CN114886865A

CN114886865A - Gefitinib tablet and preparation method thereof

Info

Publication number: CN114886865A
Application number: CN202210699249.0A
Authority: CN
Inventors: 张贵民; 郝贵周
Original assignee: Shandong New Time Pharmaceutical Co Ltd
Current assignee: Shandong New Time Pharmaceutical Co Ltd
Priority date: 2015-12-25
Filing date: 2015-12-25
Publication date: 2022-08-12
Also published as: CN106913541A

Abstract

The invention provides a gefitinib tablet, which is prepared by the following method, gefitinib is dissolved in glacial acetic acid, alkali liquor is added into the solution under the stirring condition, gefitinib is separated out, filtered and dried, then the gefitinib tablet is mixed with adhesive, filling agent and disintegrating agent, granulated and dried, lubricant is added into dry granules, and tabletting is carried out. Compared with the prior art, the invention does not need to prepare the dispersoid by a special process; the preparation processing equipment is simple, and special equipment is not needed; the dissolution rate of gefitinib is improved.

Description

Gefitinib tablet and preparation method thereof

The application is a divisional application with the application date of 2015.12.25 and the application number of CN201510998261.1 and the name of the invention of gefitinib tablet and a preparation method thereof.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a gefitinib tablet and a preparation method thereof.

Background

Gefitinib (chemical name: N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine) is a selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor, and is suitable for three-line, two-line and even one-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with sensitive mutation of epidermal growth factor receptor tyrosine kinase (EGFR TK) gene.

Gefitinib tablet (trade name "Iressa", Iressa) was first developed by astrazen pharmaceutical limited, uk, and was approved in the us and japan for marketing as a three-line drug for the treatment of non-small cell lung cancer in 2003, which is highly effective in asian population. Subsequent researches show that the curative effect of the compound is closely related to EGFR mutation, and the compound is approved by European Union drug administration to be marketed as a targeted therapeutic medicament by 7-1 month in 2009 and is used for the first-line, second-line and third-line treatment of local advanced or metastatic non-small cell lung cancer of EGFR gene mutation of adults. In 2004, 12 months, "Yiruisha" entered China for locally advanced or metastatic non-small cell lung cancer that had been subjected to chemotherapy, and in 2010, "Yiruisha" was approved in China for first-line treatment for locally advanced or metastatic non-small cell lung cancer patients with sensitive mutations in the EGFR tyrosine kinase gene.

Currently, only astrazeneca pharmaceutical limited company and indian nato Pharma company produce and sell the variety worldwide, and since iressa (gefitinib tablet produced by astrazeneca, hereinafter the same) is expensive (about 600 yuan/tablet), many patients have to choose to use a relatively inexpensive gefitinib tablet produced by indian nato Pharma company, but it was found by comparative studies that the in vitro dissolution of the gefitinib tablet produced by indian nato Pharma company is very poor.

Absorption of a drug after oral administration of a solid formulation depends on dissolution or release of the drug from the formulation, dissolution of the drug under physiological conditions, and permeation in the gastrointestinal tract. Since the dissolution of a drug has an important influence on absorption, an in vitro dissolution test can predict the in vivo behavior to a certain extent. Gefitinib belongs to low-solubility-high-permeability medicines in BCS (biological medicament classification system), the dissolution of the medicines is the rate-limiting step of medicine absorption, and the Gefitinib has better in-vivo and in-vitro correlation; the in vivo drug release process can be indirectly reflected through the dissolution curves measured in different in vitro media; therefore, the in vitro dissolution of the gefitinib preparation in different dissolution media can be used as an important index for evaluating the curative effect of the medicament.

Gefitinib is a slightly basic compound containing two basic groups with pKa of 5.3 and 7.2, so that gefitinib is soluble in pH1, but its solubility decreases sharply between pH4 and pH6 with increasing pH, and is hardly soluble above pH 7. The results of an experiment with healthy volunteers showed that there was a 47% reduction in gefitinib absorption when the pH was maintained above 5. The difficulty in the research of gefitinib preparation is caused by the fact that gefitinib is difficult to dissolve in water at a pH value of 5 or above. In vitro dissolution tests of the product in Europe and America, 5% Tween-80 aqueous solution is selected as a dissolution medium, the gefitinib tablet of Indian NATCO Pharma company is only dissolved by about 30% in 60 minutes under the condition, the dissolution rate is not obviously increased in 90 minutes, and the situation that a large amount of gefitinib is not released at all, so that the effective concentration for treatment cannot be reached is shown.

In addition, the experimental research on the Iressa in the market finds that the stability of the Iressa is not ideal, the dissolution curve of the product is obviously changed close to the effective period, and even in a hydrochloric acid solution which is very easy to release, the dissolution rate of 45 minutes is reduced from 99% to about 75%, so that the quality standard requirement of the medicine cannot be met. That is, the release of the drug in the body is not well enough to reach the desired rate of treatment, which will undoubtedly result in a decrease in efficacy, and will, in the least, prolong the healing period and, in the most severe case, delay the optimal period of treatment so that the patient loses the chance of recovery.

CN 103006608A discloses a pharmaceutical composition containing gefitinib, wherein the gefitinib tablet adopts the following particle size distribution: d (0.1) ═ 2-6 μm, D (0.5) ═ 11-20 μm, and D (0.9) ═ 35-50 μm. However, even if the particle size is controlled, the 45min dissolution is only 92%, and the drug is not completely dissolved.

CN 102631347a discloses a gefitinib pharmaceutical composition, which is composed of gefitinib, diluent, solubilizer, binder, disintegrant and lubricant. Gefitinib can also exist in an amorphous state, thereby further improving dissolution efficiency. However, since amorphous gefitinib is theoretically inferior in stability to crystalline gefitinib, the present invention solves the problem of slow dissolution, but has a new problem of poor stability.

CN 201110196655.7 discloses a gefitinib dispersible tablet, a preparation method and an application thereof, wherein an acidulant is added to improve the dissolution rate of gefitinib. Gefitinib is an alkaline substance, the solubility of gefitinib is expected to be improved under acidic conditions, but tests show that the dispersible tablet and the preparation method can not actually achieve the effect of improving the dissolution of a medicament, and analysis shows that the dispersible tablet is characterized by quick release, so the gefitinib dispersible tablet prepared by the method is quickly released in the stomach after being taken, the stomach is an acidic environment and does not need to be additionally provided with an acidifier, the absorption of gefitinib in the stomach is limited, the intestinal tract is a main absorption part of the medicament, and the product prepared by the method can not effectively improve the absorption of the medicament in the gastrointestinal tract, and excessive intake of the acidic substance can increase the burden of the stomach to cause discomfort of a patient.

Disclosure of Invention

In view of the deficiencies of the prior art, the inventors intend to provide a fast dissolving gefitinib tablet. The inventors first considered that gefitinib has poor solubility, and in the prior art, even when gefitinib is pulverized to D90 ═ 35 μm, gefitinib is difficult to dissolve out quickly. The inventor adopts a multiple micronization technology, the particle size is crushed to D90 of about 500nm, the dissolution rate of the preparation in 30min is 82%, and the dissolution is still incomplete.

Based on the above experiments, the inventors realized that it is difficult to improve the dissolution rate of the drug again by the pulverization technique alone. In the prior art, gefitinib is dissolved in acid, and then the solution is granulated on pharmaceutically available auxiliary materials, so that the dissolution rate can be improved, but the content of the acid in a tablet is high, so that the compression molding is difficult and the taking compliance is poor.

Considering that gefitinib is easy to dissolve in glacial acetic acid, the inventor considers that an alkaline substance can be added into a glacial acetic acid solution of a medicament, the medicament is precipitated by utilizing an acid-base neutralization principle, filtered and dried to obtain ultrafine gefitinib, and the experimental result shows that the particle size of fine powder D90 is 150nm, the fine powder is granulated on auxiliary materials, then dried, mixed with a lubricant and tabletted, and the dissolution rate is 94% after 45 min. A better effect is obtained.

Specifically, the invention is realized by the following technologies:

the invention provides a gefitinib tablet, which is prepared by the following method, gefitinib is dissolved in glacial acetic acid, alkali liquor is added into the solution under the stirring condition, gefitinib is separated out, filtered and dried, then the gefitinib tablet is mixed with adhesive, filling agent and disintegrating agent, and is granulated, dried, lubricant is added into dry granules, and tabletting is carried out.

In the gefitinib tablet, the weight ratio of gefitinib to glacial acetic acid is 1: 5-7; preferably, the weight ratio is 1: 6.

The alkali liquor is one or more of sodium hydroxide aqueous solution, sodium carbonate aqueous solution and sodium bicarbonate aqueous solution; the base is added in such an amount that the pH of the final system is between 4 and 11.

The gefitinib tablet is characterized in that the filler is one or more of lactose, mannitol, microcrystalline cellulose, starch, pregelatinized starch and a starch-lactose compound.

The disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose.

The adhesive is one or more of povidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

The lubricant is one or more of magnesium stearate, sodium stearyl fumarate and zinc stearate.

The medicinal auxiliary materials, namely the adhesive, the filling agent and the disintegrating agent, are all in conventional dosage.

Compared with the prior art, the invention has the following advantages:

(1) the medicine can be completely dissolved out within 45min, so that the curative effect of the medicine is ensured;

(2) the surfactant is not required to be added, so that the stimulation of the surfactant to the gastrointestinal tract is avoided.

(3) Complex micro-powder treatment is not needed.

Detailed Description

The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art according to the present invention are also included in the scope of the present invention.

Example 1

The preparation process comprises the following steps:

dissolving gefitinib with a prescription amount in glacial acetic acid, slowly dropwise adding a sodium carbonate solution into the solution under stirring, separating out gefitinib, filtering, drying at 60 ℃, then uniformly mixing with lactose, microcrystalline cellulose, sodium carboxymethyl starch and povidone, adding a proper amount of pure water for granulation, drying at 60 ℃, adding magnesium stearate into dry granules, uniformly mixing, and tabletting.

Example 2

The preparation process comprises the following steps:

dissolving gefitinib with a prescription amount in glacial acetic acid, slowly dropwise adding a sodium hydroxide solution into the solution under stirring, separating out gefitinib, filtering, drying at 60 ℃, then uniformly mixing with mannitol, microcrystalline cellulose, crospovidone and povidone, adding a proper amount of 95% ethanol solution for granulation, drying at 45 ℃, adding magnesium stearate into dry granules, uniformly mixing and tabletting.

Example 3

The preparation process comprises the following steps:

the gefitinib is dissolved in glacial acetic acid according to the prescription amount, sodium bicarbonate solution is slowly dripped into the solution under the stirring condition, the gefitinib is separated out, filtered and dried at 65 ℃, then the gefitinib is uniformly mixed with lactose, hydroxypropyl cellulose and sodium carboxymethyl starch, a proper amount of 90 percent ethanol solution is added for granulation, the drying is carried out at 45 ℃, magnesium stearate is added into dry granules, the mixture is uniformly mixed, and the tablet is prepared.

Comparative example 1

The preparation process comprises the following steps:

(1) micronizing gefitinib to obtain powder with D90 ═ 6.5 μm;

(3) weighing sodium carboxymethyl starch, povidone, lactose, microcrystalline cellulose and micronized gefitinib according to the prescription amount, uniformly mixing, adding a proper amount of pure water, granulating, drying, granulating, adding magnesium stearate according to the prescription amount, uniformly mixing, and tabletting.

Comparative example 2

The preparation process comprises the following steps:

dissolving polyvidone and sodium dodecyl sulfate in hydrochloric acid solution with pH of 1 to obtain granulating solution;

weighing the gefitinib, lactose, microcrystalline cellulose and croscarmellose sodium powder which are not crushed according to the prescription amount, and uniformly mixing; adding the granulating solution for granulating; drying the obtained granules by using a fluidized bed; granulating, adding magnesium stearate, and mixing; and (4) pressing into tablets.

Verification examples

1. Dissolution testing method. Taking the product, according to a dissolution determination method (second method of appendix XC of the second part of the 2010 edition of Chinese pharmacopoeia), taking 900ml of pH4.5 acetate buffer solution as a dissolution medium, rotating at 50 revolutions per minute, operating according to the method, taking 10ml of solution after 45 minutes, filtering, and taking a subsequent filtrate as a test solution. Taking about 27.8mg of abiraterone acetate reference substance, placing the abiraterone acetate reference substance into a 10ml measuring flask, adding methanol for dissolving and diluting to a scale, shaking up, precisely measuring 1ml, placing the abiraterone acetate reference substance into the 10ml measuring flask, adding a dissolving medium for diluting to the scale, and shaking up to obtain a reference substance solution. According to the chromatographic conditions under the content determination item, 10 μ l of each of the test solution and the reference solution is respectively injected into a liquid chromatograph, and the chromatogram is recorded. The dissolution rate of each tablet is calculated by the peak area according to an external standard method. The limit is 75% of the indicated amount and should be met.

Results of measurement in each example

Examples	0 day dissolution (%)	Dissolution after 6 months accelerated at 40 ℃ with 75% RH (%)
			Example 1	96.3	94.2
Example 2	97.4	95.3
			Example 3	97.7	95.6
Comparative example 1	20.4	20.1
			Comparative example 2	37.2	35.4

As can be seen from the table, the dissolution of the inventive examples 1-3 is rapid, and the dissolution is complete within 45min, so that the rapid dissolution is realized after the accelerated examination; comparative example 1 the prior art is adopted, the raw materials are processed by micro powder and the particle size is controlled, and the dissolution is slower than that of the invention; comparative example 2, using the prior art, is slower than the present invention.

Claims

1. A gefitinib tablet is characterized by being prepared by the following method, gefitinib is dissolved in glacial acetic acid, alkali liquor is added into the solution under the condition of stirring, gefitinib is separated out, filtered and dried, then the gefitinib tablet is mixed with adhesive, filling agent and disintegrating agent, and is granulated and dried, a lubricating agent is added into dry granules, and the gefitinib tablet is prepared by tabletting; the weight ratio of the gefitinib to the glacial acetic acid is 1: 5-7; the lye is added in such an amount that the pH of the final system is from 4 to 11.

2. Gefitinib tablet according to claim 1, characterized in that the weight ratio of gefitinib to glacial acetic acid is 1: 6.

3. Gefitinib tablet according to claim 1, wherein the alkaline solution is one or more of aqueous sodium hydroxide solution, aqueous sodium carbonate solution, and aqueous sodium bicarbonate solution.

4. Gefitinib tablet according to claim 1, wherein the filler is one or more of lactose, mannitol, microcrystalline cellulose, starch, pregelatinized starch, starch lactose complex.

5. Gefitinib tablet according to claim 1, characterized in that the disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose.

6. Gefitinib tablet according to claim 1, wherein the binder is one or more of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose.

7. Gefitinib tablet according to claim 1, characterized in that the lubricant is one or more of magnesium stearate, sodium stearyl fumarate, zinc stearate.