CN112741814A

CN112741814A - Canagliflozin tablet and preparation method thereof

Info

Publication number: CN112741814A
Application number: CN202110184507.7A
Authority: CN
Inventors: 潘新; 高原; 殷学治
Original assignee: Shanghai Tianhenian Pharmaceutical Co ltd; Zhejiang Nord Pharmaceutical Co ltd; Zhejiang Tianyu Pharmaceutical Co Ltd
Current assignee: Shanghai Tianhenian Pharmaceutical Co ltd; Zhejiang Nord Pharmaceutical Co ltd; Zhejiang Tianyu Pharmaceutical Co Ltd
Priority date: 2021-02-08
Filing date: 2021-02-08
Publication date: 2021-05-04

Abstract

The invention provides a canagliflozin tablet and a preparation method thereof, which are used for improving the using effect of the canagliflozin tablet. The canagliflozin tablet, wherein: comprises 50-60% of canagliflozin, 34-44% of diluent, 1-3% of disintegrant or 3-5% of adhesive by mass, and is obtained by utilizing the raw materials and carrying out wet granulation, fluidized bed drying, total mixing, tabletting and coating. The invention ensures the uniformity and good fluidity of the mixed particles, reduces the variation coefficient of the absorption of the medicine in the body and ensures the safety and the effectiveness of the medicine by adding auxiliary materials into the particle size of the raw materials and controlling the mixing process.

Description

Canagliflozin tablet and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a canagliflozin tablet and a preparation method thereof.

Background

Canagliflozin is a sodium-glucose cotransporter (SGLT-2) inhibitor and is clinically used for the treatment of type 2 diabetes. The product is developed by Boringer-Vargehne and Gift company, and has the dosage form of tablet and the trade name of Yikean.

The canagliflozin is poor in water solubility and almost insoluble in an aqueous medium with the pH value of 1.1-12.9, and how to improve the in vitro dissolution degree of the preparation is the key point influencing the curative effect of the preparation. The EMEA publication shows that particle size control is performed during the feedstock preparation.

The patent CN 103655539A relates to a canagliflozin oral solid pharmaceutical composition and a preparation method thereof, the composition contains canagliflozin and pharmaceutic adjuvant, wherein the canagliflozin is in an amorphous form, and the average particle size of particles of the canagliflozin is 2.5-30 mu m. The composition effectively solves the technical problems of crystal transformation and poor compressibility of amorphous canagliflozin in the preparation process of solid preparations. According to the invention, by carrying out amorphous micronization on canagliflozin, particles with the average particle size of 2.5-30 μm are obtained, and by controlling the particle size of the raw material medicine, the compressibility and dissolution of canagliflozin can be effectively improved without using a granulating solvent, so that the important technical problem that the amorphous canagliflozin is crystallized and has poor compressibility in the preparation process is effectively solved. As is known, micronization is one of effective ways to improve the dissolution of a drug, but micronization has a plurality of defects that the strong electrostatic adsorption effect is not favorable for uniform mixing, the re-aggregation is easy to occur, the dissolution rate is reduced, and the like. .

Disclosure of Invention

In order to overcome the defect of poor administration effect of canagliflozin in the prior art, the canagliflozin tablet and the preparation method thereof are provided, so that the use effect of the canagliflozin tablet is improved.

In order to solve the technical problems, the invention provides a canagliflozin tablet, which comprises the following technical scheme: comprises 50-60% of canagliflozin, 34-44% of diluent, 1-3% of disintegrant or 3-5% of binder by mass fraction.

Preferably, the composition comprises 55% of canagliflozin, 39% of diluent, 2% of disintegrant or 4% of binder by mass fraction.

Preferably, the beverage also comprises additional materials, and the additional auxiliary materials comprise 90% of dry particles, 8% of microcrystalline cellulose, 1% of colloidal silicon dioxide and 1% of magnesium stearate in percentage by mass; wherein the dry granules are obtained by drying wet granules prepared by adopting canagliflozin, a diluent, a disintegrating agent or an adhesive through wet granulation.

Preferably, the diluent comprises one or more of lactose, microcrystalline cellulose or calcium hydrogen phosphate; the disintegrant comprises one or more of sodium carboxymethyl starch, croscarmellose sodium and crospovidone; the binder comprises one or more of hydroxypropyl cellulose and povidone.

As another aspect of the present invention, the present invention provides a process for preparing a canagliflozin tablet, which comprises the steps of (1) pulverizing a raw material to control a particle size distribution D90 < 100 μm, and preparing wet granules using a wet granulation technique; (2) drying the wet granules by a fluidized bed, and controlling the water content of the product to be not higher than 2%; 3) adding additional auxiliary materials, and performing total mixing, wherein the water content is not higher than 6.0% after mixing; (4) the proportion of the total mixed particle with the particle size distribution below 100 meshes is not less than 70 percent; (5) tabletting, controlling the hardness within 100-200N, and coating.

Preferably, the total mixing is divided into a total mixing I stage and a total mixing II stage, the total mixing I stage is to add colloidal silicon dioxide and microcrystalline cellulose for mixing, and the total mixing II stage is to continue adding magnesium stearate for mixing.

Preferably, in the step (2), the water content of the product is controlled to be not higher than 2.0%, and the drying is carried out, wherein the inlet air temperature is 60-80 ℃, and the end point temperature is 40-60 ℃.

Preferably, in step (3), the water content after mixing is not higher than 3.0%, and the ratio of the total particle size obtained after mixing to 60 mesh is not less than 50%, preferably not less than 70%, and more preferably not less than 80%.

Preferably, in the step (5), the temperature of the tablet core is controlled to be 35-45 ℃, and then the coating is carried out, wherein the temperature of the inlet air is controlled to be 50-70 ℃ and the temperature of the tablet bed is controlled to be 30-50 ℃ during the coating.

Preferably, in the step (3), the ratio of the particle size of the total mixture obtained after mixing to be below 60 meshes is not less than 80%.

The invention has the beneficial effects that:

(1) by optimizing the granulation process, the particle size distribution D90 of the raw materials is controlled to be less than 100 mu m so as to improve the powder flowability of the raw materials, reduce the difference of in vitro dissolution, reduce the variation coefficient of the absorption of the medicine in vivo and ensure the safety and the effectiveness of the medicine.

(2) After the wet particles are prepared, drying the wet particles by adopting a fluidized bed, and strictly controlling the moisture of the particles; the particle size distribution of the particles is determined by the crushing of the granulator, and the uniformity of the content and the moisture of the particles is ensured, so that the good fluidity of the particles is ensured, and more importantly, the small fluctuation of the hardness, the tablet weight range and the like of the subsequent tabletting process can be ensured.

(3) The other content of the invention is that the total mixing machine is adopted to carry out total mixing on the granules, and the uniformity and good fluidity of the mixed granules are ensured by adding the additional auxiliary materials and controlling the mixing process, so that the water content of the total mixed granules is in a target range.

(4) In the tabletting process, due to the narrow fluctuation range of the tablet weight, the proper hardness is controlled to ensure the absorption and metabolism uniformity of the product in human body, and the product has small variation coefficient and high safety performance.

Drawings

FIG. 1 shows dissolution curves of canagliflozin tablet product and a reference formulation prepared in the examples.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below.

Example 1: wet granulation process for preparing granules

Prescription:

composition (I)	Batch (g)
		Canagliflozin	300
Lactose	150
		Microcrystalline cellulose	100
Croscarmellose sodium	60
		Povidone	30

The process comprises the following steps:

mixing and granulating raw materials and auxiliary materials: adding the raw and auxiliary materials in the formula amount into a wet granulator, and stirring for 3 minutes at the rotating speed of a stirring paddle of 300rpm and the rotating speed of a shearing knife of 1200 rpm; adding purified water into a wet mixing granulator, stirring and granulating, setting the operating speed of a hopper mixer to be 12rpm, and discharging after granulating for 2 minutes to obtain wet granules.

Example 2: drying and crushing wet particles:

drying the wet particles by adopting a fluidized bed, wherein the process parameters and the center control are as follows:

process parameter/central control item	Actual range
		Temperature of inlet air	60-70℃
Air inlet quantity	1000m³/h
		Temperature of the product	45-55℃
Moisture content	1.35%

Placing the prepared wet granules in a fluidized bed, setting the air inlet temperature to be 70 ℃, continuously drying the granules until the moisture of the granules is less than 2%, and discharging to obtain the finished product, wherein the actual discharged moisture is 1.35%, and the yield is 93%. And (4) crushing the dried wet particles by using a granulator, and granulating the particles by using a screen with the aperture of 0.8mm to obtain dry particles.

Example 3: intermediate particle total mixture

Composition (I)	Batch (g)
		Dry granules	500
Microcrystalline cellulose	45
		Silica gel micropowder	5.5
Magnesium stearate	5.5

The mixing process comprises the following steps:

total mixing I: adding the whole dry granules into a hopper mixer, respectively adding microcrystalline cellulose and colloidal silicon dioxide in a prescription amount into the hopper mixer, setting the operating speed of the hopper mixer to be 12rpm, and starting the hopper mixer to mix for 10 min.

Total mixing II: the prescribed amount of magnesium stearate was added to a fixed hopper mixer operating at 12rpm and the hopper mixer was turned on to mix for 5 min.

The total mixed particles have the water content of 1.45 percent, the angle of repose of 31.3 degrees and better fluidity after being measured.

Example 4: tabletting

And adding the totally mixed materials into a rotary tablet press for pressing, calculating the weight of tablets to be pressed in the batch production according to the content of the particles, and performing tabletting at the tabletting speed of 100 thousand tablets/h and the feed speed of 40rpm by calculating the target hardness of 100-200N to obtain the plain tablets. According to the determination, the hardness difference of the plain tablets prepared by the process is 150 +/-30N, and the tablet weight difference is 600mg +/-3%.

Example 5: coating film

Preparing a coating solution: adding a prescription amount of purified water into a container, adding a prescription amount of film coating premix while stirring, starting timing after the film coating premix is completely added, stirring for 60min to completely disperse the film coating premix, and passing the prepared coating solution through a perfect 80-mesh screen for later use;

coating: adding the plain tablets into a coating pot, adjusting the height of a coating spray gun according to the thickness of a tablet bed, preheating the tablet cores to 35-45 ℃, and then starting coating; in the coating process, the rotating speeds of the high-efficiency coating machine and the peristaltic pump are adjusted according to the temperature of the tablet bed and the condition of the coated tablet, the air inlet temperature is set to be 60 ℃, and the temperature of the tablet bed is controlled to be 35-45 ℃.

The coating is non-functional, the coating layer only has the functions of moisture resistance, light resistance, wear resistance and the like, the coating is stopped when the weight of the coating is increased to 3 percent, and the coating is finished; the coated tablet is a light yellow film coated tablet, has fine, complete and smooth surface, uniform color, complete corners, and no phenomena of rough surface, mottle, dried orange peel, peeling or lack of pieces, loose pieces, splintering, etc.

Example 6: influence of bulk drug particle size on dissolution curve

The preparation method comprises the steps of adopting raw material medicines with different particle sizes (D90 is less than 50 mu m, D90 is less than 75 mu m, D90 is less than 100 mu m, and D90 is less than 125 mu m) to prepare the canagliflozin tablets according to the prescription process. According to the second method of 0931 of the general rules of the four parts of the pharmacopoeia 2015 year edition, the dissolution medium: the dissolution curve of tablets of different raw material medicaments and a reference preparation is measured and fitted by taking a hydrochloric acid solution (with 0.1 percent SDS) with pH1.2 as a dissolution medium and 900ml of rotation speed of 50 revolutions per minute. The experimental results show that in simulated gastric acid solution, the dissolution curve of the tablets prepared by raw materials with the particle sizes of D90 < 50 mu m, D90 < 75 mu m and D90 < 100 mu m is close to that of a reference preparation, but the dissolution of D90 < 125 mu m is obviously slower than that of the reference preparation.

The invention relates to a canagliflozin tablet and a preparation method thereof, which adopt a wet granulation process, and control the granularity of raw material medicines, the grain diameter of intermediate granules and moisture, so that the prepared canagliflozin tablet has stable content, better uniformity and flowability, stable tablet hardness and better control of tablet weight difference. The canagliflozin tablet prepared by the preparation method provided by the invention is stable in process, has a good dissolution effect and small dissolution fluctuation, and is favorable for ensuring the safety of medication and the clinical application effect. By controlling the preparation process, the content uniformity of the tablet is good, the variability of the tablet in a human body is reduced, the bioavailability is improved, and the safety of the tablet for human administration is improved.

It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.

Claims

1. A canagliflozin tablet is characterized in that: comprises 50-60% of canagliflozin, 34-44% of diluent, 1-3% of disintegrant or 3-5% of binder by mass fraction.

2. The canagliflozin tablet of claim 1, wherein: the composition comprises 55% of canagliflozin, 39% of diluent, 2% of disintegrant or 4% of binder by mass fraction.

3. The canagliflozin tablet of claim 1 or 2, wherein: the coating also comprises an additional material, wherein the additional auxiliary material comprises 90% of dry particles, 8% of microcrystalline cellulose, 1% of colloidal silicon dioxide and 1% of magnesium stearate in percentage by mass;

wherein the dry granules are obtained by drying wet granules prepared by adopting canagliflozin, a diluent, a disintegrating agent or an adhesive through wet granulation.

4. The canagliflozin tablet of claim 3, wherein: the diluent comprises one or more of lactose, microcrystalline cellulose or calcium hydrophosphate; the disintegrant comprises one or more of sodium carboxymethyl starch, croscarmellose sodium and crospovidone; the binder comprises one or more of hydroxypropyl cellulose and povidone.

5. A preparation method of a canagliflozin tablet is characterized by comprising the following steps: comprises the following steps of (a) carrying out,

(1) crushing the raw materials, controlling the particle size distribution D90 to be less than 100 mu m, and preparing wet granules by adopting a wet granulation technology;

(2) drying the wet granules by a fluidized bed, and controlling the water content of the product to be not higher than 2%;

(3) adding additional auxiliary materials, and performing total mixing, wherein the water content is not higher than 6.0% after mixing;

(4) the proportion of the total mixed particle with the particle size distribution below 100 meshes is not less than 70 percent;

(5) tabletting, controlling the hardness within 100-200N, and coating.

6. The process for preparing a canagliflozin tablet as claimed in claim 5, wherein: the total mixing comprises a total mixing stage I and a total mixing stage II, wherein the total mixing stage I is to add colloidal silicon dioxide and microcrystalline cellulose for mixing, and the total mixing stage II is to continue to add magnesium stearate for mixing.

7. The process for preparing a canagliflozin tablet as claimed in claim 5, wherein: in the step (2), the water content of the product is controlled to be not higher than 2.0%, and the drying is carried out, wherein the inlet air temperature is 60-80 ℃, and the end point temperature is 40-60 ℃.

8. The process for preparing a canagliflozin tablet as claimed in claim 5, wherein: in the step (3), the water content after mixing is not higher than 3.0%, and the proportion of the total mixed particles with the particle size of below 60 meshes is not less than 50%, preferably not less than 70%, and more preferably not less than 80%.

9. The process for preparing a canagliflozin tablet as claimed in claim 5, wherein: in the step (5), the temperature of the tablet core is controlled to be 35-45 ℃, and then the coating is carried out, wherein the air inlet temperature is controlled to be 50-70 ℃ and the temperature of the tablet bed is controlled to be 30-50 ℃ during the coating.

10. The process for preparing a canagliflozin tablet as claimed in claim 8, wherein: in the step (3), the ratio of the particle size of the total mixed particles below 60 meshes is not less than 80%.