WO2022156240A1

WO2022156240A1 - Xuesaitong dispersible tablet and preparation method therefor

Info

Publication number: WO2022156240A1
Application number: PCT/CN2021/118216
Authority: WO
Inventors: 许丹青; 余国新; 耿亮; 朱亚东
Original assignee: 海南海力制药有限公司
Priority date: 2021-01-22
Filing date: 2021-09-14
Publication date: 2022-07-28
Also published as: CN112618590A

Abstract

A method for preparing a Xuesaitong dispersible tablet, the method comprising: micronizing Panax notoginseng saponins as a raw material, adding water and calcium hydrophosphate, adding an acid, and stirring same until there is no precipitate, then adding a sodium carbonate solution to adjust the pH to 7, separating out a precipitate, and stirring and drying the precipitate and the liquid phase together to obtain a dry material, micronizing the dry material again, then adding a disintegrating agent, uniformly mixing same, preparing a soft material by using an adhesive, preparing wet granules from the soft material, drying same, then adding an additional disintegrating agent, a glidant and a lubricating agent, mixing same, and then granulating and tabletting same to obtain the Xuesaitong dispersible tablet.

Description

A kind of Xuesaitong dispersible tablet and preparation method thereof

technical field

The invention relates to the technical field of traditional Chinese medicine, in particular to a Xuesaitong dispersible tablet and a preparation method thereof.

Background technique

In recent years, many pharmacological workers have conducted extensive research on the pharmacological effects of Panax notoginseng saponins, and studies have shown that it can protect ischemic brain injury, protect ischemic myocardial injury, improve arrhythmia, resist platelet aggregation, and resist thrombosis. It has a significant role in fighting liver fibrosis, protecting liver ischemia damage, improving immune function, etc., and its mechanism of action has been studied in detail and in-depth. The results show that Panax notoginseng saponins are non-specific calcium pump agonists. The study also confirmed that Panax notoginseng can correct the pathological state of myocardial energy imbalance. It can significantly increase the activity of calcium pump on the sarcoplasmic reticulum in myocardial cells while reducing blood pressure and improving left ventricular diastolic function. Department of Internal Medicine, Yunnan Provincial Hospital of Traditional Chinese Medicine, used Panax notoginseng saponins granules to treat 26 cases of senile cardiovascular and cerebrovascular diseases from March to June 1993, and all achieved satisfactory results. Among the 9 patients with cerebral arteriosclerosis (including 2 patients with cerebral thrombosis), 8 patients' cerebral blood flow returned to normal after treatment.

Cun Shufen et al., Yunnan Provincial People's Hospital, from October 1994 to February 1995, used Panax notoginseng tablets to treat vertigo, stroke hemiplegia, and chest paralysis patients with TCM symptoms of rotational vertigo, headache, limb numbness, hemiplegia, and speech. There were 50 cases of unfavorable, chest pain and other symptoms, and the clinical symptoms were improved. Among the 20 patients with vertigo, 11 patients had abnormalities (mainly due to insufficient blood supply) through cranial Doppler examination. After treatment, 5 patients had improved to varying degrees; there were 10 patients with thoracic paralysis, including abnormal ECG examinations. 6 cases (for myocardial ischemia, T wave changes, etc.), 4 cases improved to varying degrees after treatment. The conclusion is that the effective rate is 75% to 80%, and no adverse reactions were found during the treatment.

Since Xuesaitong tablets and capsules are both traditional dosage forms, they have the disadvantages of slow dissolution and incomplete absorption in taking. Therefore, after research and development, more suitable Xuesaitong dispersible tablets have appeared, such as:

The Chinese invention patent with the authorization announcement number CN1164264C discloses a dispersible tablet of Panax notoginseng saponins and a preparation method thereof. Alcohol and cross-linked PVP, mix evenly; use 90% ethanol as a wetting agent to make soft material, granulate with 18-24 mesh sieve, and dry the wet granules at 50-80°C. Use a 18-24 mesh sieve to granulate, add magnesium stearate, mix evenly, and press to obtain a finished product.

The Chinese invention patent with application number CN202010563504.X discloses a Xuesaitong dispersible tablet and a preparation method thereof. The preparation method is to weigh microcrystalline cellulose, crospovidone, croscarmellose sodium, low-substituted hypromellose, magnesium stearate, and silicon dioxide, then microcrystalline cellulose, crospovidone, croscarmellose sodium, low-substituted hypromellose, magnesium stearate, and dimethicone The silicon oxide is mixed to obtain a mixture; the mixture is tabletted by a tablet machine to obtain Xuesaitong dispersible tablets.

The Chinese invention patent with the authorization announcement number CN1323667C discloses a kind of Panax notoginseng dispersible tablet, which has better disintegration effect and dissolution rate by internal and external addition of disintegrating agent through the secondary granulation method.

The Chinese invention patent with the authorization announcement number CN105055476B discloses a Xuesaitong dispersible tablet and a preparation method thereof. Homogeneous, use 50% ethanol to make soft material, granulate with a 16-mesh sieve, dry at 80 degrees Celsius, and then granulate with a 16-mesh sieve, add crospovidone and micropowder silica gel for addition, and press into tablets.

To sum up, at present, Xuesaitong dispersible tablets or Panax notoginseng dispersible tablets are made by using the total saponins of Panax notoginseng as raw materials, adding disintegrants, fillers, glidants, lubricants, etc. This kind of dispersible tablet made by this kind of method has the following problems:

1. Since the degree of micronization of total saponins of Panax notoginseng will affect its dissolution rate, that is, the smaller the particle size of micronization, the higher the degree of dissolution. Free energy will automatically decrease, small particles tend to aggregate and affect drug dissolution, while larger particles will affect bioavailability.

2. because the preparation principle is roughly the same, it is to disintegrate by the disintegrating agent expansion by moisture after the external addition and the internal addition, and the Chinese Pharmacopoeia requires it to disintegrate within 3 minutes, so the blood clot in the prior art. The disintegration time of the dispersible tablets was longer.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a Xuesaitong dispersible tablet which can be rapidly disintegrated in an acidic environment, has a high degree of dissolution and high bioavailability, and provides a preparation method thereof.

In order to achieve the above purpose, the present invention provides a kind of Xuesaitong dispersible tablet, which is composed of total saponins of Panax notoginseng, calcium hydrogen phosphate, filler, disintegrant, glidant, lubricant and adhesive. The dispersible tablet disintegrates within 60 seconds in a liquid environment with pH less than 5.5, 36 to 38 degrees, and the dissolution rate is greater than 99% in 120 seconds.

Wherein, the filler is microcrystalline cellulose;

Described disintegrating agent is carboxymethyl starch and cross-linked polyvinylpyrrolidone;

Described glidant is magnesium stearate;

The lubricant is micropowder silica gel;

The binder is 95% ethanol.

Wherein, the above-mentioned each component distribution ratio is 20 parts by weight of Panax notoginseng saponins, 90-110 parts by weight of calcium hydrogen phosphate, 60-80 parts by weight of microcrystalline cellulose, 20-30 parts by weight of carboxymethyl starch, 10- 30 parts by weight of cross-linked polyvinylpyrrolidone, 1-10 parts by weight of magnesium stearate, 1-5 parts by weight of micropowder silica gel and 20-30 parts by weight of 95% ethanol.

The present invention also provides the preparation method of above-mentioned Xuesaitong dispersible tablet, comprising the following steps:

S1 micronizes the raw materials of Panax notoginseng saponins;

S2, add the micronized Panax notoginseng saponins into water and add calcium hydrogen phosphate and then homogenize in a homogenizer. During the homogenization process, add hydrochloric acid to maintain pH 6-6.5 until there is no precipitation;

S3 adds sodium carbonate solution to pH 7 while stirring in the liquid phase of S2, and separates out precipitation simultaneously;

S4 stirs and dries the precipitation and liquid phase in S3 under an environment of not higher than 70 degrees to obtain a dry material with a water content of less than 10%;

S5 adds carboxymethyl starch after micronizing the dry material and mixes it evenly;

After S6, add 95% ethanol to make soft material, make granules, and dry the wet granules at a temperature greater than 75 degrees;

S7 is granulated, add magnesium stearate, micropowder silica gel, cross-linked polyvinylpyrrolidone, mix well, and press into tablets to obtain Xuesaitong dispersible tablets.

Wherein, the micronized particle size in step S1 is 20-30 nanometers.

Wherein, the micronized particle size in step S5 is 40-60 nanometers.

The beneficial effects of Xuesaitong dispersible tablets provided by the invention are:

1. It disintegrates within 60 seconds in a liquid environment with pH less than 5.5, 36 to 38 degrees, and the dissolution rate is greater than 99% in 120 seconds.

2. The total saponins of Panax notoginseng have small micronized particle size and high bioavailability.

Description of drawings

The present invention will be described in further detail below with reference to the accompanying drawings and specific embodiments.

Fig. 1 is the process flow block diagram of Xuesaitong dispersible tablet of the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention can also be implemented in other ways different from those described herein, and those skilled in the art can do so without departing from the connotation of the present invention. Similar promotion, therefore, the present invention is not limited by the specific embodiments disclosed below.

The invention provides a Xuesaitong dispersible tablet, which is composed of Panax notoginseng saponins, calcium hydrogen phosphate, a filler, a disintegrant, a glidant, a lubricant and a binder. The Xuesaitong dispersible tablet has a pH lower than 5.5, 36 to 38 degrees liquid environment disintegrates within 60 seconds and the dissolution rate is greater than 99% in 120 seconds.

The above-mentioned filler is microcrystalline cellulose; the disintegrant is carboxymethyl starch and cross-linked polyvinylpyrrolidone; the glidant is magnesium stearate; the lubricant is micropowder silica gel; the adhesive 95% ethanol.

The proportion of each component is 20g of Panax notoginseng saponins, 90-110g of calcium hydrogen phosphate, 60-80g of microcrystalline cellulose, 20-30g of carboxymethyl starch, 10-30g of cross-linked polyvinylpyrrolidone, 1- 10g of magnesium stearate, 1-5g of micropowder silica gel and 20-30g of 95% ethanol are used to make one thousand dispersible tablets.

The preparation method of above-mentioned Xuesaitong dispersible tablet, comprises the steps:

S1 micronizes the raw material of Panax notoginseng saponins of the recipe quantity to a particle size of 20-30 nanometers;

S2, add the micronized Panax notoginseng saponins into 2000ml of water and add the calcium hydrogen phosphate of the recipe quantity, and then homogenize, keep pH6-6.5 by adding 0.5mol/L hydrochloric acid during the homogenization process, until there is no precipitation;

S5 is to add the carboxymethyl starch of the recipe quantity after the dry material is micronized and mix evenly, and the micronized particle size is 40-60 nanometers;

After S6, add the recipe amount of 95% ethanol to make soft material, make granules, and dry the wet granules at a temperature greater than 75 degrees;

S7 is granulated, and the prescribed amounts of magnesium stearate, micropowder silica gel, and cross-linked polyvinylpyrrolidone are added, mixed, and pressed into tablets to obtain Xuesaitong dispersible tablets.

Example 1

20g Panax notoginseng total saponins were micronized to an average particle size of 20 nanometers, added to 2000ml of water and 100g of calcium hydrogen phosphate was added simultaneously in a homogenizer, and 1mol/L hydrochloric acid was added to maintain pH6, and homogenize to no precipitation; After the liquid phase is introduced into the stirring dryer, the sodium carbonate solution is added to the liquid phase to adjust the pH to 7 and stirring at the same time to precipitate precipitation. After the dry material was taken out and micronized to an average particle size of 40 nanometers, 27.5 g of carboxymethyl starch was added to the micronized dry material and mixed evenly, 20 g of 95% ethanol was added to the mixture to make a soft material, and the soft material was passed through a 24-mesh sieve. Granulation is carried out, the wet granules are dried at 80 degrees, granulated with a 24-mesh sieve, and then 20g of cross-linked polyvinylpyrrolidone, 2g of magnesium stearate, 0.6g of micro-powder silica gel are added, and the blood plug is obtained by tableting. Disperse tablets.

Dissolution test: Use drug dissolution apparatus and high performance liquid chromatography to determine the main active components _of _three kinds _of Panax notoginseng saponins in water at pH 5.5 and 37 degrees. The dissolution rate of 90 seconds and 120 seconds was tested ten times at each time point and the average value was obtained. The results are shown in Table 1.

Routine disintegration test: Use a disintegration time limiter to measure whether the disintegration is completed within 3 minutes in 20°C + 1°C water, and whether it can pass the No. 2 sieve. The result is the average of three tests, see Table 2.

Disintegration test in acidic environment: use a disintegration time limit tester to measure the disintegration time in pH 5.5, 37-degree water, whether it can pass the No. 2 sieve after complete disintegration, and the result is the average value of three tests, see Table 2.

The pH5.5, 37 degree liquid is used to simulate the acidic environment of the human stomach.

Embodiment 2

20g Panax notoginseng total saponins were micronized to an average particle size of 20 nanometers, added to 2000ml of water and 100g of calcium hydrogen phosphate was added simultaneously in a homogenizer, and 1mol/L hydrochloric acid was added to maintain pH6, and homogenize to no precipitation; After the liquid phase is introduced into the stirring dryer, the sodium carbonate solution is added to the liquid phase to adjust the pH to 7 and stirring at the same time to precipitate precipitation. After the dry material was taken out and micronized to an average particle size of 60 nanometers, 27.5g of carboxymethyl starch was added to the micronized dry material and mixed evenly, 20g of 95% ethanol was added to the mixture to make a soft material, and the soft material was passed through a 24-mesh sieve. Granulation is carried out, the wet granules are dried at 80 degrees, granulated with a 24-mesh sieve, and then 20g of cross-linked polyvinylpyrrolidone, 2g of magnesium stearate, 0.6g of micro-powder silica gel are added, and the blood plug is obtained by tableting. Disperse tablets.

The methods of disintegration and dissolution experiments are the same as those in Example 1, the results of the dissolution experiments are shown in Table 1, and the results of the disintegration experiments are shown in Table 2.

Embodiment 3

20g of Panax notoginseng saponins were micronized to an average particle size of 30 nanometers, added to 2000ml of water and 100g of calcium hydrogen phosphate was added simultaneously in a homogenizer, and 1 mol/L hydrochloric acid was added to maintain pH 6 to homogenize to no precipitation; After the liquid phase is introduced into the stirring dryer, the sodium carbonate solution is added to the liquid phase to adjust the pH to 7 and stirring at the same time to precipitate precipitation. After the dry material was taken out and micronized to an average particle size of 40 nanometers, 27.5 g of carboxymethyl starch was added to the micronized dry material and mixed evenly, 20 g of 95% ethanol was added to the mixture to make a soft material, and the soft material was passed through a 24-mesh sieve. Granulation is carried out, the wet granules are dried at 80 degrees, granulated with a 24-mesh sieve, and then 20g of cross-linked polyvinylpyrrolidone, 2g of magnesium stearate, 0.6g of micro-powder silica gel are added, and the blood plug is obtained by tableting. Disperse tablets.

Disintegration and dissolution test methods are the same as in Example 1, and the results of the dissolution experiments are shown in Table 1, and the results of the disintegration experiments are shown in Table 2.

Comparative Example 1

In this example, compared with Example 1, only the micronized average particle size of Panax notoginseng saponins is modified to 10 nanometers, and the rest are the same as Example 1.

Comparative Example 2

Compared with Example 1, this example only modifies the average particle size of the micronized dry material to 30 nanometers, and the rest are the same as Example 1.

Comparative Example 3

Take the dispersible tablet prepared in Example 1 provided by the Chinese invention patent with the authorization announcement number CN1164264C and carry out dissolution test and disintegration test. Disintegration and dissolution test methods are the same as in Example 1. The results are shown in Table 2.

Comparative Example 4

Take the dispersible tablet obtained by the method of the third embodiment of the Chinese invention patent with the authorization announcement number of CN1323667C and carry out the dissolution test and the disintegration test. The experimental results are shown in Table 2.

Comparative Example 5

Dissolution test and disintegration test were carried out with the dispersible tablet prepared in Example 1 provided by the Chinese invention patent with the authorization announcement number of CN105055476B, and the disintegration and dissolution test methods were the same as in Example 1. The results are shown in Table 2.

Comparative Example 6

Micronize 20g of Panax notoginseng saponins to an average particle size of 20 nanometers, add 100g of calcium hydrogen phosphate and 27.5g of carboxymethyl starch and mix evenly, add 20g of 95% ethanol to the mixture to make a soft material, and pass the soft material through a 24-mesh sieve. Granulate, dry the wet granules at 80 degrees, use a 24-mesh sieve to granulate, and then add 20g of cross-linked polyvinylpyrrolidone, 2g of magnesium stearate, 0.6g of micropowder silica gel, mix well, and press into tablets. In the ratio, only calcium hydrogen phosphate is used as a filler, and the disintegration and dissolution test methods are the same as those in Example 1. The dissolution test results are shown in Table 1, and the disintegration test results are shown in Table 2.

Table 1: Dissolution Test Results

It can be seen from Table 1 that:

1. The tablet obtained in Example 1 has a fast dissolution rate and an optimal dissolution rate, and all of Examples 1 to 3 can achieve good dissolution rate and dissolution rate;

2. Compared with Comparative Example 1 and Comparative Example 2, Example 1 can be found that when the micronized particle size of the raw materials of Panax notoginseng saponins is too small, or the micronized particle size of the dry material is too small, the dissolution rate will be reduced, that is, particles will appear. Aggregation, and the minimum value of the micronized particle size, that is, the preparation method and conditions with the highest bioavailability, were tested by comparison.

3. Compared with Comparative Examples 3 to 5, Example 1 can be found that, with respect to the Xuesaitong dispersible tablets in the prior art, the Xuesaitong dispersible tablets provided in the present invention can be rapidly dissolved in a short time and reach a good quality. dissolution rate.

4. Compared with comparative example 6, embodiment 1 can be found that in comparative example 6, the micronized particle size of the same drug substance is 20 nanometers, but only calcium hydrogen phosphate is used as a filler, and the subsequent dry material is not micronized. In operation, the disintegration rate and dissolution rate are not ideal. Considering that when the raw material is micronized to a particle size of 20 nanometers, particle aggregation occurs during the dissolution process, resulting in insufficient dissolution rate.

Table 2: Disintegration Test Results

As can be seen from Table 2: Examples 1-3 and Comparative Examples 1-5 can all reach the requirements for dispersible tablets in the Chinese Pharmacopoeia, but in the case of simulating the acidic environment of the human stomach, the dispersible tablets provided by the present invention are compared with existing ones. The existing technology can disintegrate faster, and can also pass through the No. 2 sieve after disintegration, that is, the disintegration effect meets the requirements.

The above are only preferred embodiments of the present application, and are not intended to limit the present application. For those skilled in the art, the present application may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of this application shall be included within the protection scope of this application.

Claims

Xuesaitong dispersible tablet is characterized in that, described Xuesaitong dispersible tablet is composed of Panax notoginseng saponins, calcium hydrogen phosphate, filler, disintegrant, glidant, lubricant and adhesive, The dispersible tablet disintegrates within 60 seconds in a liquid environment with pH less than 5.5, 36 to 38 degrees, and the dissolution rate is greater than 99% in 120 seconds.
Xuesaitong dispersible tablet according to claim 1, is characterized in that,

The filler is microcrystalline cellulose;

Described disintegrating agent is carboxymethyl starch and cross-linked polyvinylpyrrolidone;

Described glidant is magnesium stearate;

The lubricant is micropowder silica gel;

The binder is 95% ethanol.
The Xuesaitong dispersible tablet according to claim 2, wherein the proportion of each component is 20 parts by weight of Panax notoginseng saponins, 90-110 parts by weight of calcium hydrogen phosphate, and 60-80 parts by weight of microcrystalline cellulose , 20-30 parts by weight of carboxymethyl starch, 10-30 parts by weight of cross-linked polyvinylpyrrolidone, 1-10 parts by weight of magnesium stearate, 1-5 parts by weight of micropowder silica gel and 20-30 parts by weight of 95% ethanol.
The preparation method of Xuesaitong dispersible tablet as described in any one of claims 1 to 3, is characterized in that, comprises the steps:

S1 micronizes the raw materials of Panax notoginseng saponins;

S2, add the micronized Panax notoginseng saponins into water and add calcium hydrogen phosphate and then homogenize in a homogenizer. During the homogenization process, add hydrochloric acid to maintain pH 6-6.5 until there is no precipitation;

S3 adds sodium carbonate solution to pH 7 while stirring in the liquid phase of S2, and separates out precipitation simultaneously;

S4 stirs and dries the precipitation and liquid phase in S3 under an environment of not higher than 70 degrees to obtain a dry material with a water content of less than 10%;

S5 adds carboxymethyl starch after micronizing the dry material and mixes it evenly;

After S6, add 95% ethanol to make soft material, make granules, and dry the wet granules at a temperature greater than 75 degrees;

S7 is granulated, add magnesium stearate, micropowder silica gel, cross-linked polyvinylpyrrolidone, mix well, and press into tablets to obtain Xuesaitong dispersible tablets.
The preparation method of Xuesaitong dispersible tablet according to claim 4, wherein the dosage of each component is: 20 parts by weight of Panax notoginseng total saponins, 90-110 parts by weight of calcium hydrogen phosphate, 60-80 parts by weight of Microcrystalline cellulose, 20-30 parts by weight of carboxymethyl starch, 10-30 parts by weight of crospovidone, 1-10 parts by weight of magnesium stearate, 1-5 parts by weight of micropowder silica gel and 20- 30 parts by weight of 95% ethanol.
The preparation method of Xuesaitong dispersible tablet according to claim 5, characterized in that, in step S1, the micronized particle size is 20-30 nanometers.
The preparation method of Xuesaitong dispersible tablet according to claim 6, characterized in that, in step S5, the micronized particle size is 40-60 nanometers.