inflammatory bowel disease such as Crohn's disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, appendicitis, vasoconstriction, anxiety, panic disorder. , depression, bipolar disorder, autism, sleep disturbance, jet lag syndrome, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, Progressive supranuclear palsy, dependence and addiction to nicotine, alcohol, benzodiazepines, barbiturates, opioids or cocaine, headache, migraine, stroke, traumatic brain injury (TBI), obsessive compulsive disorder (OCD), psychosis, Huntington's chorea, delayed In the treatment of dyskinesia, hyperkinesia, reading disorder, schizophrenia, multiple infarct dementia, age-related cognitive decline, epilepsy including minor seizure absence epilepsy, Alzheimer's type senile dementia, Parkinson's disease, attention deficit hyperactivity disorder (ADHD) and Tourette's syndrome can be used

Pharmaceutically, salts are developed to meet physicochemical criteria such as good solubility, good stability, and processability into tablet formulations. Examples of the pharmaceutically acceptable salt of varenicline include varenicline oxalate. Varenicline oxalate is useful for regulating the function of choline receptors by binding to neuronal nicotinic acetylcholine-specific receptor sites. Thus, varenicline oxalate may be usefully used to treat, prevent, or ameliorate dependence and addiction to nicotine or tobacco products.

However, since the tablet formulation containing varenicline oxalate has a small ratio of the main ingredient to its weight, it is a formulation with a great difference in stability depending on the mixing degree of the granules and the particle size of the main ingredient during tableting. In addition, it shows a decrease in stability under exposure to moisture, so it is an important preparation for pharmaceutical technology and moisture management in the composition containing varenicline oxalate.

Patent Document 1: WO 99/35131 (published on July 15, 1999) Patent Document 2: Korean Patent Publication No. 2016-0126696 (published on Nov. 2, 2016) Patent Document 3: WO 2003/045437 (published on June 5, 2003)

Accordingly, the present invention is to provide a pharmaceutical composition comprising varenicline oxalate or a hydrate thereof capable of improving content uniformity and stability by providing a composition for dry granulation tablets.

Another object of the present invention is to provide a method for manufacturing a dry granulated tablet containing varenicline oxalate or a hydrate thereof with improved content uniformity and stability through control of the manufacturing process of the dry granulated tablet.

In order to solve the above problems, the present invention provides a pharmaceutical composition for dry granulation tablets comprising varenicline oxalate or a hydrate thereof, a diluent, a filler, a disintegrant, a lubricant and a glidant.

According to a suitable embodiment of the present invention, varenicline oxalate hydrate has a structure of the following formula (2), and is preferably a monohydrate.

[Formula 2]

[In the above formula, n is 0.5 to 3.]

According to another suitable embodiment of the present invention, it is preferable that 19-30% by weight of a filler, 1-4% by weight of a disintegrant, and 0.5-2% by weight of a lubricant based on the total weight of the pharmaceutical composition are included.

According to another suitable embodiment of the present invention, the pharmaceutical composition for dry granulation tablets is varenicline oxalate or hydrate thereof, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. It is preferable to include

According to another suitable embodiment of the present invention, the pharmaceutical composition may further include a pharmaceutically acceptable additive.

The present invention also comprises the steps of making a first mixture by mixing a filler and a disintegrant in order to solve the above problems; a first sieving step of obtaining a primary sieve by sieving a component including varenicline oxalate or a hydrate thereof, a diluent and a fluidizing agent through a mesh size of 60 mesh or more; mixing the first sieve with the first mixture to make a second mixture by further mixing for 3 to 4 times longer than the mixing time of the first mixture; adding and mixing a lubricant to the second mixture, followed by compacting; and a secondary sieving step of sieving the granulated material produced by the compacting through a mesh having a size smaller than the primary sieve size. .

According to a suitable embodiment of the present invention, the first mixture may further comprise a diluent.

According to another suitable embodiment of the present invention, the mixing time of the second mixture is preferably about 30 to 40 minutes.

According to another suitable embodiment of the present invention, the mesh size during the secondary sieving is preferably 20 mesh to 25 mesh.

According to another suitable embodiment of the present invention, compacting is preferably carried out under the conditions of a pressure of 20 to 40 kgf/cm ² , a roller RPM of 3.0 to 5.0, and a screw RPM of 10.0 to 20.0.

According to the present invention, it is possible to provide a dry granulated tablet containing varenicline oxalate or a hydrate thereof having improved content uniformity and stability.

1 is a graph showing the results of evaluating the content uniformity of tablets prepared in Example 1 (dry granulation method), Comparative Example 1 (wet granulation method), and Comparative Example 2 (direct tableting method).
2 is a photograph showing the appearance of the uncoated tablet when the mesh size of the first sieving step is less than 60 mesh and when the mesh size is 60 mesh or more.
3 is a graph showing the results of determining the content uniformity for each sieve size according to the results of different sieve sizes in Comparative Examples 3 to 7; Comparative Example 6 was carried out in the same manner as in Example 1 with a 60 mesh.
4 is a graph showing the results of determining the content uniformity of the second mixture for each mixing time according to the results of varying the mixing time of the second mixture in Comparative Examples 8 and 9 and Examples 1 and 2;
5 is a graph showing the dissolution pattern according to the results of Examples 1, 3, 4 and Comparative Examples 10 and 11, as a result of varying the amount of croscarmellose sodium as a disintegrant.
6 is a graph showing the results of evaluating the content uniformity as a result of varying the amount of anhydrous calcium hydrogen phosphate (dicalcium phosphate (DCP)) used as a filler in Examples 1, 5, 6, and Comparative Example 12; .
7 is a graph showing the results of evaluating the dissolution pattern according to the results of Examples 1, 7, 8, and Comparative Examples 13 and 14, as a result of varying the amount of magnesium stearate as a lubricant.

Compressed tablets are manufactured through direct tableting, wet granulation, or dry granulation in a general formulation process. In the case of the direct tableting method, if the size of the raw material particles is not uniform, there may be a problem in the uniformity of the formulation, so it is not suitable for the manufacture of tablets containing varenicline oxalate. In the case of the wet granulation method, a uniform tablet can be obtained, but it may affect the stability problem due to moisture, so that it is difficult to prepare a tablet containing varenicline oxalate. On the other hand, in the case of the dry granulation method, the uniformity of the formulation can be ensured through an intermediate operation procedure such as compacting, and stability due to moisture can be secured by excluding moisture from the granule production process. In view of this, the present inventors further researched the dry granulation method, and found that the uniformity and stability of the final tablet is improved by using the mixing time of the granular material itself and controlling the particle size of the raw material before the dry granulation is produced. To find out, the present invention was completed.

According to the present invention, there is provided a pharmaceutical composition for dry granulation tablets comprising varenicline oxalate or a hydrate thereof.

Barrenicline oxalate may preferably be a hydrate, and has a structure represented by the following Chemical Formula 2 below.

[Formula 2]

[In the above formula, n is 0.5 to 3.]

In the present invention, when varenicline oxalate is a hydrate, the water content is preferably 1 to 12% by weight, as measured by Karl-Fischer Method, and the water content is about 5.2% by weight. Monohydrates inside and outside are more preferable in terms of stability.

The pharmaceutical composition for dry granulation tablets containing varenicline oxalate may contain 0.5mg or 1mg of varenicline oxalate or a hydrate thereof per tablet.

The pharmaceutical composition for dry granulation tablets comprising varenicline oxalate or a hydrate thereof may further include a diluent, a filler, a disintegrant, a lubricant, a glidant, and a pharmaceutically acceptable additive.

In order to improve content uniformity and stability, control of the process during tablet manufacturing is important, but the content of components constituting the pharmaceutical composition is also important. In particular, it has been shown that the desired dissolution rate can be secured only when the content of the disintegrant and the lubricant are within a predetermined range, and uniformity of the formulation of the tablet can be secured when the filler content also satisfies the predetermined range.

In the present invention, the disintegrant is preferably included in an amount of 1 to 4% by weight based on the total weight of the composition. By allowing it to fall within this range, the initial dissolution rate can be secured, and productivity can be secured during the tableting process. Disintegrants include, but are not limited to, povidone, croscarmellose sodium, crospovidone, and the like.

The lubricant is preferably included in an amount of 0.5 to 2% by weight based on the total weight of the composition. By including in the above range, it is possible to secure the required dissolution rate. In addition, when too little is used, the binding of the granules in the compactor occurs severely, making it difficult to secure productivity, and when using too much, there is a problem in that the dissolution rate is not secured. The lubricant may include, but is not limited to, talc, magnesium or calcium stearate, hydrogenated castor oil, talcum powder, and solid polyethylene glycol.

The filler is preferably included in an amount of 19 to 40% by weight, and more preferably in an amount of 25 to 35% by weight, based on the total weight of the composition. By including in the above range, the formulation uniformity can be maximized, and the generation of fine powder due to excessive use can be reduced. Examples of the filler include anhydrous calcium hydrogen phosphate.

The diluent is an inactive ingredient added for tableting of varenicline oxalate or its hydrate contained in a small amount in the tablet, and is preferably included in an amount of 50 to 75% by weight based on the total weight of the composition. Examples of the diluent include microcrystalline cellulose, cellulose, polyvinylpyrrolidone, and gelatin.

In addition, the fluidizing agent is a component that improves the flow characteristics of the granulation mixture, and is preferably included in an amount of 0.2 to 0.6% by weight based on the total weight of the composition so as to maximize the effect without affecting other components. Examples of the fluidizing agent include silicon dioxide, colloidal silicon dioxide, and talc.

The present invention provides a method for manufacturing a dry granulated tablet comprising varenicline oxalate or a hydrate thereof. The manufacturing method of the present invention can provide a tablet containing varenicline oxalate hydrate with improved uniformity and stability by controlling the preliminary sieving and mixing time of the raw material before the compacting process for dry granulation.

The manufacturing method comprises the steps of mixing a filler and a disintegrant to make a first mixture; a first sieving step of obtaining a primary sieve by sieving varenicline oxalate or a hydrate thereof, a diluent and a fluidizing agent with a mesh size of 60 mesh or more; mixing the first sieve with the first mixture to make a second mixture by further mixing for 3 to 4 times longer than the mixing time of the first mixture of the first mixture; adding and mixing a lubricant to the second mixture, followed by compacting; and a secondary sieving step of sieving the granules produced by the compacting through a mesh having a size smaller than the primary sieve size.

The first mixture may further include a diluent. The diluent may be added at once during the first sieve, but a part of the total amount, for example, 1/3 to 1/2, may be added when preparing the first mixture. In this case, it is preferable to improve the uniformity of the formulation.

There is no particular limitation on the sieving method for the primary sieve, but for example, varenicline oxalate may be first sifted and then the remaining components may be sifted.

It is preferable that the mesh size during the first sieving is 60 mesh or more, and even if the mesh size exceeds 60 mesh, there is no significant difference in the effect according to the mesh size. When the sieve is less than 60 mesh, the appearance uniformity of the manufactured raw tablet is deteriorated, and the content uniformity is also deteriorated.

The time to make the second mixture by mixing the primary sieve and the first mixture is preferably carried out 3 to 4 times longer than the time of the first mixture. By controlling the mixing time of the second mixture to a predetermined value, it is possible to secure content uniformity of the dry granulated tablet. According to one embodiment, it can be carried out in the range of about 30 to 40 minutes, when it is carried out for less than 30 minutes, the content uniformity is low, and when it exceeds 40 minutes, the effect according to the excess is not obtained, so it is not economical .

Mixing of the first mixture, the second mixture, and the lubricant may use a mixing method known in the art, for example, may be mixed using a mixer such as a tubular mixer (Tubular Mixer).

The mesh size during secondary sieving is not particularly limited as long as it is within a range capable of manufacturing dry granulated tablets, and for example, 20 mesh to 25 mesh may be preferably employed.

The compacting process is carried out using a roller compactor, and in order to secure the content uniformity of the dry granulated tablet, the pressure 20~40kgf/cm ² , roller RPM 3.0~5.0, screw RPM 10.0~20.0. can

Hereinafter, the present invention will be specifically described by way of Examples and Comparative Examples. However, the following examples and comparative examples are only for illustrating the present invention, and the present invention is not limited by the following examples. In addition, it will be apparent to those of ordinary skill in the art to which the present invention pertains that modifications and changes can be made without departing from the technical spirit of the present invention.

Example

Example One

1/3 of the total amount of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and croscarmellose sodium are mixed with a tubular mixer at about 50 rpm for 10 minutes. Then, varenicline oxalate monohydrate, the remaining amount of microcrystalline cellulose, and colloidal silicon dioxide are sieved through a 60 mesh (primary sieve), added to the tubular mixer, and at about 50 rpm for about 30 minutes (mixing the second mixture) time) to proceed with further mixing. Add 3/2 of the total amount of magnesium stearate used into the tubular mixer, mix for an additional 5 minutes, and then compact to form a dry granulation. Compacting conditions were a pressure of 30 kgf/cm ² , roller RPM 4.0, and screw RPM 15.0. Then, the remaining amount of magnesium stearate was added, followed by mixing for about 2 minutes. The resulting granulation was sieved through 20 Mesh. The granulated material was tableted at a pressure of 1150 kgf, and the weight was adjusted to 209.00 mg per tablet. The components and contents are shown in Table 1 below.

comparative example 1: wet granulation

Microcrystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium and colloidal silicon dioxide were mixed with a tubular mixer for about 20 minutes. Thereafter, hydroxypropyl cellulose was dissolved in 100 mg of purified water per tablet, and varenicline oxalate monohydrate was added to prepare a binding solution. The granulation produced by a high-shear granulator at 150 rpm with an agitator and at 3000 rpm with a microwave oven was dried in a chamber at 60 °C until a moisture content of less than 2%. Magnesium stearate was added to the granulate that passed through a 20 mesh sieve, and the mixture was further mixed for about 5 minutes. It was compressed with 1150 kgf pressure and adjusted to have a weight of 209.00 mg per tablet. Ingredients and contents are shown in Table 1 below.

comparative example 2: Direct tableting method

1/3 of the total amount of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and croscarmellose sodium were mixed using a tubular mixer at about 50 rpm for about 10 minutes. Thereafter, varenicline oxalate monohydrate, the remaining amount of microcrystalline cellulose, and colloidal silicon dioxide were sieved through 60 Mesh and added to the tubular mixer, followed by further mixing at about 50 rpm for about 20 minutes. After adding magnesium stearate, the mixture was further mixed for about 5 minutes, and then tableted. The tableting was adjusted to a weight of 209.00 mg per tablet at a pressure of 1150 kgf. The components and contents are shown in Table 1 below.

[Table 1]

<Test Example 1: Evaluation of content uniformity and related substances according to the manufacturing process method>

In order to examine the content uniformity of the tablets prepared in Examples and Comparative Examples 1 and 2, a content uniformity test was performed according to the formulation uniformity test method of the Korean Pharmacopoeia general test method, and the result is shown in FIG. It was. As a result of the content uniformity test, if the judgment value is within 15, the standard is satisfied.

As shown in FIG. 1 , the content uniformity according to the manufacturing process method showed a high determination value in the order of Comparative Example 1, Example 1, and Comparative Example 2. In Comparative Example 1 using a conventional wet granulation method, it seems that the determination value was improved through dissolution of varenicline oxalate monohydrate and dispersion of the binder solution. In the case of Example 1, flakes were formed through the dry granulation method and additional mixing processes were performed several times, but it was found that the effect as the liquid dispersion of Comparative Example 1 was not obtained. In the case of Comparative Example 2, the result was that the mixture with other excipients did not show a constant mixing ratio due to problems such as adhesion of the base wall and layer separation of the raw material of varenicline oxalate monohydrate.

The degree of generation of related substances (0.5% or less for individual related substances, 2.0% or less for total related substances) was evaluated at 60°C and 2 weeks after storage of the HDPE bottle. As shown in Table 2 below, it could be confirmed that the generation of related substances was remarkably occurred in Comparative Example 1 compared to Examples 1 and 2. This appears to be influenced by the change in crystal form and moisture exposure during the dissolution of the main component into the liquid phase. On the other hand, in the case of Example 1 and Comparative Example 2, the rate of generation of related substances not significantly deviated from the raw material level was shown.

From the above results, it was confirmed that content uniformity and the degree of generation of related substances could be satisfactorily achieved only in the case of the dry granulation method of Example 1 according to the present invention.

[Table 2]

Example 2, comparative example 3 to 9

A dry granulated tablet was prepared in the same manner as in Example 1 except that the mesh size and the mixing time of the second mixture during the first sieve were as shown in Table 3 below.

[Table 3]

<Test Example 2: Evaluation according to sieve size and mixing time>

The tablets prepared in Examples 1 and 2 and Comparative Examples 3 to 9 were evaluated for appearance and content uniformity, and the results are shown in FIGS. 2, 3 and 4 . Content uniformity was carried out according to the formulation uniformity test method of the Korean Pharmacopoeia general test method.

2 is a photograph showing the external properties of the compressed raw tablet. According to this, it can be seen that the compression tablet was more homogeneously compressed than when the tablet was sieved at 60 mesh or more compared to the case where it was sieved at less than 60 mesh during the first sieve.

3 is a graph showing the results of determining the content uniformity by sieve size. According to this, it can be seen that the increase in the mesh size does not significantly affect the content uniformity in the case of 60 mesh or more. In addition, FIG. 4 is a graph showing the results of determining the content uniformity for each mixing time of the second mixture, and according to this, it can be seen that an increase in the mixing time of 30 minutes or more does not significantly affect the content uniformity.

From the above results, it was confirmed that content uniformity and stability could be improved by sieving with a size of 60 mesh or more.

Example 3 to 8 and comparative example 10 to 14

A dry granulated tablet was prepared in the same manner as in Example 1 except for the content shown in Table 4 below.

[Table 4]

<Test Example 3: Evaluation of dissolution rate and formulation uniformity according to the amount of formulation component used>

The dissolution rate and content uniformity were evaluated for the uncoated tablets prepared as shown in Table 4 above. Content uniformity was carried out according to the formulation uniformity test method of the Korean Pharmacopoeia general test method.

5 is a graph showing the dissolution pattern according to the amount of croscarmellose sodium used as a disintegrant. According to this, in the case of Comparative Example 10, the final dissolution rate was 82%, which did not reach the 85% dissolution rate (determination criterion) in 30 minutes, which is presumed to be due to the delay of the initial disintegration time due to the lack of a disintegrant. In the case of Examples 3, 1, 4 and Comparative Example 11, it can be seen that the dissolution rate is improved as the disintegrant content is increased. In addition, in the case of Examples 3, 1, 4 and Comparative Example 11, all of them exhibited a dissolution rate of 85% or more at 30 minutes, but in Comparative Example 11, the degree of wear and tear due to excessive input of the disintegrant was 1.8%, which was weak in productivity. confirmed to be

Meanwhile, FIG. 6 is a graph showing the results of evaluating the content uniformity according to the amount of anhydrous calcium hydrogen phosphate (dicalcium phosphate (DCP)) as a filler. According to this, it was observed that the formulation uniformity was improved as the content of anhydrous calcium hydrogen phosphate increased. In the case of Example 5, although no judgment value exceeding the standard was shown, it can be seen that a judgment value of a significantly higher level than that of Example 1 was exhibited. After the ratio of Example 1, it was confirmed that the variability of the judgment value, ie, the formulation uniformity, did not significantly increase. However, in the case of Comparative Example 12, due to excessive input of anhydrous calcium hydrogen phosphate, excessive fine powder was generated during the compacting process, and thus a problem was found that the process yield was only about 71%.

7 is a graph showing the results of evaluating the dissolution pattern according to the input amount of magnesium stearate as a lubricant. According to this, as the amount of magnesium stearate was increased, the dissolution rate gradually decreased to reach the ratio of Comparative Example 14, and a result that did not satisfy the dissolution rate (determination criterion) of 85% of the reference value of 30 minutes was obtained. In Comparative Examples 13, 7, 1, and 8, except for Comparative Example 14, dissolution rates suitable for the determination criteria were satisfied, but in the case of Comparative Example 13, due to the trace amount of magnesium stearate in the compacting process, There was a big problem in productivity due to the strong binding of the granules, and the productivity was not good due to the sticking phenomenon with the upper punch and the lower punch in the tableting process.

From the above results, it was confirmed that the formulation uniformity and dissolution rate of the dry granulated tablet to be prepared could be obtained only when the disintegrant, the filler, and the lubricant were set to a value within a predetermined range.

Claims (10)

A pharmaceutical composition for dry granulation tablets comprising varenicline oxalate or a hydrate thereof, a diluent, a filler, a disintegrant, a lubricant and a glidant,
50-75 wt% of a diluent, 19-40 wt% of a filler, 1-4 wt% of a disintegrant, 0.5-2 wt% of a lubricant, 0.2-0.6 wt% of a glidant with respect to the total weight of the pharmaceutical composition,
The diluent is selected from the group consisting of microcrystalline cellulose, cellulose, polyvinylpyrrolidone and gelatin,
The filler is anhydrous calcium hydrogen phosphate,
The disintegrant is selected from the group consisting of povidone, croscarmellose sodium and crospovidone,
The lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, hydrogenated castor oil and talcum powder solid polyethylene glycol,
The glidant is a pharmaceutical composition for dry granulation tablets selected from the group consisting of silicon dioxide, colloidal silicon dioxide and talc.
According to claim 1,
The pharmaceutical composition for dry granulation tablets, characterized in that the varenicline oxalate hydrate is a monohydrate.
According to claim 1,
The diluent is microcrystalline cellulose,
The disintegrant is croscarmellose sodium,
The lubricant is magnesium stearate,
The glidant is colloidal silicon dioxide, a pharmaceutical composition for granulation tablets.
According to claim 1,
The pharmaceutical composition is a pharmaceutical composition for dry granulation tablets further comprising a pharmaceutically acceptable additive.
mixing a filler and a disintegrant to form a first mixture;
a first sieving step of obtaining a primary sieve by sieving a component including varenicline oxalate or a hydrate thereof, a diluent and a fluidizing agent through a mesh size of 60 mesh or more;
mixing the first sieve with the first mixture to make a second mixture by further mixing for 3 to 4 times longer than the mixing time of the first mixture;
adding and mixing a lubricant to the second mixture, followed by compacting; and
A drug for dry granulation tablets comprising the varenicline oxalate or hydrate thereof according to claim 1, comprising a secondary sieving step of sieving the granulated material produced by the compacting through a mesh having a size smaller than the primary sieve size. A method for preparing a pharmaceutical composition.
6. The method of claim 5,
The method for producing a pharmaceutical composition for dry granulation tablets comprising varenicline oxalate or a hydrate thereof, wherein the first mixture further comprises a diluent.
6. The method of claim 5,
A method for producing a pharmaceutical composition for dry granulation tablets comprising barrenicline oxalate or a hydrate thereof, characterized in that the mixing time of the second mixture is 30 to 40 minutes.
6. The method of claim 5,
The method of manufacturing a pharmaceutical composition for dry granulation tablets comprising varenicline oxalate or a hydrate thereof, characterized in that the mesh size during the second sieving is 20 mesh to 25 mesh.
6. The method of claim 5,
The compacting is a pharmaceutical for dry granulation tablets containing barrenicline oxalate or its hydrate, characterized in that the compacting is carried out under the conditions of a pressure of 20 to 40 kgf/cm ² , roller RPM 3.0 to 5.0, and screw RPM 10.0 to 20.0. A method for preparing the composition. delete

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