KR101592258B1

KR101592258B1 - formulation and method of preparing the same

Info

Publication number: KR101592258B1
Application number: KR1020140075491A
Authority: KR
Inventors: 김상엽; 명제혁
Original assignee: 보령제약 주식회사
Priority date: 2014-06-20
Filing date: 2014-06-20
Publication date: 2016-02-05
Also published as: KR20150145941A; WO2015194769A1

Abstract

The preparations comprising the inventive Erotinib or a pharmaceutically acceptable salt thereof are excellent in the quality uniformity of each individual. The dissolution rate of each preparation of the preparation according to the present invention is almost always constant and the particle size distribution ratio is kept constant. In addition, it is possible to suppress the rapid release of the drug at an early stage, thereby minimizing side effects of the drug.

Description

Formulation and method of preparing same,

The present invention relates to a formulation comprising erlotinib or a pharmaceutically acceptable salt thereof and a process for the preparation thereof. More specifically, the present invention relates to a formulation comprising elotinib hydrochloride which can minimize the individual differences of each formulation, and a method for producing the same.

Erotinib is a tyrosine kinase inhibitor and is used as a treatment for various cancers including pancreatic cancer. Erotitib has been used in the treatment of localized, non-invasive or metastatic pancreatic cancer in combination with gemcitabine or in the treatment of locally advanced or metastatic non-small cell lung cancer that has failed previous chemotherapy.

Irootinib hydrochloride is a high-permeability, low-solubility BCS class II drug that exhibits an absorption rate of about 60% when administered orally, has a Tmax of 4 hours And the bulk density is low.

As a result, it is difficult to obtain efficacy equivalence among the pharmaceutical preparations because the proportion of the drug containing the Erotinib hydrochloride as the active ingredient greatly varies depending on the degree of dissolution and the dissolution rate of the drug, There is a problem that it is difficult to ensure quality homogeneity between the preparations containing the components.

When the quality uniformity is not ensured between the formulations, a difference in the content of the active ingredient between the formulations may occur, so that a preparation which can not sufficiently exhibit the effect as an anticancer drug can be prepared. In addition, There are many attempts to secure the quality uniformity between the preparations containing the active ingredient of erlotinib or a pharmaceutically acceptable salt thereof as the active ingredient since the production efficiency may be lowered or unexpected side effects may be caused.

US 5747498 US 6900221

It is an object of the present invention to provide a formulation comprising erlotinib or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a process for the preparation of a medicament comprising erlotinib or a pharmaceutically acceptable salt thereof.

The present invention provides a formulation comprising a granulate containing erotinib or a pharmaceutically acceptable salt thereof having a particle diameter of at least 425 占 퐉 and a pharmaceutical formulation comprising a pharmaceutically acceptable additive.

In the present invention, the pharmaceutically acceptable salt may be an acid addition salt formed by a pharmaceutically acceptable free acid. As the free acid, an inorganic acid and an organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. Examples of the organic acid include citric acid, acetic acid, maleic acid, fumaric acid, But are not limited to, acetic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and aspartic acid. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid, more preferably hydrochloric acid.

The invention provides a formulation comprising a granulate containing a hydrochloride salt of elotinib having a particle diameter of 425 占 퐉 or greater and a formulation comprising a pharmaceutically acceptable additive.

In the present invention, the above-mentioned preparations have a weight ratio of granules comprising the elotinib having a particle diameter of 425 占 퐉 or more, a pharmaceutically acceptable salt thereof or the elotinib hydrochloride in an amount of 60% by weight or more based on the total weight of the composition.

In the formulation of the present invention, the composition wherein the weight ratio of the granules of the above-mentioned elotinib, its pharmaceutically acceptable salt or erloxib hydrochloride in the granules having a diameter of 425 탆 or more is 60% by weight or more based on the total weight of the above- It is possible to minimize the individual difference between the formulations and to provide a product with excellent quality uniformity. In other words, the dissolution rate of each of the manufactured product entities is kept substantially constant, and the particle size distribution ratio of the granules contained in the entities is also kept substantially constant, so that excellent quality uniformity can be ensured and the initial rapid release To minimize unexpected side effects.

In the present invention, the granules having a diameter of 425 占 퐉 or more in the granules of the above-mentioned elotinib, pharmaceutically acceptable salt thereof or ellothinib hydrochloride may have a particle diameter of preferably 425-850 占 퐉, The granules having such a particle diameter may be at least 50% by weight based on the weight of the total composition.

In the present invention, the pharmaceutically acceptable additive may be a lubricant, for example, stearic acid, sodium stearyl fumarate, talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, , White lead, titanium oxide, or a mixture thereof, preferably magnesium stearate.

In the present invention, the preparation may minimize the difference in dissolution rate between individuals, and the relative standard deviation of the dissolution rate between individuals may be less than 2%.

In addition, the above-mentioned preparation prevents elutinib, its pharmaceutically acceptable salt or elotinib hydrochloride from being rapidly eluted at an early stage in an acidic state, so that the maximum blood concentration (Cmax) of the drug is increased more than necessary due to rapid elution of the drug To minimize drug-related side effects.

In the present invention, the above granules may contain pharmaceutically acceptable additives in addition to the active ingredient, erlotinib, its pharmaceutically acceptable salt or erlotinib hydrochloride. The pharmaceutically acceptable additives may be surfactants, diluents, disintegrants, lubricants, and the like. For example, the granulate may contain, in addition to the active ingredient, erlotinib, its pharmaceutically acceptable salt or hydrochloride salt of erlotinib, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, D-mannitol, At least one selected from the group consisting of starch, sodium lauryl sulfate, colloidal silicon dioxide, croscarmellose sodium, crospovidone, copovidone, and magnesium stearate.

In the present invention, the pharmaceutical preparations for oral administration may be tablets or capsules, preferably tablets.

In the present invention, the preparation may contain 20 mg to 180 mg, more preferably 25 mg to 170 mg, of the active ingredient, erlotinib, its pharmaceutically acceptable salt or erlotinib hydrochloride, per unit preparation.

In the present invention, the preparation can be administered in an appropriate number of times depending on the condition of the patient, and preferably, the unit preparation can be administered once a day.

The present invention provides a process for the preparation of a medicament containing as an active ingredient erlotinib, a pharmaceutically acceptable salt thereof or erlotinib hydrochloride.

In the present invention,

Preparing a primary mixture by mixing Erotinib or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; And

Comprising the step of preparing a composition comprising granules containing erotinib or a pharmaceutically acceptable salt thereof having a particle diameter of at least 425 占 퐉 from said primary mixture.

In the present invention, the granules having a particle diameter of 425 탆 or more are 60% by weight or more based on the total weight of the primary mixture.

In the present invention, the pharmaceutically acceptable salt may preferably be the hydrochloride salt of erotinib.

In the present invention,

Preparing a first mixture by mixing Erotinib hydrochloride with a pharmaceutically acceptable additive; And

From the primary mixture, a granulate containing an elotinib hydrochloride having a particle diameter of 425 탆 or more.

In the present invention, the granules of the elotinib hydrochloride having a particle diameter of 425 탆 or more are 60% by weight or more based on the total weight of the primary mixture.

In the present invention, the step of preparing the composition comprises:

Preparing a primary granulate comprising the elotinib, a pharmaceutically acceptable salt thereof, or urotinib hydrochloride from the primary mixture;

Firstly selecting granules having a particle diameter of 425 탆 or more among the primary granules; And

And producing a secondary granulate from the granules having a particle diameter of less than 425 탆 in the granules among the primary granules.

In the present invention, the step of preparing the composition may further include a step of secondary selection of the granules having a particle diameter of 425 탆 or more in the prepared secondary granule.

The granules selected first among the primary granules and the secondary granules selected from the secondary granules are combined so that the selected granular material having a particle diameter of 425 탆 or more is contained in an amount of not less than 60% The process for forming additional granules may not be performed further. After collecting all the remainder of the primary mixture except for the granules of 425 탆 or more selected out of the primary granules and the secondary granules, the collected granules were mixed with the selected granules of 425 탆 or more to prepare a composition can do.

In the present invention, the granules selected first among the primary granules and the secondary granules selected from the secondary granules are combined and the selected granular material having a particle diameter of 425 탆 or more is mixed with the total weight of the primary mixture If less than 60% by weight, the additional granulation process can be carried out. That is, the granules having a particle diameter of less than 425 占 퐉 in the secondary granules can be collected and a third granule can be prepared therefrom. The granules having a particle diameter of 425 占 퐉 or more are thirdly selected from the tertiary granules, and then the primary selected granules having a particle diameter of 425 占 퐉 or more, the secondary selected granules and the tertiary selected granules are combined, If the granules having a selected particle diameter of 425 占 퐉 or more are not less than 60% by weight based on the total weight of the first mixture, the selected granules and the remaining components other than the selected granules in the first mixture Can be combined to prepare a formulation from which the composition can be prepared.

If granules having a particle diameter of 425 탆 or more selected through primary sorting, secondary sorting and tertiary sorting are still less than 60% by weight based on the total weight of the primary mixture, at least 60% by weight The same process can be repeated continuously.

In the present invention, the granules having a particle diameter of 425 탆 or more can be selected by selecting a granule which can not pass through the sieve of the above standard by using a 40 taut body (sieve size: 425 탆, KS designation: 425). This can be equally applied to the selection process which can be performed by the primary selection, the secondary selection or the tertiary selection and additionally.

In the present invention, the step of producing the primary granule may comprise:

Subjecting the primary mixture to a granulation process to produce a primary granule; And

And performing a sizing process on the primary granules.

In the present invention, the above-mentioned granulation refers to a process for preparing a mixture containing an active ingredient into granules. In the present invention, the sizing refers to the step of forming the formed granules into sized granules.

In the present invention, the sizing process may be carried out using a standard No. 16 standard (sieve size: 1.18 mm, KS designation: 1.18). For example, the primary granules prepared by performing the granulation process on the primary mixture may be passed through the 16th embodied standard to prepare the primary granules.

In the present invention, the pharmaceutical composition may be prepared by mixing the composition with a pharmaceutically acceptable additive to prepare a second mixture, and then using the second mixture. For example, if the preparation is a tablet, the tablet may be prepared by tabletting the secondary mixture.

According to the method of the present invention, the granulation process and the sizing process, which are two or more granulation processes, are carried out so that the granules having a particle diameter of 425 μm or more are at least 60% by weight of the originally used raw material, The particle size distribution can be made uniform, and a preparation having excellent quality uniformity can be produced by keeping the dissolution rate and the particle size distribution ratio between each individual formulation constant.

The present invention relates to a pharmaceutical composition comprising erotinib, a pharmaceutically acceptable salt thereof or hydrochloride salt of erlotinib as an active ingredient, wherein the granules of the active ingredient have a diameter of 425 탆 or more of not less than 60% by weight It is possible to remarkably improve the quality uniformity of the preparation by keeping the dissolution rate and the particle size distribution between the preparation products constant.

FIGS. 1 to 4 show dissolution rates of formulations of Examples and Comparative Examples of the present invention.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are intended to illustrate the present invention without limiting it thereto. Also, the reagents and materials mentioned below are purchased from Simga-Aldrich Korea unless otherwise noted.

Example 1)

Tablets containing the elotinib hydrochloride salt were prepared using the ingredients and contents described in Example 1 of Table 1 below. 163.93 mg of Erotinib hydrochloride, 99.32 mg of lactic acid hydrate, 132.75 mg of microcrystalline cellulose, 4.5 mg of colloidal silicon dioxide, 4.5 mg of sodium lauryl sulfate, 36 mg of sodium starch glycolate and 4.5 mg of magnesium stearate were added to a V-mixer A primary mixture was prepared. The above mixture was first granulated using a roller compactor (TF-208, Vector Freund). The granules were formulated into primary granules using a 16-well body standard (sieve size 1.180 mm, KR designation 1.18). The granules having a size of 425 탆 or more were firstly selected from the primary granules prepared by the No. 16 sieve using a 40-well standard body (sieve size 425 탆, KS designation 425). On the other hand, among the primary granules, granules smaller than 425 μm that passed through the 40th tumbler were put into a V-mixer and mixed. Then, secondary granules were prepared using a roller compactor (TF-208, Vector Freund) A second granule was prepared using a standard. The secondary granules prepared by the 16th tincture standard were secondly selected by using the 40th tincture standard and the granules having a size of 425 μm or more. The weight ratio of the granules having a particle size of 425 μm selected from the primary granules and the secondary granules to the total weight of the primary mixture was determined to be 60-70% by weight. In addition to the granules having the selected particle diameter of 425 占 퐉, all the rest were collected in the first mixture, added to the granules having the selected particle diameter of 425 占 퐉, and 4.5 mg of magnesium stearate was added thereto to prepare a second mixture . The secondary mixture was tableted at a tenter pressure of about 20 kN to prepare a tablet containing the elotinib hydrochloride. The tablets were coated with Opadry to prepare tablets containing Irootinib hydrochloride.

Example 2)

The tablets were prepared in the same manner as in Example 1, except that the ingredients and the contents described in Example 2 of Table 1 were used, and that the granulation, sizing and selection steps were repeated three times instead of twice. In Example 2, the particle ratio of primary to tertiary granules having a particle diameter of 425 占 퐉 or more was about 70 to 80% by weight of the primary formed primary mixture.

Example 3)

Tablets were prepared in the same manner as in Example 1, except that the ingredients and the contents described in Example 3 of Table 1 were used, and that the granulation, sizing and selection steps were repeated four times instead of twice. In Example 3, the particle ratio of the first to fourth granules having a particle diameter of 425 占 퐉 or more was about 80 to 90% by weight of the initial formed primary mixture.

Example 4)

The tablets were prepared in the same manner as in Example 1, except that the ingredients and the contents described in Example 4 of Table 1 were used, and that the granulation, sizing and selection steps were repeated 5 times instead of twice. In Example 4, the ratio of 1st to 5th granular water particles having a particle diameter of 425 占 퐉 or more in particle diameter was about 90 to 100% by weight of the first-formed primary mixture.

[Table 1] Examples 1 to 4

Example 5)

Tablets were prepared in the same manner as in Example 1 except that the ingredients and the contents described in Example 5 of the following Table 2 were used. In Example 5, the proportion of the granular particles having a particle diameter of 425 탆 or more was at least about 60% by weight of the originally formed primary mixture.

Example 6)

Tablets were prepared in the same manner as in Example 1, except that the ingredients and the contents described in Example 6 of the following Table 2 were used. In Example 6, the proportion of the granular particles having a particle diameter of 425 탆 or more was at least about 60% by weight of the originally formed primary mixture.

Example 7)

Tablets were prepared in the same manner as in Example 1 except that the ingredients and the contents described in Example 7 of the following Table 2 were used. In Example 7, the proportion of the granular particles having a particle diameter of 425 탆 or more was at least about 60% by weight of the originally formed primary mixture.

[Table 2] Examples 5 to 7

Example 8)

Tablets were prepared in the same manner as in Example 1 except that the ingredients and the contents described in Example 8 of the following Table 3 were used. In Example 8, the proportion of the granular particles having a particle diameter of 425 탆 or more was at least about 60% by weight of the originally formed primary mixture.

Example 9)

Tablets were prepared in the same manner as in Example 1 except that the ingredients and the contents described in Example 9 of the following Table 3 were used. In Example 9, the proportion of the granular particles having a particle diameter of 425 탆 or more was at least about 60% by weight of the originally formed primary mixture.

Example 10)

Tablets were prepared in the same manner as in Example 1 except that the ingredients and the contents described in Example 10 of the following Table 3 were used. In Example 10, the proportion of the granular particles having a particle diameter of 425 탆 or more was about 60% by weight or more of the originally formed primary mixture.

[Table 3] Examples 8 to 10

Example 11)

Tablets were prepared in the same manner as in Example 1 except that the ingredients and the contents described in Example 11 of Table 4 were used. In Example 11, the proportion of the granular particles having a particle diameter of 425 占 퐉 or more was at least about 60% by weight of the originally formed primary mixture.

Example 12)

Tablets were prepared in the same manner as in Example 1 except that the components and the contents described in Example 12 of the following Table 4 were used. In Example 12, the proportion of the granule particles having a particle diameter of 425 탆 or more was at least about 60% by weight of the originally formed primary mixture.

Example 13)

Tablets were prepared in the same manner as in Example 1 except that the ingredients and the contents described in Example 13 of Table 4 were used. In Example 13, the proportion of the granule particles having a particle diameter of 425 탆 or more was at least about 60% by weight of the originally formed primary mixture.

Example 14)

Tablets containing the elotinib hydrochloride salt were prepared using the ingredients and the contents described in Example 14 of Table 4 below. 163.93 mg of Erotinib hydrochloride, 99.32 mg of lactic acid hydrate, 132.75 mg of microcrystalline cellulose, 4.5 mg of colloidal silicon dioxide, 4.5 mg of sodium lauryl sulfate, 36 mg of sodium starch glycolate and 4.5 mg of magnesium stearate were added to a V-mixer A primary mixture was prepared. The first mixture was put into a high share mixer (SM5C, SEJONG) and coalesced and granulated with 45 mg of ethanol. The mixture was then dried in a dryer at 50 ° C for about 5 hours and then dried to obtain a 16- : 1.18) were used as primary granules. The primary granules were firstly selected by using a 40-well ternary standard, only granules having a diameter of 425 μm or more. On the other hand, the granules smaller than 425 탆 which passed through the standard body of the 40th tongue (sieve size: 425 탆, KS designation: 425) in the first granule were put into the V-mixer and mixed, and then the high share mixer (SM5C, SEJONG) And the mixture was combined and granulated using an appropriate amount of solvent. The mixture was dried in a dryer at 50 ° C for about 5 hours, and then dried to form a second granule using a 16th embodied standard. The secondary granules prepared by the above-mentioned standard No. 16 were subjected to the secondary selection using only a 40-gauge standard and only secondary granules having a size of 425 탆 or more. The weight ratio of the granules having a particle diameter of 425 μm selected from the primary granules and the secondary granules to the total weight of the primary mixture was determined to be not less than 60% by weight. In addition to the granules having the selected particle diameter of 425 탆, all the remainder of the primary mixture was collected and added to the granules having the selected particle diameter of 425 탆, and 4.5 mg of magnesium stearate was added thereto to prepare a secondary mixture . The secondary mixture was tableted at a tenter pressure of about 20 kN to prepare a tablet containing the elotinib hydrochloride. The tablets were coated with Opadry to prepare tablets containing Irootinib hydrochloride.

[Table 4] Examples 11 to 14

Comparative Example 1)

Using the ingredients and the contents described in Comparative Example 1 of Table 5, tablets containing the elotinib hydrochloride were prepared. 163.93 mg of Erotinib hydrochloride, 99.32 mg of lactic acid hydrate, 132.75 mg of microcrystalline cellulose, 4.5 mg of colloidal silicon dioxide, 4.5 mg of sodium lauryl sulfate, 36 mg of sodium starch glycolate and 4.5 mg of magnesium stearate were added to a V-mixer A primary mixture was prepared. The primary mixture was prepared using a roller compactor (TF-208, Vector Freund). The prepared granules were formulated into granules using a 16-well ternary standard. 4.5 mg of magnesium stearate was added to the granulate to prepare a second mixture, and the second mixture was tableted to a tablet pressure of about 20 kN to prepare a tablet containing the elotinib hydrochloride. The tablets were coated with Opadry to prepare tablets containing Irootinib hydrochloride. On the other hand, in Comparative Example 1, the proportion of the granular particles having a particle diameter of 425 占 퐉 or more was 10 to 20% by weight of the primary mixed powder.

Comparative Example 2)

Tablets were prepared in the same manner as in Comparative Example 1, except that the components and the contents described in Comparative Example 2 in Table 5 were used. In Comparative Example 2, the proportion of the granular particles having a particle diameter of 425 占 퐉 or more was about 20 to 30% by weight of the originally formed primary mixture.

Comparative Example 3)

Tablets were prepared in the same manner as in Comparative Example 1, except that the ingredients and the contents described in Comparative Example 3 in Table 5 were used. In Comparative Example 3, the proportion of the granular particles having a particle diameter of 425 占 퐉 or more was about 30 to 40% by weight of the primary mixed powder.

[Table 5] Comparative Examples 1 to 3

Comparative Example 4)

Tablets were prepared in the same manner as in Example 1 except that the ingredients and the contents described in Comparative Example 4 in Table 6 were used. In Comparative Example 4, the proportion of the granular particles having a particle diameter of 425 占 퐉 or more was about 40 to 50% by weight of the primary mixed powder.

Comparative Example 5)

Tablets were prepared in the same manner as in Example 1 except that the ingredients and the contents described in Comparative Example 5 in Table 6 were used. In Comparative Example 5, the proportion of the granular particles having a particle diameter of 425 占 퐉 or more was about 50 to 55% by weight of the originally formed primary mixture.

[Table 6] Comparative Examples 4 and 5

Comparative Example 6)

Comparative Example 6 in Table 7 is a general dry granulation method in which granulation and sizing are carried out only once. Using the components and the contents described in Comparative Example 6 in Table 7, tablets containing erotinib hydrochloride were prepared. 163.93 mg of Erotinib hydrochloride, 99.32 mg of lactic acid hydrate, 132.75 mg of microcrystalline cellulose, 4.5 mg of colloidal silicon dioxide, 4.5 mg of sodium lauryl sulfate, 36 mg of sodium starch glycolate and 4.5 mg of magnesium stearate were added to a V-mixer A primary mixture was prepared. The primary mixture was prepared using a roller compactor (TF-208, Vector Freund). The prepared granules were formulated into granules using a 16-well ternary standard. 4.5 mg of magnesium stearate was added to the granulate to prepare a second mixture, and the second mixture was tableted to a tablet pressure of about 20 kN to prepare a tablet containing the elotinib hydrochloride. The tablets were coated with Opadry to prepare tablets containing Irootinib hydrochloride. On the other hand, in Comparative Example 6, the weight ratio of the granules having a particle diameter of 425 占 퐉 or more to the primary mixture was about 27% by weight.

Comparative Example 7)

Comparative Example 7 shown in Table 7 below is a method for producing tablets by the wet granulation method generally used, and granulation and sizing were carried out only once. Using the ingredients and the contents described in Comparative Example 7 in Table 7, tablets containing erotinib hydrochloride were prepared. 163.93 mg of Erotinib hydrochloride, 99.32 mg of lactic acid hydrate, 132.75 mg of microcrystalline cellulose, 4.5 mg of colloidal silicon dioxide, 4.5 mg of sodium lauryl sulfate, 36 mg of sodium starch glycolate and 4.5 mg of magnesium stearate were added to a V-mixer A primary mixture was prepared. The primary mixture was put into a high share mixer (SM5C, SEJONG) and coalesced and granulated using 45 mg of ethanol. The mixture was then dried in a dryer at 50 ° C for about 5 hours. The dried material was then dried in a granule Respectively. 4.5 mg of magnesium stearate was added to the granulate to prepare a second mixture, and the second mixture was tableted to a tablet pressure of about 20 kN to prepare a tablet containing the elotinib hydrochloride. The tablets were coated with Opadry to prepare tablets containing Irootinib hydrochloride. On the other hand, in Comparative Example 7, the weight ratio of the granules having a particle diameter of 425 탆 or more to the primary mixture was about 21% by weight.

[Table 7] Comparative Examples 6 and 7

[Experimental Example 1] Dissolution test 1

A dissolution test of the tablets coated with tablets in each of Examples 1 to 14 and Comparative Examples 1 to 7 was carried out. The dissolution test method and analytical method are shown in Table 8, and the standard solution and the method of preparing the test solution are shown in Table 9. The dissolution test was carried out on a total of 6 tablets, and the average dissolution rate and RSD of the test for 6 tablets are shown in Table 10 below.

[Table 8] Dissolution Test Method and Analysis Method

[Table 9] Preparation method of standard solution and test solution

[Table 10] Average dissolution rate

As can be seen from Table 10, the tablets according to the examples had an RSD value of less than 2% of the dissolution rate of each of the tablets, and it was found that there was almost no difference in dissolution rate of each tablets. On the contrary, the RSD value of the dissolution rate of each of the tablets of the comparative example showed a difference of 4% or more and a maximum of 8%, indicating that the dissolution rate of each tablets was large.

[Experimental Example 2] Dissolution test 2

The elution test of the tablets coated with the tablet Erotinib hydrochloride in each of Example 1, Comparative Examples 6 and 7 was performed. The comparative dissolution test methods and analytical methods are shown in Table 11, and the standard solutions and methods for preparing the test solutions are shown in Table 12. The dissolution test was carried out on a total of 6 tablets, and the dissolution test results are shown in Figs. 1 to 4. Fig.

[Table 11] Dissolution test method and analysis method

[Table 12] Preparation method of standard solution and test solution

As can be seen from the dissolution test graphs of FIGS. 1 to 4, the dissolution rate of the coated tablet prepared as in Example 1 is significantly different from the dissolution rate of the coated tablet prepared in Comparative Examples 6 and 7. Comparing Example 1 with Comparative Examples 6 and 7, it was found that the initial dissolution rate in the pH 1.2 dissolution test was about twice higher than that in Example 1, and that there was a large deviation between purified individuals. In this case, there is a high possibility that the inter-subject variation is large, which may lead to the problem of drug-drug equivalence between tablets, and drug release may increase drug-related side effects due to the high maximum blood concentration due to initial overdose. Therefore, when the preparation is performed as in Example 1, it is possible not only to reduce the inter-subject variation, but also to prevent the initial excessive release in the drug release, thereby reducing the maximum concentration in blood and reducing drug- related adverse effects.

[Experimental Example 3] Particle size distribution test

Tablets were prepared in 3 batches using the method used in Example 1 and the method used in Comparative Example 6, and the particle size distribution and the dissolution test of the granules were carried out for each batch.

Particle size distribution of the granules was tested by particle size distribution estimation by analytical sieving method of USP Physical Tests and the equipment was tested by using HAVER EML DIGITAL PLUS (HAVER & BOECKER, Germany) model in Test Sieve Shaker. The elution test was carried out by using the same conditions and methods as in Experimental Example 1, and the RSD value of the dissolution rate was determined for each batch. The results are shown in Tables 13-15.

[Table 13] Particle size distribution test of Example 1

[Table 14] Particle size distribution test of Comparative Example 6

The preparation method of Example 1 is a particle size distribution chart for granules after re-granulation and refinement. The manufacturing method of Comparative Example 6 is a dry granulation method which is generally used after one granulation and one sizing process It is a particle size distribution diagram for granules. As can be seen from the above, the particle size distribution of the granules after the re-granulation, refinement, and re-selection process as in Example 1 showed a reproducible particle size distribution without any difference in particle size distribution even when three batches were made. However, the particle size distribution of the granules after one granulation and sizing process, which is a general dry granulation method as in Comparative Example 6, shows that the particle size distribution ratio varies between the batches when the three batches are evaluated and the reproducibility is poor , Especially when there is a large difference between the batches, the ratio of the granules above 425 μm in total granules is about 20% or more different. It was found that when the particle size distribution of the granules was not reproducible every time the batch was manufactured, there was a significant deviation in the elution of tablets. In this case, the quality uniformity of the product and the equivalence between the tablets are inevitable.

[Table 15] Dissolution test

Claims

A composition comprising a granule having a particle diameter of 425 占 퐉 or more and containing elotinib hydrochloride, and a lubricant,
The granules are at least 60% by weight based on the total weight of the composition,
Wherein the granule is selected from the group consisting of the above-mentioned elotinib hydrochloride and lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, D-mannitol, pregelatinized starch, sodium lauryl sulfate, colloidal silicon dioxide, croscarmellose sodium, crospovidone, Wherein the tablet comprises at least one additive selected from the group consisting of povidone and magnesium stearate.

delete

The tablet according to claim 1, wherein the relative standard deviation (RSD) of the average dissolution rate of the tablet is 2% or less.

delete

The present invention relates to a pharmaceutical composition comprising an effective amount of a combination of a combination of urotinib hydrochloride and at least one selected from the group consisting of lactic acid hydrate, microcrystalline cellulose, sodium starch glycolide, D-mannitol, pregelatinized starch, sodium lauryl sulfate, colloidal silicon dioxide, croscarmellose sodium, crospovidone, At least one < RTI ID = 0.0 > Mixing the additives to prepare a first mixture;
Preparing a composition from the primary mixture comprising granules having a particle diameter of 425 占 퐉 or more and containing erotinib hydrochloride; And
Adding a lubricant to the composition to produce a second mixture,
Wherein the granules having a diameter of 425 占 퐉 or more are at least 60% by weight based on the total weight of the primary mixture.

delete

7. The method of claim 6, wherein preparing the composition further comprises:
Preparing a primary granulate comprising elotinib hydrochloride from said primary mixture;
Firstly selecting granules having a particle diameter of 425 탆 or more among the primary granules; And
Preparing a second granulate from the granules having a particle diameter of less than 425 탆 in the granules among the first granules.

9. The method according to claim 8, further comprising the step of secondary selection of the granules having a particle diameter of 425 mu m or more of the granules in the secondary granules.

10. The method according to claim 9, wherein when the weight ratio of the granules having a particle diameter of 425 占 퐉 or more selected from the primary granules and the secondary granules is less than 60% by weight based on the total weight of the primary mixture, Further comprising the step of preparing a third granulate from the granules having a particle diameter of less than 425 占 퐉.

The method according to claim 8, wherein the step of firstly selecting the granules having a particle diameter of 425 탆 or more comprises:
Wherein said primary granules are selected with a 40th tincture standard.

9. The method of claim 8, wherein preparing the primary granules comprises:
Preparing a primary granulate from the primary mixture; And
Thereby forming the primary granules.

13. The method of claim 12, wherein the step of granulating the primary granules comprises:
Wherein the primary granules are formed through a 16-well body.

delete

7. The method of claim 6, further comprising the step of preparing a tablet from the secondary mixture.

The lubricant composition according to claim 1, wherein the lubricant is selected from the group consisting of stearic acid, sodium stearyl fumarate, talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hardened oil, white lead, titanium oxide, magnesium stearate, Lt; / RTI >