WO2015194769A1

WO2015194769A1 - Preparation, and manufacturing method therefor

Info

Publication number: WO2015194769A1
Application number: PCT/KR2015/005469
Authority: WO
Inventors: 김상엽; 명제혁
Original assignee: 보령제약 주식회사
Priority date: 2014-06-20
Filing date: 2015-06-01
Publication date: 2015-12-23
Also published as: KR20150145941A; KR101592258B1

Abstract

A preparation containing erlotinib or a pharmaceutically acceptable salt thereof, of the present invention, has excellent quality uniformity for each individual preparation. In the preparation according to the present invention, the dissolution rate of each preparation almost always appears to be constant and the particle size distribution ratio is maintained to be constant. In addition, the side effects of a drug can be minimized by inhibiting the initial rapid release of a drug.

Description

Formulation and preparation method thereof

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

Erlotinib is a tyrosine kinase inhibitor that is used to treat a variety of cancers, including pancreatic cancer. Elotinib is used for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed previous chemotherapy, or in combination with gemcitabine for the treatment of local, non-removable or metastatic pancreatic cancer.

Erlotinib is formulated in the form of its pharmaceutically acceptable salt, erlotinib hydrochloride. Elotinib hydrochloride is a BCS class II drug with high permeability and low solubility that exhibits an absorption of about 60% when taken orally and Tmax is 4 hours. It is poorly soluble and has a fairly low bulk density.

As a result, preparations containing erlotinib hydrochloride as active ingredients have a large difference in absorption rate depending on the degree of dissolution and dissolution rate of the drug, making it difficult to secure drug equality among the individual preparations. There is a problem that it is difficult to ensure quality homogeneity between the formulations containing as a component.

As such, when quality homogeneity is not secured between the formulations, a difference in the content of the main ingredient may occur between the formulations, thereby preparing a formulation that does not sufficiently exhibit an effect as an anti-cancer drug.In addition, when the formulation is manufactured, variations between batches may be produced. Many attempts have been made to ensure quality homogeneity between formulations in formulations containing erlotinib or its pharmaceutically acceptable salts as active ingredients, which may result in decreased production efficiency or unexpected side effects.

[Preceding technical literature]

[Patent Documents]

(Patent Document 1) US Registered Patent US 5747498

(Patent Document 2) US Patent US 6900221

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

Another object of the present invention is to provide a method for preparing a formulation comprising erlotinib or a pharmaceutically acceptable salt thereof.

The present invention provides a formulation comprising a composition comprising granules containing erlotinib or a pharmaceutically acceptable salt thereof having a diameter of at least 425 μm and 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. The free acid may be an inorganic acid and an organic acid, and the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, and the like, and the organic acid may be citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, and methanesulfur. Phonic acid, acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, and the like may be used, but is not limited thereto. Preferably, hydrochloric acid may be used as the inorganic acid, and methanesulfonic acid may be used as the organic acid, more preferably hydrochloric acid. For example, the pharmaceutically acceptable salt may be erlotinib hydrochloride.

The present invention provides a formulation comprising a composition comprising a granule containing a hydrochloride salt of erlotinib having a diameter of at least 425 μm and a pharmaceutically acceptable additive.

In the present invention, the formulations have a weight ratio of erlotinib, a pharmaceutically acceptable salt thereof, or granules comprising erlotinib hydrochloride, in which the diameter of the particles is 425 μm or more, based on the total weight of the composition.

In the formulation of the present invention, the erlotinib, a pharmaceutically acceptable salt thereof, or a granule of erlotinib hydrochloride may be prepared using a composition having a weight ratio of granules having a diameter of 425 µm or more based on the total weight of the composition. In the preparation of the present invention, it is possible to provide a formulation having excellent quality uniformity by minimizing individual differences between formulations. That is, the dissolution rate of each of the prepared formulation individuals is maintained substantially constant, and the particle size distribution ratio of the granules contained in the individual is also maintained substantially constant, so that excellent quality uniformity can be ensured and initial rapid release of the active ingredient included in the formulation. This can minimize unexpected side effects.

In the present invention, the granules of the erlotinib, pharmaceutically acceptable salts thereof, or granules of erlotinib hydrochloride may have a particle diameter of 425-850 μm, in which case The granule having the particle diameter may be at least 50% by weight based on the total weight of the 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, hard silicic anhydride, magnesium silicate, synthetic aluminum silicate, hardened oil , Lead, titanium oxide, or mixtures thereof, preferably magnesium stearate.

In the present invention, the difference in the dissolution rate between the individual may be minimized, and the relative standard deviation of the dissolution rate between the individual may be 2% or less.

In addition, the preparation prevents the rapid elution of erlotinib, its pharmaceutically acceptable salts, or erlotinib hydrochloride in the acidic state, thereby increasing the maximum blood concentration (Cmax) of the drug more than necessary by rapid dissolution of the drug. By suppressing drug-related side effects can be minimized.

In the present invention, the granules may include pharmaceutically acceptable additives in addition to erlotinib, a pharmaceutically acceptable salt thereof, or erlotinib hydrochloride thereof as an active ingredient. The pharmaceutically acceptable additives may be surfactants, diluents, disintegrants, lubricants and the like. For example, the granules can be added to the active ingredient erlotinib, a pharmaceutically acceptable salt thereof, or hydrochloride of erlotinib as an additive in addition to lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, D-mannitol, pregelatinized At least one selected from the group consisting of starch, sodium lauryl sulfate, colloidal silicon oxide, croscarmellose sodium, crospovidone, copovidone and magnesium stearate.

In the present invention, the preparation may be a tablet or capsule as a preparation for oral administration, and preferably a tablet.

In the present invention, the preparation may include 20 mg to 180 mg of erlotinib, a pharmaceutically acceptable salt thereof, or erlotinib hydrochloride thereof, as the active ingredient per unit preparation, and more preferably 25 mg to 170 mg.

In the present invention, the preparation may be administered at an appropriate number of times depending on the condition of the patient, and preferably, the unit preparation may be administered once daily.

The present invention provides a method for preparing a formulation comprising erlotinib, a pharmaceutically acceptable salt thereof, or erlotinib hydrochloride as an active ingredient.

In the present invention, the manufacturing method,

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

Preparing a composition comprising granules containing erlotinib or a pharmaceutically acceptable salt thereof having a particle diameter of at least 425 μm from the primary mixture.

In the present invention, the granule having a diameter of 425 μm or more is 60 wt% or more based on the total weight of the primary mixture.

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

In the present invention, the manufacturing method,

Mixing erlotinib hydrochloride with a pharmaceutically acceptable additive to prepare a primary mixture; And

Preparing a composition comprising granules containing erlotinib hydrochloride having a particle diameter of at least 425 μm from the primary mixture.

In the present invention, the granules of erlotinib hydrochloride having a diameter of 425 μm 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,

Preparing a primary granule comprising erlotinib, a pharmaceutically acceptable salt thereof, or erlotinib hydrochloride from the primary mixture;

Primary sorting the granules having a particle diameter of 425 μm or more in the primary granules; And

Preparing a secondary granule from granules having a particle diameter of the granules of the primary granules of less than 425 μm.

In the present invention, the step of preparing the composition may further comprise the step of secondary screening the granules having a diameter of 425 ㎛ or more in the prepared secondary granules.

60% by weight of the selected granules having a particle diameter of 425 µm or more were added to the total weight of the primary mixture by combining the first granulated granules of the first granules and the second granulated granules of the secondary granules. If more than one may not perform a step for forming additional granules. After collecting all of the remaining granules except the granules of 425 μm or more selected from the primary granules and the secondary granules in the primary mixture, the collection and granules of 425 μm or more selected are mixed to prepare a composition. can do.

In the present invention, the selected granules having a particle diameter of 425 μm or more are added to the granules selected first from the first granules and the granules selected second from the second granules, and the total weight of the first mixture is obtained. If less than 60% by weight, an additional granule forming process may be performed. That is, granules having a particle diameter of less than 425 μm may be collected from the secondary granules, and tertiary granules may be prepared therefrom. After selecting the granules having a particle diameter of 425 μm or more in the tertiary granules in the third step, the primary screened granules having a particle diameter of 425 μm or more, secondary screened granules, and tertiary screened granules are combined and If the granules having a selected particle diameter of 425 μm or more are 60 wt% or more with respect to the total weight of the primary mixture, the remaining components other than the selected granules in the selected granules and the primary mixture without performing an additional granule forming process. All of these can be combined to prepare a composition and to prepare a formulation therefrom.

If granules with a particle diameter of 425 μm or more selected through primary, secondary and tertiary screening are still less than 60% by weight relative to the total weight of the primary mixture, then more than 60% by weight of the primary mixture The same process can be repeated until

In the present invention, the granule having a particle diameter of 425 μm or more may be performed by selecting a granule that does not pass through the sieve of the standard body using a No. 40 standard body (eye size: 425 μm, KS nomenclature: 425). This can be equally applied to the first screening, the second screening or the third screening and the screening process that can be additionally performed.

In the present invention, the step of preparing the primary granules,

Preparing granules by performing granulation on the primary mixture; And

It may include the step of performing a sizing process for the primary granules.

In the present invention, the granulation means a process for preparing a mixture containing the active ingredient into granules. In the present invention, the formulation refers to the step of forming the granules formed into sized granules. That is, the granules refer to granules obtained by sieving granules prepared using a mixture containing the active ingredient.

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

In the present invention, after preparing a secondary mixture by mixing a pharmaceutically acceptable additive in the composition, a preparation may be prepared using the secondary mixture. For example, when the formulation is a tablet, tablets may be prepared by tableting the secondary mixture.

According to the method of the present invention, granulation having a granulation process of at least two granulation processes is performed at least 60% by weight of the raw materials used for the first time by performing granulation process and formulation process which are two or more granulation processes. The particle size distribution can be made uniform, whereby the dissolution rate and the particle size distribution ratio between each individual of the agent can be kept constant, thereby preparing a formulation having excellent quality uniformity.

The present invention provides a method for treating cancer using a composition comprising a granule containing erlotinib or a pharmaceutically acceptable salt thereof having a diameter of 425 μm or more and a formulation comprising a pharmaceutically acceptable additive. do.

The present invention provides a method for treating cancer using a composition comprising a granule containing a hydrochloride of erlotinib with a particle diameter of at least 425 μm and a formulation comprising a pharmaceutically acceptable additive.

The present invention provides a cancer therapeutic use of a formulation comprising a granule comprising erlotinib or a pharmaceutically acceptable salt thereof having a diameter of at least 425 μm and a pharmaceutically acceptable additive.

The present invention provides a cancer treatment use of a formulation comprising a granule comprising a hydrochloride of erlotinib with a particle diameter of at least 425 μm and a pharmaceutically acceptable additive.

The present invention provides a formulation comprising erlotinib, a pharmaceutically acceptable salt thereof, or a hydrochloride salt of erlotinib as an active ingredient, wherein the granules having a diameter of 425 μm or more in the granules of the active ingredient are 60% by weight or more. The dissolution rate and particle size distribution between the individual formulations can be kept constant to significantly improve the quality uniformity of the formulation.

1 to 4 are diagrams showing the dissolution rate of the formulations of Examples and Comparative Examples of the present invention.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are only for illustrating the present invention, and the present invention is not limited thereto. In addition, the reagents and materials mentioned below were purchased from Simga-Aldrich Korea, unless otherwise specified.

Example 1

Tablets comprising erlotinib hydrochloride were prepared using the ingredients and contents set forth in Example 1 in Table 1 below. 163.93 mg of erlotinib hydrochloride, 99.32 mg of lactose monohydrate, 132.75 mg of microcrystalline cellulose, 4.5 mg of colloidal silicon oxide, 4.5 mg of sodium lauryl sulfate, 36 mg of sodium starch glycolate and 4.5 mg of magnesium stearate were added to V-mixer The primary mixture was prepared. The above mixture was prepared using a roller compactor (TF-208, Vector Freund) to prepare primary granules. The granules were sized as primary granules using a No. 16 sieve standard (eye size 1.180 mm, KR nominal 1.18). In the primary granules established as No. 16, granules having a size of 425 μm or more were firstly selected using a No. 40 standard body (eye size 425 μm, KS no. 425). On the other hand, the granules smaller than 425㎛ passed through the No. 40 sieve of the primary granules were added to the V-mixer and mixed again to prepare a second granule using a roller compactor (TF-208, Vector Freund) and No. 16 Standard granules were used to form secondary granules. Secondary granules established as a No. 16 standard were screened secondly to granules of 425 μm or more using No. 40 standard. As a result of measuring the weight ratio of the total weight of the primary mixture of the granules having a particle size of 425 μm selected from the primary granules and the secondary granules, it was confirmed that the weight ratios corresponded to 60-70 wt%. In addition to the granules having a selected particle diameter of 425 µm, the remaining mixtures were collected from the primary mixture and added to the granulated particles having the selected particle diameter of 425 µm, and 4.5 mg of magnesium stearate was added thereto to prepare a secondary mixture. . The secondary mixture was compressed to a compression pressure of about 20 kN to prepare uncoated tablets containing erlotinib hydrochloride. Uncoated tablets were coated with Opadry to prepare tablets containing erlotinib hydrochloride.

Example 2)

Tablets were prepared in the same manner as in Example 1, except for using the ingredients and contents described in Example 2 in Table 1, and repeating the granulation, formulation, and selection steps three times instead of two times. In Example 2, the particle ratio of the primary granules having a particle diameter of 425 μm or more was about 70 to 80 wt% of the first mixture formed.

Example 3

Tablets were prepared in the same manner as in Example 1, except for using the ingredients and contents described in Example 3 in Table 1, and repeating four times instead of two times, granulation, formulation, and selection. In Example 3, the particle ratio of the primary granules having a particle diameter of 425 μm or more was about 80 to 90 wt% of the initially formed primary mixture.

Example 4

Tablets were prepared in the same manner as in Example 1, except for using the ingredients and contents described in Example 4 in Table 1, and repeating the granulation, formulation, and screening five times instead of twice. In Example 4, the proportion of the first to fifth granular particles having a particle diameter of 425 μm or more was about 90 to 100 wt% of the first mixture formed first.

TABLE 1 Examples 1-4

Example 5

Tablets were prepared in the same manner as in Example 1, except that the ingredients and contents described in Example 5 in Table 2 were used. In Example 5, the proportion of granule particles having a particle diameter of 425 μm or more was about 60 wt% or more of the initially formed primary mixture.

Example 6

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

Example 7

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

TABLE 2 Examples 5-7

Example 8

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

Example 9

Tablets were prepared in the same manner as in Example 1, except that the ingredients and contents described in Example 9 in Table 3 were used. In Example 9, the proportion of granule particles having a particle diameter of 425 μm or more was about 60 wt% or more of the first formed primary mixture.

Example 10)

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

TABLE 3 Examples 8 to 10

Example 11

Tablets were prepared in the same manner as in Example 1, except that the ingredients and contents described in Example 11 of Table 4 were used. The proportion of granule particles having a particle diameter of 425 μm or more in Example 11 was about 60% by weight or more of the first mixture formed.

Example 12)

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

Example 13

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

Example 14

A tablet comprising erlotinib hydrochloride was prepared using the ingredients and contents set forth in Example 14 in Table 4 below. 163.93 mg of erlotinib hydrochloride, 99.32 mg of lactose monohydrate, 132.75 mg of microcrystalline cellulose, 4.5 mg of colloidal silicon oxide, 4.5 mg of sodium lauryl sulfate, 36 mg of sodium starch glycolate and 4.5 mg of magnesium stearate were added to V-mixer The primary mixture was prepared. Put the primary mixture into a high share mixer (SM5C, SEJONG), coalesce and granulate with 45mg of ethanol, put it in a dryer at 50 ℃ for about 5 hours, and dry the product No. 16 (eye size: 1.18mm, KS) : 1.18) It was established as a primary granule using a standard body. The primary granules were first screened only using granules having a size of 425 μm or more using a 40-body standard. On the other hand, granules smaller than 425 μm that passed through the standard body (eye size: 425 μm, KS nomenclature: 425) in the primary granules were added to the V-mixer and mixed again, followed by high share mixer (SM5C, SEJONG). The mixture was put into a mixture, granulated using an appropriate amount of solvent, and then put into a drier at 50 ° C., dried for about 5 hours, and dried to form a secondary granule using a No. 16 standard. The secondary granules established as the No. 16 body standard were secondarily selected only for granules having a size of 425 μm or more using the No. 40 standard body. The weight ratio of the total weight of the primary mixture of the granules having a particle size of 425 μm selected from the primary granules and the secondary granules was measured, and the weight ratio was found to be 60 wt% or more. In addition to the granules having a selected particle diameter of 425 µm, all the remaining portions of the primary mixture were collected and added to the granulated particles having the selected particle diameter of 425 µm, and 4.5 mg of magnesium stearate was added thereto to prepare a secondary mixture. . The secondary mixture was compressed to a compression pressure of about 20 kN to prepare uncoated tablets containing erlotinib hydrochloride. Uncoated tablets were coated with Opadry to prepare tablets containing erlotinib hydrochloride.

TABLE 4 Examples 11-14

Comparative example 1)

Tablets comprising erlotinib hydrochloride were prepared using the ingredients and contents set forth in Comparative Example 1 in Table 5. 163.93 mg of erlotinib hydrochloride, 99.32 mg of lactose monohydrate, 132.75 mg of microcrystalline cellulose, 4.5 mg of colloidal silicon oxide, 4.5 mg of sodium lauryl sulfate, 36 mg of sodium starch glycolate and 4.5 mg of magnesium stearate were added to V-mixer The primary mixture was prepared. The primary mixture was prepared granules using a roller compactor (TF-208, Vector Freund). The granules were prepared as granules using No. 16 standard. 4.5 mg of magnesium stearate was added to the granules to prepare a secondary mixture, and the secondary mixture was compressed to a compression pressure of about 20 kN to prepare uncoated tablets containing erlotinib hydrochloride. Uncoated tablets were coated with Opadry to prepare tablets containing erlotinib hydrochloride. On the other hand, in Comparative Example 1, the particle size of the granule particles having a particle diameter of 425 μm or more was 10 to 20 wt% of the first mixture formed.

Comparative example 2)

Tablets were prepared in the same manner as in Comparative Example 1, except that the components and contents described in Comparative Example 2 of Table 5 were used. In Comparative Example 2, the proportion of granule particles having a particle diameter of 425 µm or more was about 20 to 30 wt% of the first mixture formed.

Comparative Example 3)

Tablets were prepared in the same manner as in Comparative Example 1, except that the components and contents described in Comparative Example 3 of Table 5 were used. In Comparative Example 3, the proportion of granule particles having a particle diameter of 425 μm or more was about 30 to 40 wt% of the initially formed primary mixture.

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 contents described in Comparative Example 4 of Table 6 were used. In Comparative Example 4, the proportion of granule particles having a particle diameter of 425 μm or more was about 40 to 50 wt% of the initially formed primary mixture.

Comparative Example 5)

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

TABLE 6 Comparative Examples 4 and 5

Comparative Example 6)

Comparative Example 6 in Table 7 below is a general dry granulation method using only one time of granulation and formulation. Tablets comprising erlotinib hydrochloride were prepared using the ingredients and contents set forth in Comparative Example 6 in Table 7. 163.93 mg of erlotinib hydrochloride, 99.32 mg of lactose monohydrate, 132.75 mg of microcrystalline cellulose, 4.5 mg of colloidal silicon oxide, 4.5 mg of sodium lauryl sulfate, 36 mg of sodium starch glycolate and 4.5 mg of magnesium stearate were added to V-mixer The primary mixture was prepared. Granules were prepared using the primary mixture using a roller compactor (TF-208, Vector Freund). The granules were prepared as granules using No. 16 standard. 4.5 mg of magnesium stearate was added to the granules to prepare a secondary mixture, and the secondary mixture was compressed to a compression pressure of about 20 kN to prepare uncoated tablets containing erlotinib hydrochloride. Uncoated tablets were coated with Opadry to prepare tablets containing erlotinib hydrochloride. On the other hand, in the comparative example 6, the weight ratio with respect to the primary mixture of granules whose particle diameter is 425 micrometers or more was about 27 weight%.

Comparative Example 7)

Comparative Example 7 of Table 7 is a method for preparing tablets by the wet granule method generally used, and granulation and formulation were performed only once. Tablets comprising erlotinib hydrochloride were prepared using the ingredients and contents set forth in Comparative Example 7 in Table 7. 163.93 mg of erlotinib hydrochloride, 99.32 mg of lactose monohydrate, 132.75 mg of microcrystalline cellulose, 4.5 mg of colloidal silicon oxide, 4.5 mg of sodium lauryl sulfate, 36 mg of sodium starch glycolate and 4.5 mg of magnesium stearate were added to V-mixer The primary mixture was prepared. Put the primary mixture into a high share mixer (SM5C, SEJONG), coalesce and granulate with 45mg of ethanol, put it in a 50 ℃ drier, and dry it for about 5 hours. It was established. 4.5 mg of magnesium stearate was added to the granules to prepare a secondary mixture, and the secondary mixture was compressed to a compression pressure of about 20 kN to prepare uncoated tablets containing erlotinib hydrochloride. Uncoated tablets were coated with Opadry to prepare tablets containing erlotinib hydrochloride. On the other hand, in Comparative Example 7, the weight ratio to the primary mixture of granules having a particle diameter of 425 μm or more was about 21 wt%.

TABLE 7 Comparative Examples 6 and 7

Experimental Example 1 Dissolution Test 1

The dissolution test of the erlotinib hydrochloride tablets of the tablets tableted and coated in each of Examples 1 to 14 and Comparative Examples 1 to 7 was performed. Dissolution test methods and analytical methods are shown in Table 8, and standard and sample solutions are shown in Table 9. Dissolution test was carried out for a total of six tablets, respectively, the average dissolution rate and RSD of the test for six tablets are shown in Table 10 below.

[Table 8] Dissolution test method and analysis method

[Table 9] Preparation Method of Standard Solution and Sample Solution

[Table 10] Average Dissolution Rate

As can be seen in Table 10, the tablets according to the examples were found to have almost no difference in the dissolution rate of each tablet as the RSD value of the dissolution rate of each tablet was less than 2%. On the contrary, the RSD values of the dissolution rates of the tablets of the Comparative Example showed a difference of 4% or more and up to 8%, indicating that the dissolution rates of the purified individuals were large.

Experimental Example 2 Dissolution Test 2

Elution tests of the erlotinib hydrochloride tablets compressed and coated in each of Examples 1 and 6 and 7 were performed. Table 11 shows the comparative dissolution test method and analysis method, and Table 12 shows the preparation method of the standard solution and the sample solution. The dissolution test was carried out on a total of six tablets, respectively, and the dissolution test results are shown in FIGS. 1 to 4.

[Table 11] Dissolution test method and analysis method

[Table 12] Preparation Method of Standard Solution and Sample Solution

As can be seen through the dissolution test graphs of FIGS. 1 to 4, the dissolution rate of the coated tablets prepared as in Example 1 was significantly different from the dissolution rates of the coated tablets prepared as in Comparative Examples 6 and 7. Comparing Example 1 with Comparative Examples 6 and 7, the initial dissolution rate in the pH 1.2 dissolution test was not only about 2 times higher than that of Example 1, and it was found that the variation among the purified individuals was large. In this case, there is a high possibility of causing a drug equality problem between tablets because of the large variation among individuals, and the drug-related side effects may be increased due to the high maximum blood concentration due to the initial overrelease in drug release. Therefore, when prepared as in Example 1 can not only reduce the variation between individuals, but also prevent the initial over-release in the drug release can reduce the drug-related side effects by reducing the maximum concentration of blood than necessary.

Experimental Example 3 Particle Size Distribution Test

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

Here, the particle distribution of the granules was tested according to the particle size distribution estimation by analytical sieving method in USP Physical Tests, and the apparatus used was tested using a HAVER EML DIGITAL PLUS (HAVER & BOECKER, Germany) model of Test Sieve Shaker. The dissolution test was measured 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 to 15.

TABLE 13 Particle size distribution test of Example 1

Table 14 particle size distribution test of Comparative Example 6

The manufacturing method of Example 1 is a particle size distribution of the granules after the re-granulation, re-establishment process, the manufacturing method of Comparative Example 6 is a dry granulation method that is generally used after only one granulation and then once Particle size distribution for granules. As can be seen above, the particle size distribution of the granules that have undergone re-granulation, re-arrangement, and re-selection as in Example 1 showed that the particle size distribution was reproducible with almost no difference in the particle size distribution ratio even though three batches were produced. However, the particle size distribution of the general dry granulation method, one granule, and the granulated granules, which were processed through three batches, was evaluated in three batches, and the reproducibility was poor. In particular, when the difference between batches is severe, it can be seen that the ratio of granules of more than 425㎛ of the total granules is about 20% or more. When the particle size distribution of the granules could not be reproducibly produced every batch production, it was found that a severe dissolution difference of tablets occurred. In addition, this will cause problems of product quality homogeneity and drug equality between tablets.

[Table 15] Dissolution Test

Claims

A composition comprising granules containing erlotinib or a pharmaceutically acceptable salt thereof having a diameter of at least 425 μm, and a pharmaceutically acceptable additive,

The granules are 60% by weight or more based on the total weight of the composition.
The formulation of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride salt of erlotinib.
The formulation according to claim 1 or 2, wherein the relative standard deviation (RSD) of the average dissolution rate of the formulation is 2% or less.
The formulation of claim 1, wherein the granules further comprise a pharmaceutically acceptable additive.
The method of claim 4, wherein the pharmaceutically acceptable additives included in the granules are lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, D-mannitol, starch gelatinized starch, sodium lauryl sulfate, colloidal silicon oxide And at least one selected from the group consisting of croscarmellose sodium, crospovidone, copovidone and magnesium stearate.
Preparing a primary mixture by mixing erlotinib or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; And

Preparing a composition comprising granules containing erlotinib or a pharmaceutically acceptable salt thereof having a particle diameter of at least 425 μm from the mixture,

Granules having a diameter of 425 ㎛ or more of the particles is a method for producing a formulation of 60% by weight or more based on the total weight of the primary mixture.
The method of claim 6, wherein the pharmaceutically acceptable salt is hydrochloride of erlotim.
The method of claim 6 or 7, wherein preparing the composition,

Preparing a primary granule comprising erlotinib hydrochloride from the primary mixture;

Primary sorting the granules having a particle diameter of 425 μm or more in the primary granules; And

Method for producing a formulation comprising the step of preparing a secondary granules from the granules of the granules of the granules of the granules of the primary granules less than 425㎛.
The method of claim 8, further comprising the step of secondary screening the granules of the granules of the granules in the secondary granules of 425㎛ or more.
The method of claim 9, wherein when the weight ratio of the granules having a particle diameter of 425 μm or more selected from the primary granules and the secondary granules is less than 60 wt% based on the total weight of the primary mixture, A method for producing a formulation, further comprising the step of preparing a tertiary granule from granules having a particle diameter of less than 425 μm.
According to claim 6 or 7, wherein the step of primary screening the granules of 425㎛ or more,

Method for producing a formulation of the primary granules selected from 40 body standard.
The method of claim 6 or 7, wherein preparing the primary granules,

Preparing primary granules from the mixture; And

Method for producing a formulation comprising the step of establishing the primary granules.
The method of claim 12, wherein the step of establishing the primary granules,

Formulation method of the formulation of the primary granules through the body No. 16 standard.
8. The method of claim 6 or 7, further comprising preparing a secondary mixture by adding a pharmaceutically acceptable additive to the composition.
The method of claim 14, further comprising preparing a formulation from the secondary mixture.