KR101739731B1

KR101739731B1 - Pharmaceutical composition containing gefitinib

Info

Publication number: KR101739731B1
Application number: KR1020150191215A
Authority: KR
Inventors: 안병락; 민미홍; 정현준
Original assignee: 환인제약 주식회사
Priority date: 2015-12-31
Filing date: 2015-12-31
Publication date: 2017-05-25
Also published as: WO2017116031A1

Abstract

The present invention relates to a pharmaceutical composition comprising gefitinib as a pharmacologically active ingredient. The present invention allows the weight and volume of the final formulation when formulated to be optimized in terms of the patient ' s ease of taking and is able to be administered to patients suffering from diabetes.

Description

[0001] PHARMACEUTICAL COMPOSITION CONTAINING GEFITINIB [0002] The present invention relates to a pharmaceutical composition containing gefitinib,

The present invention relates to an oral solid pharmaceutical composition comprising gefitinib as one of the active ingredients.

[Gepytinib]

Is a quinazolinone derivative having a structure of the following formula 1 and having a systematic name according to IUPAC: N- (3-chloro-4-fluoro-phenyl) -7-methoxy- 6- (3-morpholin-4-ylpropoxy) quinazolin-4-amine.

[Chemical Formula 1]

Gefitinib has been shown to be useful in the treatment of the tyrosine kinase domain (EGFR) of the epithelial cell growth factor receptor (EGFR), which is known to be the cause of overexpression of malignant tumors, such as non-small cell lung cancer, through in vitro experiments disclosed in International Patent Publication No. 96/33980 tyrosine kinase domain in the rat brain.

Since then, gefitinib has been clinically proven to be effective in the treatment of locally advanced or metastatic non-small cell lung cancer with active mutations in epithelial cell growth factor (EGFR) and non-small cell lung cancer Lt; / RTI >

[Design of formulation of gefitinib]

Generally, the drug is orally administered and then absorbed while moving along the gastrointestinal tract such as the esophagus, stomach, duodenum, small intestine, rectum, etc., and is transported to the operative site through the vasculature such as blood or lymphatic fluid. The gastrointestinal tract, etc., The hydrogen ion concentration of the hydrogen ion is different. For example, depending on the dilution with water or the presence of food, the pH of the stomach is 1.0-3.0, and the pH of the duodenum is 5.0-6.0 in the small intestine. 7.0-8.0. Therefore, drugs with a solubility sensitive to pH may exhibit undesirable pharmacokinetic properties by varying the bioavailability by patient or dose.

Gaptiinib is a basic compound having two basic groups whose pKa is 5.3 and 7.2, and these basic groups may protonate or deprotonate depending on the pH, which may significantly affect the solubility of the compound. That is, the solubility of gefitinib differs greatly depending on the pH. For example, in the free base form of gefitinib, in the aqueous medium at pH 1, the solvent needed to dissolve 1 g is soluble in 10-30 ml, but in the aqueous medium at pH 4-6 it is necessary to dissolve 1 g Solubility is poorly soluble in more than 10,000 ml and is substantially insoluble in aqueous media of pH 7 and above.

Gepetinib has a high solubility in the acidic environment above, but tends to precipitate out of solution when the pH environment changes locally due to migration to a small intestine, dietary and water uptake, or the like. For this reason the bioavailability of gefitinib is very variable. Also, since the maximum natural absorption region of gepetinib is known to be the upper part of the intestinal tract, not the stomach, it is necessary to improve the solubility sensitivity depending on the pH when designing the formulation of gepetinib.

In this regard, Korean Patent No. 1002374 discloses that when naphthol containing gefitinib is coated with a water-soluble cellulose ether such as hydroxypropyl methylcellulose or an ester base of water-soluble cellulose ether, the drug is not precipitated even in an environment of pH 6.5 The technical idea of being able to be able to

WO-A-96/33980 Korea Patent No. 1002374

In designing a compound that exhibits pharmacological activity, it is necessary to grasp the state of the component after its administration in the body, transplantation, drug metabolism, excretion, It is necessary to examine the dynamics of various additives that can affect the reaction.

In addition, it is desirable to develop the optimal formulation for the weight and volume of the final formulation in consideration of convenience of taking the patient during formulation.

Among the drugs currently on the market, there is an ejaculation product containing gefitinib as an active ingredient.

The present invention is a tablet embodied by the technical idea disclosed in Patent No. 1002374, which comprises combining 250 mg of gefitinib with a specific additive and a water-soluble cellulose ether and a wetting agent to improve the solubility sensitivity of the gepetinib according to pH .

However, the emulsion is a film coated tablet having a total weight of about 512 mg, with a major axis of about 11 mm and a thickness of about 5.3 mm. Most cancer patients suffer from difficulty in swallowing large tablets. Therefore, when the entire tablet can not be swallowed even in the method of taking the tablet, it is required to be dispersed in water. Therefore, There is an advantage that convenience can be improved. Also, there are contraindications to prevent the administration of Ereasure to patients who have genetic problems such as galactose intolerance, Lapp lactose dehydrogenase deficiency or glucose-galactose uptake disorder because they contain lactose during refining.

Therefore, the present invention aims to provide a composition which can reduce the weight of tablets and increase the convenience for patients to take and also can be used in patients suffering from diarrhea.

The present invention has solved the above-mentioned problems through the following means.

(1) A pharmaceutical composition which comprises at least 65% of the total weight of the formulation and at least one selected from the group consisting of dextrates and isomalt, and at least one disintegrant of 6-14% &Lt; / RTI >

(2) The composition of (1) above, wherein the disintegrant comprises more preferably 7-10% by weight relative to the total weight per sex.

(3) The composition of (1) above, wherein the dextrates comprise 2-5% of the total weight of the composition.

(4) The composition according to the above (1), wherein the isomalt comprises 2-5% of the total weight of the composition.

(5) The composition according to any one of (1) to (4) above, wherein the disintegrant is at least one selected from the group consisting of crospovidone and corn starch.

(6) The composition according to any one of (1) to (5), further comprising a pharmaceutically usable additive, a stabilizer, a lubricant and a binder.

(7) The composition according to (6), wherein the stabilizer is Eudragit E-PO.

(8) The composition according to the above (7), wherein Eudragit E-PO comprises 1-5% of the total weight of the composition.

(9) 65-75% gepetinibe relative to the total weight of the composition; 2-5% dextrates and / or 2-5% isomalt; Stabilizers; And from 6 to 14% of one or more disintegrants per sex.

(10) The composition according to (9), wherein the disintegrant is at least one selected from the group consisting of crospovidone and corn starch.

(11) The composition according to the above (9), wherein the stabilizer is Eudragit E-PO.

(12) The composition according to the above (11), wherein Eudragit E-PO comprises 1-5% of the total weight of the composition.

The present invention can prevent sedimentation of gefitinib in accordance with pH change, and can ensure drug equivalence with existing commercial products containing gefitinib. In addition, according to one embodiment of the present invention, the dissolution stability (stability of the dissolution rate depending on the storage state) is excellent.

The weight and volume of the final formulation at the time of formulation of the present invention is smaller than that of the existing gepitibea-containing commercial formulation, thereby maximizing the convenience of taking the patient.

The present invention can solve the above-described problems even when lactose is not contained, unlike existing marketed preparations containing gefitinib, and can be administered to patients suffering from diarrhea.

The present invention can improve the process hindrances and provide formulations that can occur when the proportion of active ingredient is high, even though it contains more than 65% of gepetinib, based on the total weight of the composition.

Fig. 1 shows the results of precipitation test of gepetinib according to the pH change of the tablets prepared with the preparation alone (API alone), the commercial formulation (irrecipitation formulation) and the composition according to the present invention (Example 1).
2 shows the dissolution test results of the commercial tablets, purified water (1000 ml, including polysorbate 80 and 5%) of tablets prepared in Example 1 and Comparative Examples 20 to 23 in the eluate.
FIG. 3 shows the results of a comparison of the results of the tablets prepared in Comparative Examples 13 to 19 and Examples 12 to 13 in the harsh stability chamber for the first, second, and fourth weeks, respectively, followed by the addition of purified water (1000 ml, polysorbate 80, And the elution stability of the eluant.
4 is a graph showing the results of measurement of pH, 1.2, 900 ml eluate, pH 4.0, 900 ml eluate and purified water (including 1000 ml, polysorbate 80, 5%) of the tablets prepared in Example 1, The results of dissolution test on the eluate are shown.
FIG. 5 compares the serum concentration of gefitinib with the passage of time when the commercial formulation and the tablets of Example 1 were orally administered to beagle dogs.

As used herein, " gefitinib " refers to a gpatineib and its pharmaceutically acceptable salts or prodrugs thereof, which, when not otherwise specified, have a principal component capable of exhibiting the same pharmacological effect as gefitinib in the human body It is interpreted as a concept including all.

&Quot; Disintegrants ", " lubricants ", and " other pharmaceutically acceptable additives ", as used herein, refer to additives that are pharmaceutically known in their function and composition and are described, for example, in HANDBOOK OF PHARMACEUTICAL EXCIPIENTS And interpret it as a concept that includes all of the enemy's selectable ingredients.

The inventors of the present invention recognized the disadvantage that existing commercial preparations containing gefitinib had a large weight and a large volume and were inconvenient to use, and various experiments were conducted to improve them. As a result, the present invention has been completed.

The inventors of the present invention first reduced the amount of microcrystalline cellulose and lactose, which are excipients in the nasal formulations of Examples 1 and 2 of Japanese Patent No. 1002374, while minimizing the volume of conventional commercial products, under the same conditions. As a result, the dissolution rate of phytiniflavin was not satisfactory, and especially when the amount of lactose was reduced, the bulk density was relatively high, so that the flowability was poor when the tableting process was applied, did.

However, after continued experimentation, the present inventors accidentally adopted the disintegrant combination of dextrate and / or isomalt as an excipient in an amount of 6-14%, preferably 7-10% It was found that the dissolution rate of gefitinib is excellent, the weight and volume of the preparation can be reduced, and it is suitable for mass production.

SUMMARY OF THE INVENTION The present invention is directed to solving the aforementioned problems by providing a pharmaceutical composition comprising gefitinib, dextrates and / or isomalt, a ratio of 6-14%, more preferably 7-10% , And may optionally contain stabilizers, pharmaceutically acceptable lubricants and binders for better expression of the desired effect.

Dextrates or isomates are preferably 2-5% of the total weight of the formulation, respectively. In case of mixing less than 2% by weight of the present amount, stinging may occur, which may cause a problem in the process. If it exceeds 5% by weight, it is difficult to obtain comparative dissolution equivalent of gepetinib with a commercial product Respectively.

As the disintegrant, it is possible to use one or more kinds of optional ingredients known as pharmaceutically compoundable additives. However, when at least one selected from the group consisting of crospovidone and corn starch is selected as the disintegrant, it is possible to more effectively improve the property of the gatifutin having a solubility in accordance with the change of pH. The amount of disintegrant is 6-14% per component, more preferably 7-10%, based on the total weight of the composition per sex. It is difficult to ensure elution equality between the commercial formulation and the gepetinib, and when the formulation is out of the upper limit, the hygroscopic phenomenon occurs, which causes problems in the process of the tableting disorder and the stability of the pharmaceutical product . It is well known that a disintegrant can be formulated into pharmaceutical compositions, but it is not known at all that it is possible to use a disintegrant to solve the solubility problem due to the pH sensitivity of gepetinib, so the effect of the disintegrating formulation Was a very surprising result.

The present invention can be optionally combined with other additives well known in the art to the extent that the present invention does not inhibit the manifestation of the desired effect. As other additives, stabilizers, lubricants, and binders can be used in amounts that can be selected by those skilled in the art.

As the stabilizer, Eudragit E-PO can be selected as a substance capable of maintaining elution stability of the gefitinib, and may contain 1-5% of the total weight of the formulation. When the content is out of the lower limit of the content, the elution stability effect of gefitinib can not be obtained as much as desired, and if it exceeds the upper limit, sticking and other process failures may occur.

As the lubricant, magnesium stearate, sodium stearyl fumarate, castor oil, talc and the like which can be usually used can be used.

Examples of the binder include polyvinylpyrrolidone, corn starch, hydroxypropylcellulose, gum, and the like, which can be commonly used.

[Formulation]

Example 1 can be formulated into tablets, capsules or the like through known means. As a non-limiting example, the active ingredient may be mixed with an excipient or the like to prepare granules, followed by tableting and tabletting, or filling the capsules to obtain capsules.

One embodiment according to the present invention can be formulated into tablets through the following process.

(1) Preparation of binding solution

The binder is completely dissolved in the water by stirring.

(2) mixing

The preparation, dextrates (and / or isomalt), various additives and disintegrants are mixed in a mixer.

(3) Union, construction and construction

(2) is put into a coalescing machine, and the coalescing solution of (1) is added to the coalesce, followed by drying and drying.

(4) After mixing and tableting

(3) are put into a mixer, and the disintegrant is added to the mixture. When the primary mixing is completed, the lubricant is added and then the secondary mixture is mixed to prepare the final mixture, which is then tableted using a tablet machine.

(5) Coating

(4) is sprayed with a coating agent to form a film coating.

When formulating with film-coated tablets as described above, a commercially available coating agent can be selected, and a coating agent based on HPMC or PVA can be selected as a non-limiting example. The amount of the coating agent may be appropriately selected by a person skilled in the art.

Hereinafter, the present invention will be described in more detail with reference to specific examples. It should be noted, however, that the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

[Experimental Example 1]

Tablets were prepared in the amounts shown in Table 1 below.

(1) Preparation of binding solution

Povidone, a binder in water, is completely dissolved in purified water or solvent.

(2) mixing

The active ingredient, dextrates, isomalt, Eudragit E-PO and disintegrant are mixed in a mixer.

(3) Union, construction and construction

(2) is put into a coalescing machine, and the coalescing solution is put into the coalescing solution of (1), and the coalesced solution is dried in a tray dryer and dried.

(4) After mixing and tableting

(3) is put into a mixer, and a lubricant is added to the mixture to carry out post-mixing to prepare a final mixture, followed by compression molding to prepare tablets.

(5) Coating

(4) is coated with a coating agent.

Purpose of blending Ingredients Commercial product Control Example Example 1 mg / T weight % mg / T weight % mg / T weight % chief ingredient Gepetinib 250.0 48.8 250.0 48.8 250.0 67.6 Excipient additive 250.0 48.8 Excipient Lactose 163.5 31.9 Excipient Microcrystalline cellulose 50.0 9.8 Excipient Dextrose 10.0 2.7 Excipient Isomalt 10.0 2.7 Excipient Eudragit E-PO 12.0 3.2 Disintegration Crospovidone 35.0 9.5 Disintegration Corn starch 32.5 8.8 Disintegration Cros Carmel
Sodium 20.0 3.9 Binder Povidone 10.0 2.0 7.0 1.9 slush Sodium lauryl sulfate 1.5 0.3 slush Magnesium stearate 5.0 1.0 3.5 0.9 Mud 500.0 97.6 500.0 97.6 360.0 97.3 Coater HPMC Mechanism 12.25 2.4 12.25 2.4 Coater Opadry II 10.0 2.7 Coating 512.3 100.0 512.3 100.0 370.0 100.0 Tablet size Long axis: 11 mm, Thickness: 5.3 mm Long axis: 11 mm, Thickness: 5.3 mm Long axis: 9.5 mm, thickness: 4.7 mm Purification hardness 22 kp 22 kp 20 kp

As shown in Table 1, the tablets prepared in Example 1 were significantly smaller in weight and volume than commercial tablets, and thus convenience for taking was greatly improved. The control sample was prepared in the same manner as the napped composition of Examples 1 and 2 of the registered patent No. 1002374, and then coated with the same amount as that of the commercial formulation with the HPMC base.

The pH conversion test was carried out on the commercially available preparation and the tablets prepared in Example 1 as follows.

The pH conversion elution test was performed according to the dissolution test method (paddle method) of the Korean Pharmacopoeia, and the paddle rotation speed was set at 50 rpm. In this method, the dissolution rate was measured for 60 minutes in 750 ml of a 0.1 M hydrochloric acid solution (about pH 1.2) as an acid solution. After 60 minutes, 250 ml of a 0.2 M sodium phosphate solution was rapidly added to convert to pH 6.5 or higher , And the dissolution rate was evaluated.

As a result, the tablets prepared in Example 1 were superior to the tablets (API alone) and the commercially available tablets (Iris tablets) at pH 6.5 as shown in the following Table 2 and FIG.

Eluent condition Time (minutes) Agent alone Commercial product Example 1 0.1 M hydrochloric acid solution
750 ml 0 101.0 70.0 81.8 10 101.0 70.0 81.8 15 101.1 80.5 92.3 30 100.8 90.6 94.6 60 102.8 96.9 100.1 0.1 M hydrochloric acid solution
750 ml
+
250 ml of 0.2 M sodium phosphate solution 65 4.8 44.3 49.6 70 2.0 16.3 27.5 75 1.1 8.0 8.3 90 0.8 7.2 5.3

Comparative tablets prepared in Example 1 and Comparative Example 1 were subjected to a comparative dissolution test at pH 1.2, pH 4.0, and purified water (1000 ml, polysorbate 80 and 5%) as follows.

As a result, as shown in Fig. 4, the initial elution of the tablets prepared in Example 1 was rapid in all eluates.

[Experimental Example 2] Comparative experiment of effects of dextrates and isomalt amounts

Tablets were prepared in the amounts shown in Table 3 below.

Ingredients Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Example 2 Example 3 Comparative Example 6 Comparative Example 7 Example 4 Example 5 Comparative Example 8 Gepetinib 71.5% 71.5% 71.5% 71.5% 73.4% 71.5% 69.4% 67.4% 73.4% 71.5% 69.4% 67.4% Lactose 2.9% Microcrystalline cellulose 2.9% Calcium hydrogen phosphate 2.9% Light anhydrous silicic acid 2.9% Isomalt 1.0% 2.9% 5.0% 7.0% Dextrose 1.0% 2.9% 5.0% 7.0% Crospovidone 10.0% 10.0% 10.0% 10.0% 10.0% 10.0% 10.0% 10.0% 10.0% 10.0% 10.0% 10.0% Corn starch 9.5% 9.5% 9.5% 9.5% 9.5% 9.5% 9.5% 9.5% 9.5% 9.5% 9.5% 9.5% Povidone K-30 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% Stearic acid
magnesium 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% Opadry II 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2%

*% In Table 3 represents weight%.

The tablets prepared according to the prescriptions of Comparative Examples 1 to 8 and Examples 2 to 5 were found to have obstacles in their processability or whether the dissolution rate was appropriate as compared with the commercially available tablets. The results are shown in Table 4 below.

Evaluation items Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Example 1 Example 2 Comparative Example 6 Comparative Example 7 Example 4 Example 5 Comparative Example 8 Process impairment X X O O O X X X O X X X Elution adequacy evaluation incongruity incongruity incongruity incongruity incongruity fitness fitness incongruity incongruity fitness fitness incongruity

* Table 4 shows the sticking, laminating, capping, etc. of tablets that can occur when tablets are tableted. O and X are judged based on whether or not the tablets are subjected to 100 tablets or more continuously during tableting.

* The elution adequacy evaluation in Table 4 refers to the results of the analysis of the eluate under the conditions of purified water (1000 ml, polysorbate 80, and 5%) after the test according to the dissolution test method (paddle method) of the Korean Pharmacopoeia , And compliance and non-compliance were judged based on a dissolution rate of 85% or more after 45 minutes from the start of the dissolution test.

[Experimental Example 3] Comparative experiment of effect according to amount of disintegrant

Tablets were prepared in the amounts shown in Table 5 below.

Ingredients Comparative Example 9 Example 6 Example 7 Comparative Example 10 Comparative Example 11 Example 8 Example 9 Comparative Example 12 Example 10 Example 11 Gepetinib 84.3% 82.3% 79.3% 74.3% 84.3% 82.3% 79.3% 74.3% 75.3% 69.3% Isomalt 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% Dextrose 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% Crospovidone 5.0% 7.0% 10.0% 15.0% 7.0% 10.0% Corn starch 5.0% 7.0% 10.0% 15.0% 7.0% 10.0% PVP K-30 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% Stearic acid
magnesium 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% Opadry II 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2%

* The percentages in Table 5 represent weight percentages.

The tablets prepared by the prescriptions of Comparative Examples 9 to 12 and Examples 6 to 11 were found to have obstacles in their processability or to determine the dissolution rate when compared with the commercial products, and the results were as shown in Table 6 below.

Evaluation items Comparative Example 9 Example 6 Example 7 Comparative Example 10 Comparative Example 11 Example 8 Example 9 Comparative Example 12 Example 10 Example 11 Process impairment X X X O X X X O X X Elution adequacy evaluation incongruity fitness fitness fitness incongruity fitness fitness incongruity fitness fitness

* Table 6 shows sticking, laminating, capping, etc. of tablets that can occur when tablets are tableted, and O and X are determined based on whether or not the tablets are subjected to continuous tableting for more than 100 tablet occasions.

* The elution adequacy evaluation in Table 6 above refers to the result of the analysis of the eluate under the conditions of purified water (1000 ml, polysorbate 80, and 5%) after performing the test according to the dissolution test method of the Korean Pharmacopoeia (paddle method) , And compliance and non-compliance were judged based on a dissolution rate of 85% or more after 45 minutes from the start of the dissolution test.

In particular, the comparative dissolution test results of Comparative Example 9 with the commercial product and the control sample were as shown in Fig. 4. In the dissolution test results at pH 1.2 and pH 4.0, the input ratio of disintegrant did not have a great influence, In the case of low-solubility purified water (including 1000 ml, polysorbate 80 and 5%), the ratio of disintegrant input had a large effect and was not suitable for the dissolution criterion. As a result of the experiment, it was found that the disintegrant should be added by at least 6%, more preferably by 7% or more based on the total weight of the composition per one component, so that the release of the drug was smooth.

[Experimental Example 4] Comparative experiment of effects according to kind and amount of stabilizer

Tablets were prepared in the amounts shown in Table 7 below.

Ingredients Comparative Example 13 Comparative Example 14 Comparative Example 15 Comparative Example 16 Comparative Example 17 Comparative Example 18 Example 12 Example 13 Comparative Example 19 Gepetinib 74.2% 71.3% 73.3% 64.3% 73.3% 69.3% 68.3% 64.3% 59.3% Isomalt 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% Dextrose 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% 2.3% Crospovidone 15.0% 15.0% 15.0% 15.0% 15.0% 15.0% 10.0% 10.0% 10.0% Corn starch 10.0% 10.0% 10.0% PVP K-30 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% 1.9% Sodium lauryl sulfate 0.1% 3.0% Cyclodextrin 1.0% 10.0% Polyethylene glycol 1.0% 5.0% Eudragit E-PO 1.0% 5.0% 10.0% Stearic acid
magnesium 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% Opadry II 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2% 3.2%

*% In Table 7 represents weight%.

The tablets prepared in accordance with the prescriptions of Comparative Examples 13 to 19 and Examples 12 and 13 were subjected to a process hindrance or to a stability chamber set at a severe stability test condition (60 DEG C, 80% RH) Were left for the initial, two weeks, and four weeks, respectively.

As a result, when Eudragit E-PO was used as a stabilizer as shown in Table 8 and FIG. 3 below, the initial and 4-week elution stability was appropriate.

For reference, Comparative Example 19 shows that although the Eudragit E-PO is blended, a process failure such as sticking may occur when the content of the Eudragit E-PO is out of the range of the present invention.

Evaluation items Comparative Example 13 Comparative Example 14 Comparative Example 15 Comparative Example 16 Comparative Example 17 Comparative Example 18 Example 12 Example 13 Comparative Example 19 Process impairment O O O O O O X X O Elution adequacy evaluation
(Early) fitness fitness fitness fitness fitness fitness fitness fitness fitness Elution adequacy evaluation
(2 weeks) incongruity incongruity incongruity incongruity incongruity incongruity fitness fitness fitness Elution adequacy evaluation
(4 weeks) incongruity incongruity incongruity incongruity incongruity incongruity fitness fitness fitness

* Table 8 shows the sticking, laminating, capping, etc. of tablets that can occur when tablets are tableted. O and X are determined based on whether or not the tablets have been damaged during continuous tableting for more than 100 tablets.

* The elution adequacy evaluation in Table 8 refers to the results of the test in accordance with the dissolution test method (paddle method) of the Korean Pharmacopoeia in the effluent under the conditions of purified water (1000 ml, polysorbate 80, and 5%) , Compliance and non-compliance were judged based on a dissolution rate of 85% or more after 45 minutes from the start of the dissolution test

[Experimental Example 5] Comparative experiment of effects according to kinds of excipients

As shown in Table 9, tablets of Comparative Examples 20 to 23 were prepared in a similar amount to the tablets prepared in Example 1 of Table 2, and Comparative Example 23 contained tablets having compositions of Examples 1 and 2 of Patent No. 1002374 The tablets were prepared by reducing the contents of microcrystalline cellulose and lactose, which are excipients.

Purpose of blending Ingredients Example 1 Comparative Example 20 Comparative Example 21 Comparative Example 22 Comparative Example 23 mg / T mg / T mg / T mg / T mg / T chief ingredient Gepetinib 250.0 250.0 250.0 250.0 250.0 Excipient Isomalt 10.0 Excipient Dextrose 10.0 Excipient Lactose 20.0 55.0 Excipient Calcium hydrogen phosphate 20.0 Excipient Microcrystalline cellulose 20.0 23.0 Disintegration Croscarmellose sodium 20.0 Disintegration Crospovidone 35.0 35.0 35.0 35.0 Disintegration Corn starch 32.5 32.5 32.5 32.5 Binder Povidone K-30 7.0 7.0 7.0 7.0 7.0 Solubilizing agent Sodium lauryl sulfate 1.5 Stabilizer Eudragit E-PO 12.0 12.0 12.0 12.0 slush Magnesium stearate 3.5 3.5 3.5 3.5 3.5 Mud 360.0 360.0 360.0 360.0 360.0 Coater HPMC Mechanism 12.25 Coater Opadry II 10.0 10.0 10.0 10.0 Coating 370.0 370.0 370.0 370.0 372.25

The physical properties of the tablets prepared according to the prescription of Table 9 above and the tablets prepared according to the prescription of Example 1 of Table 2 mentioned in Experimental Example 1 and the elution adequacy evaluation (1000 ml of purified water, 80% of polysorbate, Speed 50 rpm, elution of 85% or more for 45 minutes). The results are shown in Table 10 and FIG. 2 below.

Evaluation items Example 1 Comparative Example 20 Comparative Example 21 Comparative Example 22 Comparative Example 23 Carr's Index 17 24 23 30 25 Process impairment X X X X X Elution adequacy evaluation fitness incongruity incongruity incongruity incongruity

* Carr's Index in Table 10 is an index for evaluating the flowability and flowability of granules (powder). The higher the fluidity and flowability of the granules, the more the quantitative filling and mixing uniformity is increased. Is a very important criterion. The lower the Carr's Index value is, the better the flowability is.

* Table 10 shows the sticking, laminating, capping, etc. of tablets that can occur when tablets are tableted, and O and X are determined based on whether or not the tablets have failed during the continuous tableting process for 100 tablet or more.

* The elution adequacy evaluation in Table 10 above refers to the results obtained by performing the test according to the dissolution test method (paddle method) of the Korean Pharmacopoeia in the eluent with the conditions of purified water (1000 ml, polysorbate 80, and 5%) , And compliance and non-compliance were judged based on a dissolution rate of 85% or more after 45 minutes from the start of the dissolution test.

As shown in Table 10, when the isomalt and dextrates were converted to calcium hydrogen phosphate, lactose or microcrystalline cellulose (Comparative Examples 20 to 22), the elution adequacy evaluation results were unsuitable, and in order to reduce the tablet size, Even if the content of microcrystalline cellulose and lactose as the excipients of Examples 1 and 2 was simply reduced, the elution adequacy evaluation result was inadequate (Comparative Example 23).

[Experimental Example 6] The drug-equivalence test of Example 1 and a commercial product

The tablets prepared in Example 1 of Table 2 and the commercially available tablets were administered to beagle dogs at the same time, and blood was collected at each hour to measure the drug concentration in the blood.

As a result, an equivalent blood concentration was exhibited at the same time as in Fig. 5, and the drug equivalence of the commercial formulation and Example 1 was proved.

Claims

A composition comprising at least 65% of the total weight of gefitinib, at least one selected from the group consisting of dextrates and isomalt, and one or more disintegrants, wherein the deckle Wherein the straightening comprises 2-5% of the total weight of the composition, and wherein the isomalt comprises 2-5% of the total weight of the composition, wherein the disintegrant is selected from the group consisting of crospovidone and corn starch At least one, and no lactose.

The composition of claim 1, wherein each component of the disintegrant individually comprises 7-10% by total weight of the disintegrant when it comprises at least one disintegrant.

delete

3. The composition according to claim 1 or 2, further comprising Eudragit E-PO.

8. The composition of claim 7, wherein the Eudragit E-PO comprises 1-5% of the total weight.

delete