CN111329840B

CN111329840B - Imidapril hydrochloride tablet and preparation method thereof

Info

Publication number: CN111329840B
Application number: CN202010304861.4A
Authority: CN
Inventors: 刘宇晶; 郑柏松; 白靳飞; 边华欣; 谌宗永
Original assignee: Beijing Sunshine Nuohe Pharmaceutical Research Co ltd
Current assignee: Anhui Jiahe Pharmaceutical Co.,Ltd.
Priority date: 2020-04-17
Filing date: 2020-04-17
Publication date: 2021-02-09
Anticipated expiration: 2040-04-17
Also published as: CN111329840A

Abstract

The invention discloses imidapril hydrochloride tablets and a preparation method thereof. The imidapril hydrochloride tablet comprises the following raw materials in parts by mass: 10 parts of imidapril hydrochloride, 70-74 parts of lactose, 60007-8 parts of polyethylene glycol and 0.4-0.5 part of magnesium stearate. The grain diameter D90 of the imidapril hydrochloride is less than or equal to 30 mu m; the lactose is a mixture of lactose with the size of 200 meshes and lactose T80 according to the mass ratio of 4: 1-2. The preparation method comprises the following steps: pouring lactose accounting for 40-50% of the mass, imidapril hydrochloride and the rest lactose into a wet mixing granulator in sequence and mixing uniformly; adding aqueous solution of polyethylene glycol 6000 to prepare soft material; granulating; drying and finishing the particles by using a fluidized bed; putting magnesium stearate and the dried granules into a three-dimensional motion mixer, mixing uniformly, and tabletting. Compared with the tablets prepared by the traditional tabletting method, the imidapril hydrochloride tablets prepared by the invention have the advantages of obviously improved medicine content uniformity, better dissolution effect and higher product quality.

Description

Imidapril hydrochloride tablet and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to imidapril hydrochloride tablets and a preparation method thereof.

Background

(4S) -3- [ (2S) -2- [ (1S) -1-ethoxycarbonyl-3-phenylpropyl ] aminopropionyl ] -1-methyl 2-oxoimidazoline-4-carboxylic acid hydrochloride, also known as imidapril hydrochloride, trade name Dashuang, has a structural formula shown in formula I:

the active metabolite imidapril of imidapril hydrochloride can be used in the renin-angiotensin (RA) system in vivo with high selectivity, inhibit the generation of angiotensin II, inhibit the secretion of sympathetic neurotransmitter and aldosterone, thus reduce the peripheral pressure and achieve the purpose of lowering blood pressure.

Imidapril hydrochloride Tablets were first developed by Ri Honda pharmaceutical corporation (Shi Tian Mitsubishi pharmaceutical corporation) in 1983, and were approved by the Ming province of Kyoho in Japan in 1993 at 10 months, and were marketed under the trade name of TANATRIL Tablets, which were 2.5mg, 5mg and 10mg, respectively; the Chinese patent specification is 5mg approved to be on the market in 1999, the Chinese patent specification is 10mg approved to be on the market in 2003, and the trade names of the two specifications are Dashuang in China. Imidapril hydrochloride tablets play an important role in lowering blood pressure. At present, the dry method direct compression is mainly adopted for preparation, and the problem of uneven content distribution exists, so that the existing tablet formula and preparation process need to be improved.

Disclosure of Invention

The invention aims to provide imidapril hydrochloride tablets and a preparation method thereof.

The imidapril hydrochloride tablet provided by the invention comprises the following raw materials in parts by mass: 10 parts of imidapril hydrochloride, 70-74 parts of lactose, 7-8 parts of adhesive and 0.4-0.5 part of lubricant;

wherein the adhesive is polyethylene glycol 6000, and the lubricant is magnesium stearate.

Further, the particle size D90 of the imidapril hydrochloride is less than or equal to 30 mu m; the lactose is 200 mesh lactose

With lactose T80

The 200-mesh lactose can be specifically German Mei-Er 200-mesh lactose (type is Dermatole) according to a mass ratio of 4:1-2 (preferably a mass ratio of 4: 1)

The particle size of the magnesium stearate is 80 meshes, and the passing rate is 100%.

Specifically, the imidapril hydrochloride tablet is composed of the following raw materials in parts by mass: 10 parts of imidapril hydrochloride, 72.35 parts of lactose, 7.2 parts of adhesive and 0.45 part of lubricant.

Specifically, the imidapril hydrochloride tablet is composed of the following raw materials in parts by mass: 10 parts of imidapril hydrochloride, 57.88 parts of lactose with 200 meshes, 8014.47 parts of lactose, 7.2 parts of adhesive and 0.45 part of lubricant.

Specifically, the imidapril hydrochloride tablet is composed of the following raw materials in parts by mass: 10 parts of imidapril hydrochloride, 48.24 parts of lactose with 200 meshes, T8024.12 parts of lactose, 7.2 parts of adhesive and 0.45 part of lubricant.

The preparation method of imidapril hydrochloride tablets provided by the invention comprises the following steps:

1) pretreating raw materials and auxiliary materials: taking imidapril hydrochloride as a raw material, and controlling the particle size D90 to be less than or equal to 30 mu m; sieving magnesium stearate with 80 mesh sieve; slowly adding the polyethylene glycol 6000 in parts by mass into continuously stirred water until the polyethylene glycol 6000 is completely dissolved, and preparing an aqueous solution of the polyethylene glycol 6000 with the mass concentration of 45-55% (preferably an aqueous solution of the polyethylene glycol 6000 with the mass concentration of 50%);

2) sequentially adding lactose accounting for 40-50% of the mass of the lactose, imidapril hydrochloride and the rest of lactose into a wet mixing granulator, and uniformly mixing to obtain a premixed material;

3) adding the aqueous solution of the polyethylene glycol 6000 in the step 1) into the wet mixing granulator to prepare a soft material;

4) granulating the soft material obtained in the step 4) by using a swing granulator;

5) drying the particles by using a fluidized bed, and finishing the dried particles by using a swing granulator;

7) putting the magnesium stearate in parts by mass and the dried granules obtained in the step 6) into a three-dimensional motion mixer to be uniformly mixed;

8) tabletting to obtain imidapril hydrochloride tablet.

In step 2) of the method, the wet mixing granulator is a multifunctional wet mixing granulator, and the model is as follows: HLSG50A, manufacturer: the research institute of aviation engineering in Beijing of the Zhonghang industry.

The wet mixing granulator comprises the following technological parameters: stirring at 250-300rpm, cutting at 800-850rpm, and mixing for 4.5-5.5 min; the preferred process parameters are as follows: stirring speed 300rpm, cutting speed 800rpm, mixing for 5 min.

The lactose in the step 2) is prepared by firstly mixing lactose with the model of 200 meshes and lactose T80

Mixing according to the mass ratio of 4:1-2 to obtain a mixture, and adding the mixture into a wet mixing granulator in batches.

In step 3), the wet mixing granulator has the following process parameters: stirring at 200-250rpm, cutting at 1100-1200rpm for 1-1.5min, and stirring for 1.5-2 min; the preferred process parameters are: stirring speed 200rpm, cutting speed 1200rpm, taking 1min, then stirring was continued for 2 min.

In the step 4), the granulation is to granulate the material through a 20-mesh screen by using a rocking granulator.

In the step 5), the temperature of the material is controlled within the range of 40-45 ℃ in the drying process, and the moisture content of the dried particles is lower than 5%;

and the granulating is to granulate the dried granules by using a 20-mesh screen of a swing granulator.

In the step 6), the three-dimensional moving mixer may be a model SYH-50 three-dimensional moving mixer manufactured by Jirui mechanical manufacturing, Inc. in Jiangyin.

The technological parameters of the three-dimensional motion mixer are as follows: frequency 30HZ, mix for 4 min.

The method also comprises the step of sampling and detecting the appearance, content and moisture of the particles after the step 6) and before the step 7).

The tabletting in the step 7) of the method is carried out in a rotary tablet press, a 6.5mm round shallow concave punch is adopted, the hardness is 30-50N, and the friability is less than or equal to 1.0%.

Compared with the prior art, the invention has the following beneficial effects:

the imidapril hydrochloride tablet is granulated by a wet method, and an optimal preparation method is obtained by investigating the particle size of a main drug, the type and the proportion of lactose, the dosage and the use concentration of a binder polyethylene glycol 6000 and optimizing process parameters in the preparation process, so that the imidapril hydrochloride tablet with excellent quality is obtained. Compared with the existing tablet prepared by directly tabletting mainly by a dry method, the tablet overcomes the problem of uneven content distribution. Compared with the tablets prepared by the traditional tabletting method, the imidapril hydrochloride tablets prepared by the invention have the advantages of obviously improved medicine content uniformity, more stable dissolution effect and higher product quality.

Detailed Description

The present invention is described below with reference to specific embodiments, but the present invention is not limited thereto, and any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.

The compound used in the following examples was prepared according to the method in CN201610466134.1, and the purity was 99.8% or more.

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

In the quantitative tests in the following examples, three replicates were set up and the results averaged.

The lactose T80 used in the examples described below was Mei-Do-le, Germany, product type

Lactose 200 mesh from Deguo Mei Diole, product type is

The wet mixing granulator in the following examples is specifically a multifunctional wet mixing granulator, and the model is as follows: HLSG50A, manufacturer: the research institute of aviation engineering in Beijing of the Zhonghang industry.

As the three-dimensional motion mixer described in the following examples, a three-dimensional motion mixer available from Jirui mechanical manufacturing Co., Ltd., Jiangyin, model No. SYH-50, was specifically used.

The standard dissolution test in the examples described below was performed according to the 0931 dissolution and release test of the fourth general rule of the chinese pharmacopoeia 2015 edition. The cumulative dissolution was measured by sampling four dissolution media, i.e., 900mL of hydrochloric acid solution of pH1.2, pH4.0McIlvaine buffer solution of pH6.8, and water at six time points of 5, 10, 15, 20, 30, and 45min, with stirring speed of 50rpm (apparatus 2) and dissolution medium of 900mL at 37. + -. 0.5 ℃. Test dissolution data results are the average from 12 tablets.

EXAMPLE 1 preparation of imidapril hydrochloride tablets

The prescription of a 10mg standard imidapril hydrochloride tablet is shown in table 1 (batch 10 ten thousand tablets).

TABLE 1

Purified water is used in the formulation of the binder and is removed during particle drying.

The preparation method of the imidapril hydrochloride tablet comprises the following steps:

1. pretreating raw materials and auxiliary materials: taking imidapril hydrochloride as raw material, and controlling particle size D₉₀Less than 30 μm; and sieving the magnesium stearate with a 80-mesh sieve for later use.

2. The polyethylene glycol with the prescription amount is slowly added into water which is continuously stirred until the polyethylene glycol is completely dissolved, and an aqueous solution with the concentration of 50% (w/w) is prepared.

3. Firstly, lactose with the model number of 200 meshes and lactose T80

And uniformly mixing according to the mass ratio of 4:1 to obtain the mixed lactose. Then about half of the mixed lactose, imidapril hydrochloride and the rest of lactose are weighed and poured into a wet mixing granulator in sequence, and the stirring speed is 300The rpm and the cutting speed are 800rpm, and the materials are mixed for 5min to be uniform.

4. Adding polyethylene glycol aqueous solution into the premixed material to prepare soft material, stirring at 200rpm and cutting at 1200rpm for 1min, continuing stirring for 2min, totally taking 3min, and discharging;

5. granulating the materials by a 20-mesh screen by using a swing granulator;

6. and (3) drying the particles by using a fluidized bed, controlling the temperature of the material to be within 40-45 ℃, controlling the moisture content of the particles to be lower than 5%, and sieving the dried particles by using a swing granulator through a 20-mesh sieve for granule finishing.

7. Weighing the added magnesium stearate converted according to the prescription amount, putting the magnesium stearate and the dry granules into a three-dimensional mixer together, and mixing for 4min at the frequency of 30 HZ; sampling to detect the appearance, content and moisture of the particles;

8. tabletting: and (3) converting the weight of the tablet according to the content of the semi-finished product, tabletting, and punching by using a 6.5mm circular shallow concave punch, wherein the hardness is 30-50N, and the friability is less than or equal to 1.0%.

The resulting tablet appearance was a white smooth tablet; the limit of weight variation. + -. 5%.

EXAMPLE 2 preparation of imidapril hydrochloride tablets

TABLE 2

3. Firstly, lactose with the model number of 200 meshes and lactoseT80

And uniformly mixing according to the mass ratio of 4:2 to obtain the mixed lactose. Then weighing about half of the mixed lactose, imidapril hydrochloride and the rest lactose, sequentially pouring into a wet mixing granulator, stirring at 300rpm, cutting at 800rpm, and mixing for 5min to make the materials uniform;

5. granulating the materials by a 20-mesh screen by using a swing granulator;

EXAMPLE 3 preparation of imidapril hydrochloride tablets

TABLE 3

2. The polyethylene glycol with the prescription amount is slowly added into the water which is continuously stirred until the polyethylene glycol is completely dissolved, and the aqueous solution with the concentration of 45 percent (w/w) is prepared.

3. Firstly, lactose with the model number of 200 meshes and lactose T80

And uniformly mixing according to the mass ratio of 4:1.5 to obtain the mixed lactose. Then weighing about half of the mixed lactose, imidapril hydrochloride and the rest lactose, sequentially pouring into a wet mixing granulator, stirring at 300rpm, cutting at 800rpm, and mixing for 5min to make the materials uniform;

5. granulating the materials by a 20-mesh screen by using a swing granulator;

Comparative example 1 preparation of imidapril hydrochloride tablets

TABLE 4

The preparation method is as in example 1.

The imidapril hydrochloride tablets prepared in examples 1 to 3 and comparative example 1 were subjected to content measurement, and the results are shown in table 5 below, wherein the following contents are all in mass percent:

TABLE 5 content uniformity of imidapril hydrochloride tablets prepared in examples 1-3

Dissolution rate measurements were performed on imidapril hydrochloride tablets prepared in examples 1-3 and comparative example 1, and the results are shown in tables 6-9 below.

TABLE 6 dissolution in hydrochloric acid solution at pH1.2

TABLE 7 dissolution in pH4.0McIlvaine buffer

TABLE 8 dissolution in phosphate solution at pH6.8

Table 9 dissolution in water

EXAMPLE 4 examination of the Effect of different addition sequences on the uniformity of mixing in the premixing procedure

The formulation is the same as in example 1.

Preparation method steps 1) -2) the same as example 1.

The premixing procedure of step 3) examines the mixing uniformity of the following three premixing modes:

a. mixing lactose of 200 meshes with lactose T80

And uniformly mixing according to the mass ratio of 4:1 to obtain the mixed lactose. Then weighing about half of the mixed lactose, imidapril hydrochloride and the rest lactose, sequentially pouring into a wet mixing granulator, stirring at 300rpm, cutting at 800rpm, and mixing for 5min to make the materials uniform;

b. mixing lactose of 200 meshes with lactose T80

And uniformly mixing according to the mass ratio of 4:1 to obtain the mixed lactose. Then weighing the mixed lactose, imidapril hydrochloride and the rest lactose which are equal to the imidapril hydrochloride, sequentially pouring the weighed mixed lactose, imidapril hydrochloride and rest lactose into a wet mixing granulator, and uniformly mixing the materials at a stirring speed of 300rpm and a cutting speed of 800rpm for 5 min;

c. mixing lactose T80

Sequentially pouring imidapril hydrochloride and lactose with the model of 200 meshes into a wet mixing granulator, stirring at 300rpm and cutting at 800rpm, and mixing for 5min to ensure that the materials are uniform;

each group was premixed with 6 parts and measured by high performance liquid chromatography.

TABLE 9 premix content (%) results of raw and auxiliary materials

From the above observations: and the mixing mode RSD% in the premixing process a is minimum, and the premixing effect is optimal.

Example 5 examination of the Effect of premixing time on the uniformity of mixing in the premixing step

The formulation is the same as in example 1.

The preparation method is basically the same as that of example 1.

The difference lies in that: and (3) in the premixing procedure, inspecting the processes with the premixing time of 3min, 5min and 8min respectively.

Each group was premixed with 6 parts and the content was measured by high performance liquid chromatography.

TABLE 10 content uniformity data for different premixing times

And (4) conclusion: with the prolonging of the mixing time, the RSD value tends to become smaller, the RSD value is the largest at 3min, the RSD values are basically consistent at 5min and 8min, and the premixing time is determined to be 5 min.

Example 6 the effect of total mixing time on dissolution profile was examined.

The formulation is the same as in example 1.

The preparation method is basically the same as that of example 1.

The difference lies in that: and (4) inspecting the processes with the total mixing time of 3min, 5min and 8min respectively in the total mixing procedure of the step 4).

The dissolution results in pH4.0McIlvaine medium at different total mixing times were compared, respectively.

TABLE 11 dissolution curves for media of different total mixing times pH4.0McIlvaine

And (4) conclusion: and (3) determining that the dissolution trends in a pH4.0McIlvaine medium are basically consistent according to different total mixing time, and determining that the total mixing time is 5 min.

Example 7 examine the effect of the drying temperature of the fluidized bed on the substances involved.

The formulation is the same as in example 1.

The preparation method is basically the same as that of example 1.

The difference lies in that: the drying temperatures in step 5) were set to 40 ℃ and 60 ℃ respectively.

TABLE 12 comparison of substances associated with different drying temperatures

And (4) conclusion: under different drying temperatures, the results of related substances are basically consistent, which shows that the related substances are not sensitive to the temperature, and the drying temperature is determined to be 40-60 ℃.

Example 8 examination of the Effect of the solution concentration of the binding agent PEG6000 on the granulation

The effect of PEG6000 aqueous solutions with mass concentrations of 25%, 50% and 75% as the binder on the granulation effect was examined. The formulation and the preparation of the tablets were the same as in example 1.

The PEG6000 water solution with the mass concentration of 50 percent has good granulation effect when being used as the adhesive, the one-time granulation can reach more than 90 percent, and the particle size is normally distributed.

The PEG6000 water solution with the mass concentration of 25% has poor granulation effect when being used as the adhesive, the one-time granulation is only 50%, the large particles are more, and the prepared soft material block sticks to hands.

The PEG6000 aqueous solution with the mass concentration of 75% has poor granulation effect as a binder, the one-time granulation is 70%, but the distribution of large, medium and small particles is not obviously different, and the prepared particles are excessively subdivided.

In conclusion, the invention selects PEG6000 aqueous solution with mass concentration of 50% as the adhesive.

Example 9 examination of the Effect of different polyethylene glycol 6000 levels in the formulation on tablet dissolution

The formulation and the preparation of the tablets are essentially the same as in example 1. Except that the amount of polyethylene glycol 6000 is adjusted.

TABLE 13 compositions of formulations with different polyethylene glycol 6000 content

TABLE 14 dissolution of tablets with 8% polyethylene glycol 6000 content

And (4) conclusion: as the amount of polyethylene glycol used was decreased, the dissolution result became faster, and about 8% of the amount was determined to be the most suitable.

Claims

1. The imidapril hydrochloride tablet is prepared from the following raw materials in parts by mass: 10 parts of imidapril hydrochloride, 72.35 parts of lactose, 7.2 parts of adhesive and 0.45 part of lubricant;

wherein the adhesive is polyethylene glycol 6000, and the lubricant is magnesium stearate;

the grain diameter D90 of the imidapril hydrochloride is less than or equal to 30 mu m; the lactose is a mixture of lactose with the model number of 200 meshes and lactose T80 according to the mass ratio of 4: 1; the particle size of the magnesium stearate is 80 meshes, and the passing rate is 100%;

the imidapril hydrochloride tablet is prepared by the following steps:

1) pretreating raw materials and auxiliary materials: taking imidapril hydrochloride as a raw material, and controlling the particle size D90 to be less than or equal to 30 mu m; sieving magnesium stearate with 80 mesh sieve; adding the polyethylene glycol 6000 in parts by mass into water which is continuously stirred until the polyethylene glycol 6000 is completely dissolved, and preparing an aqueous solution of the polyethylene glycol 6000 with the mass concentration of 45-55%;

2) pouring lactose accounting for 40-50% of the mass of the lactose, imidapril hydrochloride and the rest of lactose into a wet mixing granulator in sequence, and uniformly mixing to obtain a premixed material;

4) granulating the soft material obtained in the step 3) by using a swing granulator;

6) putting the magnesium stearate in parts by mass and the dried granules obtained in the step 5) into a three-dimensional motion mixer to be uniformly mixed;

7) tabletting to obtain imidapril hydrochloride tablet;

in the step 2), the process parameters of the wet mixing granulator are as follows: stirring at 250-300rpm, cutting at 800-850rpm, and mixing for 4.5-5.5 min;

in the step 3), the process parameters of the wet mixing granulator are as follows: stirring speed is 200-250rpm, cutting speed is 1100-1200rpm, time consumption is 1-1.5min, and then stirring is continued for 1.5-2 min.

2. A process for preparing imidapril hydrochloride tablets as claimed in claim 1, comprising the steps of:

7) tabletting to obtain imidapril hydrochloride tablet;

3. The method of claim 2, wherein: in the step 4), the granulation is to granulate the material through a 20-mesh screen by using a rocking granulator.

4. The method of claim 2, wherein: in the step 5), the temperature of the material is controlled within the range of 40-45 ℃ in the drying process, and the moisture content of the dried particles is lower than 5%;

5. The method of claim 2, wherein: in the step 6), the technological parameters of the three-dimensional motion mixer are as follows: frequency 30HZ, mixing for 4 min;

6. The method of claim 2, wherein: and 7) tabletting is carried out in a rotary tablet press, a 6.5mm round shallow concave punch is adopted, the hardness is 30-50N, and the friability is less than or equal to 1.0%.