CN107961224B

CN107961224B - Acertinib tablet and preparation method thereof

Info

Publication number: CN107961224B
Application number: CN201711276952.6A
Authority: CN
Inventors: 刘文民; 单衍强; 苏东晓; 方春苗; 刘敏
Original assignee: QILU PHARMACEUTICAL (HAINAN) CO Ltd; Qilu Pharmaceutical Co Ltd
Current assignee: QILU PHARMACEUTICAL (HAINAN) CO Ltd; Qilu Pharmaceutical Co Ltd
Priority date: 2017-12-06
Filing date: 2017-12-06
Publication date: 2021-05-04
Anticipated expiration: 2037-12-06
Also published as: CN107961224A

Abstract

The invention discloses an axitinib tablet and a preparation method thereof. In the tablet, the axitinib accounts for 0.5-5% of the weight of the tablet, the diluent accounts for 85-95% of the weight of the tablet, the disintegrant accounts for 1-5% of the weight of the tablet, the lubricant accounts for 0.5-1% of the weight of the tablet, the solubilizer accounts for 0.25-1% of the weight of the tablet, and the sum of the weight percentages of the components is 100%. The D90 of the axitinib raw powder is in the range of 15-25 μm. Compared with the prior art, the axitinib tablet disclosed by the invention has the advantages that a small amount of solubilizer is added into the material under the condition of a certain particle size range, the degradation, waste and energy loss of the raw material in the micronization process are reduced, the good dissolution effect and safety are realized, the production process is simple, the production requirement is met, and the perfect combination of the improvement of the dissolution rate, the guarantee of the safety and the simple process is realized.

Description

Acertinib tablet and preparation method thereof

The technical field is as follows:

the invention relates to the technical field of pharmaceutical preparations, in particular to axitinib tablets and a preparation method thereof.

Background art:

axitinib (Axitinib) is a multi-target tyrosine kinase inhibitor developed by Pfizer company, can inhibit vascular endothelial cell growth factor receptors VEGFR1, VEGFR2, VEGFR3, platelet-derived growth factor receptor and c-KIT, is used for treating ineffective advanced kidney cancer by other systems, and is approved by FDA on 1/27 of 2012 for marketing. The axitinib product currently on the market is a tablet.

The axitinib has extremely low solubility, belongs to insoluble medicines, and has the solubility of 0.2ug/ml in water according to literature data. And the bulk drug is unstable to light, heat and moisture and is easy to degrade. How to ensure the dissolution of the drug is therefore a very important issue. Patent document CN105769785A reports a method for preparing axitinib tablets, in which the particle size of axitinib is strictly controlled, so that the drug dissolution rate meets the requirement, in the disclosed examples, when the particle size of axitinib D90 is less than or equal to 12 μm, the dissolution rate reaches over 90%, when D90 is less than or equal to 36 μm, the dissolution rate is 87.25%, and when D90 is less than or equal to 60 μm, the dissolution rate can only reach 80.45%. And it is mentioned in patent document CN103826618A that axitinib has an average particle size with acceptable content uniformity in embodiments, and a suitable particle size of axitinib may be D (v,0.5) NMT25 micrometers or D (v,0.9) NMT81 micrometers, but the dissolution rate of tablets prepared by this particle size is not written in examples, but it is reported in patent document CN105769785A that the dissolution rate of axitinib tablets produced by fevery company, the holder of patent document CN103826618A, is 83.3% in 5mg size and 89.4% in 1mg size, is measured. The difference between the dissolution rates is large, and the control range of the particle size is likely to be large.

But the particle size of the raw material is reduced, particularly the particle size D90 is strictly controlled within the range of less than or equal to 12 microns, the difficulty is very high, the raw material needs to be crushed for multiple times, the raw material loss is large, the sample injection amount of the equipment is small, the time consumption is long, and the waste of materials, energy and working hours is easily caused. Therefore, how to prepare a product with high dissolution rate by a simpler method still needs to be further researched.

The invention content is as follows:

in view of the above, the present invention aims to provide an axitinib tablet with simple preparation process, smooth production process, high safety, good tablet content uniformity and high dissolution rate.

The effective method for improving the drug dissolution rate mainly comprises the steps of preparing solid dispersion, micronizing raw materials, adding a surfactant and the like. The solid dispersion technology is one of the commonly used means for improving the dissolution rate of insoluble drugs, and is to dissolve a drug and a certain carrier material, such as polyvidone K30, hydroxypropyl cellulose, hypromellose and the like, into a proper amount of organic solvent, then remove the solvent by reduced pressure evaporation, crush and screen the mixture to obtain the solid dispersion, thereby improving the dissolution rate of the drug. The inventor tries a large amount of carrier materials, organic solvents and different preparation methods, and can not obtain samples with qualified organic residues.

Patent document CN105769785A adopts a method of micronization, but as described above, it is difficult to reduce the particle size of the raw material, and particularly, it is difficult to strictly control the particle size D90 ≦ 12 μm, and the loss of the raw material is large, which causes a series of problems.

The addition of sodium lauryl sulfate as a surfactant is mentioned in patent document CN106913547A, but it can be seen from the patent document that in comparative example 4, after axitinib and sodium lauryl sulfate are mixed and micronized, D90 is controlled to be less than 5 μm, and after the mixture is mixed with other auxiliary materials and granulated, the dissolution rate is measured to be 77.9%, and is reduced to 76.1% after being accelerated for 6 months at 40 ℃ at 75% RH, which shows that the addition of a higher amount of sodium lauryl sulfate as a surfactant still cannot meet the requirement of dissolution rate, so the addition of lauryl sulfuric acid to improve the dissolution rate is not adopted in the patent document.

However, the inventor of the present invention has repeatedly conducted a large number of experiments to find that the dissolution rate of the tablet obtained in the combination range can reach more than 90% by controlling the particle size of the micronized raw materials and the amount of the added sodium dodecyl sulfate in an optimal combination, and meanwhile, side effects such as hemolysis and the like are not caused, all requirements of the tablet can be met, and the preparation process is simple and the production process is smooth.

The invention adopts the following technical scheme:

the axitinib tablet with high dissolution rate comprises a tablet core and a coating, and is characterized in that the tablet core consists of the following components: the composition comprises axitinib, a diluent, a disintegrating agent, a lubricant and a solubilizer.

According to the axitinib tablet, the tablet core comprises, by weight, 0.5% -5% of axitinib, 85% -95% of diluent, 1% -5% of disintegrating agent, 0.5% -1% of lubricant, 0.25% -1% of solubilizer and 100% of the total weight of the components.

According to the axitinib tablets of the invention, the particle size of the axitinib has a D90 in the range of 15 μm to 25 μm, preferably a D90 in the range of 18 μm to 25 μm or 15 μm to 20 μm.

According to the axitinib tablet, the diluent is one or a mixture of lactose and microcrystalline cellulose; preferably a mixture of the two.

According to the axitinib tablet, the used disintegrating agent is one or more of starch, croscarmellose sodium and sodium carboxymethyl starch; preferably croscarmellose sodium.

According to the axitinib tablet, the used lubricant is selected from one or more of talcum powder and magnesium stearate; magnesium stearate is preferred.

According to the axitinib tablet, the used solubilizer is selected from solubilized tweens, spans and sodium dodecyl sulfate; preferably sodium lauryl sulfate.

According to the axitinib tablet, the particle size D90 of the axitinib is controlled within the range of 15-25 μm, and the solubilizing agent is added, so that the problem of low dissolution rate of the axitinib is effectively solved. And the particle size range of 15-25 μm is easily achieved under proper pressure for a general jet mill without repeated pulverization. The waste of raw materials is reduced. And through repeated tests on the solubilizer, the requirement of dissolution can be met when the dosage of the solubilizer is within 0.25-1% of the weight of the tablet.

In the preparation method process of the tablet, a method of direct powder compression and wet granulation compression is adopted, and the method of direct powder compression comprises the following process flows:

(1) micronizing the axitinib raw material to ensure that the D90 is within the range of 15-25 μm;

(2) uniformly mixing micronized axitinib, a solubilizer, a diluent, a disintegrating agent and a lubricant according to an equivalent progressive method to obtain a mixed material;

(3) tabletting and coating the mixed material obtained in the step 2) to obtain the axitinib tablets.

The axitinib tablet with uniform content and high dissolution rate is obtained.

Since axitinib is easily degraded, in the present invention, a coating material capable of preventing degradation of axitinib is used in the coating step, and preferably the coating material and the coating method mentioned in WO2013/046113a1 are used. And the weight of the coating is 3.0-4.0% of the weight of the plain tablets.

Compared with the existing method for preparing the axitinib tablet by strictly controlling the particle size D90 to be less than or equal to 12 microns through micronization, the method has the advantages of reducing the degradation and waste of raw materials and energy loss in the micronization process, simultaneously having good dissolution effect and safety, meeting the production requirements, and realizing the perfect combination of improving the dissolution rate, ensuring the safety and having simple process.

Detailed Description

The present invention will be described in detail below with reference to specific examples in order to enable those skilled in the art to better understand the technical invention of the present invention. The following description of the embodiments is only intended to aid in the understanding of the method of the invention and its core ideas. It should be noted that modifications and improvements can be made to the invention by those skilled in the art without departing from the principle of the invention, and these modifications and improvements also fall within the scope of the claims of the invention.

Example one

Composition (I)	mg/tablet (Specification: 5mg)	Function(s)
			Axitinib	5	Active ingredient
Microcrystalline cellulose	107	Diluent
			Lactose	56	Diluent
Croscarmellose sodium	5.25	Disintegrating agent
			Sodium dodecyl sulfate	1.5	Solubilizer
Magnesium stearate	1.3	Lubricant agent
			OPADRY	6	Coating agent

The preparation process comprises the following steps:

1) micronizing axitinib, and controlling the D90 of the axitinib to be in the range of 18-25 μm;

2) respectively mixing the pulverized axitinib raw material medicine with sodium dodecyl sulfate, microcrystalline cellulose, lactose and crosslinked carboxymethyl cellulose sodium in a multidimensional mixing cylinder according to an equivalent progressive method for 20min to obtain an intermediate A

3) Mixing the intermediate A with magnesium stearate for 5min to obtain intermediate B

4) And (4) tabletting the intermediate B, and coating a film coat to obtain the axitinib tablet.

Example two

Composition (I)	mg/tablet (Specification: 1mg)	Function(s)
			Axitinib	1	Active ingredient
Microcrystalline cellulose	63.5	Diluent
			Lactose	32.5	Diluent
Croscarmellose sodium	3	Disintegrating agent
			Sodium dodecyl sulfate	0.5	Solubilizer
Magnesium stearate	0.75	Lubricant agent
			OPADRY	4	Coating agent

The preparation process comprises the following steps:

1) micronizing axitinib, and controlling the D90 of the axitinib to be within the range of 15-20 μm;

Comparative example 1

Prescription (Specification 5 mg/tablet)

The preparation process comprises the following steps:

1) micronizing axitinib, and controlling the D90 of the axitinib to be within the range of 30-36 μm;

2) and respectively mixing the crushed axitinib raw material medicine, sodium dodecyl sulfate, microcrystalline cellulose, lactose and cross-linked sodium carboxymethyl cellulose in a multidimensional mixing cylinder for 20min according to an equivalent progressive method to obtain an intermediate A.

3) Mixing the intermediate A with magnesium stearate for 5min to obtain an intermediate B;

Comparative example 2

Prescription (Specification 5 mg/tablet)

The preparation process comprises the following steps:

1) micronizing axitinib, and controlling the D90;

Experimental example 1

Taking the tablet samples prepared in examples 1-2, comparative example 1 and comparative example 2 and the commercial axitinib tablet

(1 mg/tablet, Perey, USA), at 37 ℃, using 900ml of 0.01M hydrochloric acid solution as dissolution medium, using pulp plate method at 50 rpm, measuring dissolution rate of tablet after 30 minutes, the results are shown in tables 1 and 2:

table 1:

	example 1(5 mg/tablet)	Example 2(1 mg/tablet)	Commercially available product
				Dissolution rate	93.1％	91.7％	86.5％

Table 2:

experimental example 2

(specification is 1 mg/tablet, pfeiri, usa), content uniformity (a +1.8S) was determined according to the method in appendix XE of second part of chinese pharmacopeia, 2010 edition, and relevant substance detection was performed by high performance liquid chromatography, with the results shown in tables 3 and 4:

table 3:

	example 1(5 mg/tablet)	Example 2(1 mg/tablet)	Commercially available product
				Content uniformity	2.9	3.5	3.5
Maximum single impurity (%)	0.08	0.07	0.14
				Related substance (%)	0.23	0.21	0.29

Table 4:

the results of the above experimental examples show that the dissolution rate of the axitinib tablets (self-products) prepared in examples 1-2 is significantly higher than that of the original product, the content of the largest single impurity and related substances is lower than that of the original product, and the content uniformity meets the requirement.

In comparative example 1, a fixed particle size was used and tableting was performed by adjusting the amount of surfactant, and in comparative example 2, a smaller amount of surfactant was used and the particle size was adjusted, and experiments were conducted, and it was found that the amount of surfactant used needs to be increased in the case of a larger particle size, but the amount of surfactant used is decreased because of its potential hemolytic property, and the dissolution requirement is achieved by decreasing the particle size of the raw material.

Claims

1. An axitinib tablet with high dissolution rate comprises a tablet core and a coating, wherein the tablet core consists of 0.5-5 wt% of axitinib, a diluent, a disintegrating agent, a lubricant and a solubilizer, and is characterized in that the tablet core consists of the following components in percentage by weight, wherein the axitinib accounts for 0.5-5 wt% of the tablet, the diluent accounts for 85-95 wt% of the tablet, the disintegrant accounts for 1-5 wt% of the tablet, the lubricant accounts for 0.5-1 wt% of the tablet, the solubilizer accounts for 0.25-1 wt% of the tablet, and the sum of the weight percentages of the components is 100%; d90 of the particle size of the axitinib is within the range of 15-20 μm, and the solubilizer is sodium dodecyl sulfate; the preparation method of the tablet comprises the following steps of, wherein the preparation method does not contain a solvent, and the direct tabletting method comprises the following process flows:

(1) micronizing the axitinib raw material to ensure that the D90 is within the range of 15-20 μm;

(2) uniformly mixing the micronized axitinib, the solubilizer, the diluent, the disintegrant and the lubricant in turn according to an equivalent progressive method to obtain a mixed material;

(3) and (3) tabletting and coating the mixed material obtained in the step (2) to obtain the axitinib tablets.

2. The axitinib tablet of claim 1, wherein the diluent is one or a mixture of lactose and microcrystalline cellulose.

3. The axitinib tablet of claim 1, wherein the disintegrant is one or a mixture of starch, croscarmellose sodium and sodium carboxymethyl starch.

4. The axitinib tablet of claim 3, wherein the disintegrant is croscarmellose sodium.

5. The axitinib tablet of claim 1, wherein the lubricant is selected from one or both of talc and magnesium stearate.

6. The axitinib tablet of claim 5, wherein the lubricant is magnesium stearate.