CN115364073A

CN115364073A - Urapidil dispersion sustained-release capsule and preparation method thereof

Info

Publication number: CN115364073A
Application number: CN202211057490.XA
Authority: CN
Inventors: 张乐; 朱明月; 董伟昌; 李海英; 赵鹏; 王朝卿; 吴欢欢; 赵文鹤; 何银红
Original assignee: Shijiazhuang No 4 Pharmaceutical Co Ltd
Current assignee: Shijiazhuang No 4 Pharmaceutical Co Ltd
Priority date: 2022-08-31
Filing date: 2022-08-31
Publication date: 2022-11-22
Anticipated expiration: 2042-08-31
Also published as: CN115364073B

Abstract

The invention belongs to the technical field of sustained-release preparations, and particularly provides an urapidil dispersion sustained-release capsule and a preparation method thereof. According to the sustained-release urapidil capsule, xanthan gum, ethyl cellulose and hydroxypropyl methyl cellulose phthalate in a specific ratio are used as auxiliary materials, so that stable and slow release of the urapidil sustained-release capsule in the gastrointestinal tract is realized, degradation of urapidil in the stomach is reduced, the effectiveness and safety of a medicament are improved, impurity generation in the preparation and storage processes of the preparation is reduced, and the quality stability of the product is improved; the material temperature of the medicine feeding link in the preparation process is further controlled to be 35-50 ℃, and the product quality is further improved by controlling the process parameters of the dispersing, medicine feeding and coating links. The sustained-release capsule provided by the invention has a simple preparation process, does not need to carry out aging treatment on sustained-release pellets, uses an aqueous solution system in the drug loading link, reduces the use amount of organic solvents in production, is more environment-friendly, and is beneficial to industrial production and application.

Description

Urapidil dispersion sustained-release capsule and preparation method thereof

Technical Field

The invention belongs to the technical field of sustained-release pharmacy, and particularly relates to an urapidil dispersion sustained-release capsule and a preparation method thereof.

Background

Urapidil was developed by Byk Gulden company, wutian company imported Urapidil hydrochloride injection in China as early as 1992, and then products made in China are bought in a dispute. In terms of dosage forms, the injection approval factories are numerous, 10 enterprises exist, the first time in 2000, the west anli monarch drug approval is urapidil hydrochloride injection, and Shandong Luo Xin is the first approved powder injection in 2005; in the aspect of solid preparation, sustained-release capsules and sustained-release tablets are approved in China, the manufacturers for obtaining the sustained-release capsules are Hua Yu (without tin) pharmacy and the pharmaceutical industry of Xian Yuandade Dadestian, and the manufacturers for obtaining the sustained-release tablets are the manufacturers for obtaining the drug of the xi' anli monarch and the drug of the Heilongjiang Fu. At present, the sustained-release preparation is not evaluated by the drug consistency of domestic manufacturers.

At present, two kinds of sustained-release urapidil capsule reference preparations are included in a catalogue of imitation-pharmaceutical reference preparations released by the national drug administration, one is a product (30 mg, 60mg and 90 mg) marketed in Germany in Wutian, and the other is a product (15 mg and 30 mg) marketed in Japan in scientific research and pharmaceutical, and after the reference preparations are fully researched by enterprises, the consistency evaluation work is selected and carried out as appropriate.

In the research process of the Japanese reference preparation of the sustained-release capsule, the reference preparation is unstable under the acidic condition of a medium with pH1.2, can be degraded to generate impurities D and F, and has the chemical structure shown in the specification, so that the release stability is also poor in the acceleration test process, the impurities are also increased, and the product quality and the medication safety are influenced. Therefore, the urapidil sustained-release capsule which reduces the impurity content, improves the preparation stability, ensures the sustained-release effect and is safer and more effective in clinical medication needs to be developed.

Disclosure of Invention

The invention aims to provide an urapidil dispersion sustained-release capsule with low impurity content and stable release and a preparation method thereof aiming at the defects of the prior art. According to the invention, the xanthan gum, the ethyl cellulose and the hydroxypropyl methylcellulose phthalate in a specific ratio are used, so that the stable and slow release of the urapidil sustained-release capsule in the gastrointestinal tract is realized, the degradation of urapidil in the stomach is reduced, the effectiveness and the safety of the drug are ensured, the generation of impurities in the preparation and storage processes of the preparation is obviously reduced, and the quality stability of the product is improved.

In order to realize the purpose of the invention, the following technical scheme is adopted:

the invention aims to provide an urapidil dispersion sustained-release capsule which consists of sustained-release pellets and a capsule shell, wherein the sustained-release pellets comprise blank pellet cores, a medicine feeding layer and a coating layer, the medicine feeding layer comprises urapidil and xanthan gum, the coating layer comprises sustained-release materials and enteric-coated materials, and the mass ratio of the xanthan gum to the sustained-release materials to the enteric-coated materials is 1:0.7 to 1: 1.7-2.3, wherein the enteric material is hydroxypropyl methylcellulose phthalate HP50.

Optionally, the slow release material is ethyl cellulose.

Further, the upper drug layer of the sustained-release pellet also comprises magnesium stearate.

Optionally, the blank pellet core of the sustained-release pellet is a lactose pellet core.

Further, the preparation of the sustained-release pellet comprises the following steps: and (3) feeding the blank pellet core through a fluidized bed to prepare a medicine-feeding pellet, and spraying a coating liquid into the medicine-feeding pellet to obtain the slow-release pellet, wherein the temperature of a medicine-feeding material is controlled to be 35-50 ℃ in the fluidized bed medicine-feeding process, and is more preferably 35-45 ℃.

Further, the solid content of the coating liquid is 7-9%.

Further, the solvent of the coating solution is ethanol with the mass concentration of 80%.

Optionally, the sustained-release pellet comprises the following components in percentage by mass: 16-20% of urapidil, 3.8-4.5% of xanthan gum, 3.2-3.8% of ethyl cellulose, 7.6-9.0% of hydroxypropyl methylcellulose phthalate HP50, 63.3-64.9% of lactose pill core and 1.3-2.7% of magnesium stearate.

Further, the urapidil dispersion sustained-release capsule comprises the following components in percentage by mass:

the invention also aims to provide a preparation method of the urapidil dispersion sustained-release capsule, which comprises the following steps:

step a, weighing xanthan gum, urapidil and magnesium stearate according to the formula amount, and uniformly mixing to obtain a mixed material;

b, slowly adding the mixed material into water, and uniformly dispersing to obtain a suspension;

step c, spraying the suspension onto the surface of the lactose pellet core through a fluidized bed to obtain a drug-loading pellet;

step d, weighing ethyl cellulose and hydroxypropyl methylcellulose phthalate HP50 according to the prescription amount, and dissolving the ethyl cellulose and the hydroxypropyl methylcellulose phthalate HP50 in 80% ethanol solution to obtain coating solution; and then spraying the coating solution onto the surfaces of the medicine-feeding pellets through a fluidized bed to obtain the sustained-release pellets, and filling to obtain the urapidil dispersion sustained-release capsule.

Further, in the step b, the dispersion process adopts a high-shear dispersion emulsifying machine for dispersion, the process parameters are that the rotating speed is 10000-13000 r/min, and the stirring time is set to be 8-15min.

Furthermore, in the step c, the fluidized bed process parameters of the medicine feeding procedure are that the air inlet temperature of the fluidized bed is 40-55 ℃, the material temperature is controlled at 35-50 ℃, and the atomization pressure is 1.0-1.5bar.

Furthermore, in the step d, the fluidized bed process parameters of the coating procedure are that the air inlet temperature of the fluidized bed is 35-45 ℃, the material temperature is controlled at 30-40 ℃, and the atomization pressure is 1.3-1.8bar.

By adopting the technical scheme, the invention has the following beneficial effects:

(1) The original preparation has obvious degradation phenomenon in a hydrochloric acid medium, degradation impurities F and degradation impurities G are obviously increased, the invention uses xanthan gum, slow-release materials and enteric materials with specific mixture ratio, specifically, the mass ratio of the xanthan gum, the ethyl cellulose and the hydroxypropyl methyl cellulose phthalate HP50 is 1:0.7 to 1: 1.7-2.3, the sustained-release urapidil capsule can be stably and slowly released in gastrointestinal tracts, the degradation of the sustained-release capsule in the stomach is reduced, the effectiveness and the safety of the medicament are ensured, the quality stability of the preparation in the preparation and storage processes is improved, and the generation of impurities is reduced. Xanthan gum can dissolve fast in aqueous, has very good water solubility, and xanthan gum aqueous solution has the characteristic of low concentration high viscosity, mixes the back with urapidil, has stabilizing effect and high suspension effect, makes whole process of applying medicine more stable even, and the swelling effect of xanthan gum when dissolving forms gel type protection film simultaneously, is difficult for receiving the influence of stomach acid environment, guarantees the stable release of medicine simultaneously.

(2) Because urapidil is unstable to high temperature conditions, the temperature of materials in the medicine applying link is controlled to be 35-50 ℃, and is preferably controlled to be 35-45 ℃, so that the production of impurities is reduced, and the release effect is improved. Meanwhile, because the temperature of the material is too high, when the raw material is attached to the surface of the pill core, the drying speed is too high, so that the surface of the pill is rough and not smooth, and the medicine-carrying pill core is coated unevenly, so that a better slow-release effect cannot be achieved.

(3) The invention further optimizes the technological parameter conditions, the rotating speed of the dispersing emulsifying machine in the dispersing link of the preparation process is 10000-13000 r/min, and the stirring time is set to be 8-15min; the air inlet temperature of the fluidized bed in the medicine feeding link is 40-55 ℃, the material temperature is controlled at 35-50 ℃, and the atomization pressure is 1.0-1.5bar; and the air inlet temperature of the fluidized bed in the coating link is 35-45 ℃, the material temperature is controlled at 30-40 ℃, and the atomization pressure is 1.3-1.8bar, so that the medicine is more stably released in the gastrointestinal tract, and the generation of impurities is reduced.

(4) The process indexes of the dispersing link in the preparation method can influence the dispersing effect of the suspension, further influence the release behavior of the sustained-release capsule and the like, under the condition of reducing the rotating speed, the expected dispersing and emulsifying effect cannot be achieved even if the dispersing time is increased, such as the rotating speed of 8000r/min and the stirring time of 25min, and under the condition of increasing the rotating speed, the expected dispersing and emulsifying effect cannot be achieved even if the dispersing time is shortened, such as the rotating speed of 14000r/min and the stirring time of 5min. The rough core of the drug-loaded pill causes uneven coating, the release can not reach the effect of stable slow release, and the water can easily enter the pill, so that the related substances are obviously increased after the acceleration test, and the stability of the finished product is poor. Too fast release in medium at pH1.2 also leads to degradation of urapidil and an increase in the related substances.

(5) The preparation process is simple, the sustained-release pellets do not need to be aged, an aqueous solution system is used in the drug loading process, the usage amount of organic solvents in production is reduced, the preparation method is more environment-friendly, and the industrial production and application are facilitated.

Detailed Description

The following detailed description is provided to facilitate an understanding of the invention and to enable one skilled in the art to make and use the invention without limiting the invention in any way.

Example 1

An urapidil sustained release capsule comprises the following components in percentage by mass:

the preparation method comprises the following steps:

1. pretreatment: weighing xanthan gum, urapidil and magnesium stearate according to the prescription amount, and uniformly mixing;

2. dispersing: slowly dispersing the mixture in 200g of water, and scattering by using a high-shear dispersion emulsifying machine at the rotating speed of 12000r/min for 10min to obtain a suspension;

3. medicine application: placing the lactose pill core into a fluidized bed pan body, spraying the dispersed suspension on the lactose pill core to prepare the medicine-feeding pellets, wherein the air inlet temperature of the fluidized bed is 43-46 ℃, the material temperature is controlled at 37-41 ℃, and the atomization pressure is 1.2-1.4bar;

4. coating: weighing ethyl cellulose and hydroxypropyl methylcellulose phthalate HP50 according to the prescription amount, dissolving in 80% ethanol to prepare coating liquid with solid content of 8%, spraying the coating liquid onto the surface of the drug-loading pellet in a fluidized bed pan body, wherein the air inlet temperature of the fluidized bed is 37-41 ℃, the material temperature is controlled at 32-36 ℃, and the atomization pressure is 1.4-1.6bar, so as to obtain the sustained-release pellet;

5. canning: detecting the content of the sustained-release pellets, and filling according to the content to obtain the urapidil sustained-release capsule.

Example 2

the preparation method comprises the following steps:

2. dispersing: slowly dispersing the mixture in 200g of water, and scattering by using a high-shear dispersion emulsifying machine at the rotation speed of 10000r/min for 15min to obtain a suspension;

3. medicine application: placing the lactose pill core into a fluidized bed pan body, spraying the dispersed suspension on the lactose pill core to prepare the medicine-feeding pellets, wherein the air inlet temperature of the fluidized bed is 40-45 ℃, the material temperature is controlled at 35-40 ℃, and the atomization pressure is 1.0-1.3bar;

4. coating: weighing ethyl cellulose and hydroxypropyl methylcellulose phthalate HP50 according to the prescription amount, dissolving in 80% ethanol to prepare coating liquid with solid content of 7%, spraying the coating liquid onto the surface of the drug-loading pellet in a fluidized bed pan body, wherein the air inlet temperature of the fluidized bed is 35-39 ℃, the material temperature is controlled at 30-34 ℃, and the atomization pressure is 1.3-1.5bar, so as to obtain the sustained-release pellet;

Example 3

the preparation method comprises the following steps:

2. dispersing: slowly dispersing the mixture in 200g of water, and scattering by using a high-shear dispersion emulsifying machine at the rotating speed of 13000r/min for 8min to obtain a suspension;

3. medicine application: placing the lactose pill core into a fluidized bed pan body, spraying the dispersed suspension on the lactose pill core to prepare the medicine-feeding pellets, wherein the air inlet temperature of the fluidized bed is 46-50 ℃, the material temperature is controlled at 41-45 ℃, and the atomization pressure is 1.3-1.5bar;

4. coating: weighing ethyl cellulose and hydroxypropyl methylcellulose phthalate HP50 according to the prescription amount, dissolving in 80% ethanol to prepare coating liquid with solid content of 8%, spraying the coating liquid onto the surface of the drug-loading pellet in a fluidized bed pot body, wherein the air inlet temperature of the fluidized bed is 40-45 ℃, the material temperature is controlled at 36-40 ℃, and the atomization pressure is 1.5-1.8bar, so as to obtain the sustained-release pellet;

Example 4

the preparation method comprises the following steps:

1. pretreatment: weighing xanthan gum, urapidil and magnesium stearate according to the formula amount, and uniformly mixing;

2. dispersing: slowly dispersing the mixture in 200g of water, and scattering by using a high-shear dispersion emulsifying machine at the rotating speed of 11000r/min for 12min to obtain a suspension;

3. medicine application: placing the lactose pill core into a fluidized bed pan body, spraying the dispersed suspension on the lactose pill core to prepare the medicine-feeding pellets, wherein the air inlet temperature of the fluidized bed is 43-47 ℃, the material temperature is controlled at 38-43 ℃, and the atomization pressure is 1.1-1.3bar;

4. coating: weighing ethyl cellulose and hydroxypropyl methylcellulose phthalate HP50 according to the prescription amount, dissolving in 80% ethanol to prepare coating liquid with solid content of 9%, spraying the coating liquid onto the surface of the drug-loading pellet in a fluidized bed pan body, wherein the air inlet temperature of the fluidized bed is 38-43 ℃, the material temperature is controlled at 33-37 ℃, and the atomization pressure is 1.5-1.7bar, so as to obtain the sustained-release pellet;

Example 5

The formula is the same as that of the example 1, and the difference is that the fluidized bed process parameters in the medicine feeding link in the step 3 in the preparation process are different, the air inlet temperature of the fluidized bed is 52-55 ℃, the material temperature is controlled at 48-50 ℃, and the atomization pressure is 1.0-1.3bar.

Comparative example 1

Reference preparation, batch number: K13970.

comparative example 2

The urapidil sustained release capsule of the comparative example 2 comprises the following components in percentage by mass:

comparative example 3

The urapidil sustained release capsule of the comparative example 3 comprises the following components in percentage by mass:

comparative example 4

The urapidil sustained release capsule of comparative example 5, which is the same as the preparation method of example 4 except that the formulation is different, comprises the following components in percentage by mass:

test example 1 Release behavior study

In order to examine the in-vitro release behavior of the product, for the samples prepared in examples 1-5 and comparative examples 2-4 and the product sold in comparative example 1, the release curve of the urapidil sustained-release capsule is detected according to the method for detecting the dissolution curve library of the preparation sold in Japan, and the value of the F2 factor is calculated according to the release data, the specific calculation method can refer to the dissolution curve guiding principle published by the national drug administration, the release uniformity is calculated, and the research result is shown in Table 1.

The release curve detection method comprises the following steps: experiment device II (paddle method), rotating speed of 50r/min, pH6.8 medium, medium volume 900ml.

Table 1 release behavior study test data

And (4) test conclusion:

the release curves of examples 1-4 in the medium of ph6.8 are all similar to that of comparative example 1 (reference formulation) by a factor F2 above 85, which is very similar to that of the reference formulation, and example 5 has an F2 of 78.6, reaching above 50, which also meets the similar requirements as the release curve of the reference formulation, while comparative examples 2-4 have an F2 below 50, which is not similar to that of the reference formulation. In example 5, the material temperature in the drug loading process is slightly higher, so that the surface of the drug-loaded pellet is slightly rough and not smooth, the coating effect is not uniform enough, the release is influenced, and the release curve of the drug-loaded pellet is slightly reduced by similar factors with the release curve of a reference preparation. Comparative example 2 the release rate decreased significantly and was slow with increasing amounts of xanthan gum, which was dissimilar to comparative example 1. Comparative example 3 the release rate was significantly increased due to the reduced amount of xanthan gum, which is not similar to comparative example 1. Comparative example 4 the xanthan gum was changed to guar gum and although the release reached 100% at 6 hours, the release was too slow in the early stage and accelerated in the late stage, which is not similar to comparative example 1.

Test example 2 degradation study of Release Medium

In order to examine the degradation degree of the product in the medium release process of pH1.2, the samples prepared in examples 1-5 and comparative examples 2-4 and the commercial product of comparative example 1 were tested for the release curve of urapidil sustained release capsule according to the test method of the dissolution curve library of the commercial preparations in Japan, and samples were taken at 0.5 hour of the release dissolution to immediately test the related substances of each sample, and the results are shown in Table 2.

The release curve detection method comprises the following steps: experimental apparatus II (paddle method), rotating speed of 50r/min, pH1.2 hydrochloric acid medium, medium volume 900ml.

The related substance detection method comprises the following steps: measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general rules 0512).

0.02mol/L sodium perchlorate solution (2.81 g sodium perchlorate monohydrate was weighed, dissolved in 900mL water, adjusted to pH 2.0 with 70% perchloric acid solution, diluted to 1000mL with water) -methanol (25.

Taking 20 granules of the test solution, precisely weighing an appropriate amount (about equivalent to 25mg of urapidil), adding the diluent to dissolve, quantitatively diluting to obtain a solution containing about 1mg of urapidil per 1mL, shaking up, and filtering.

The control solution is prepared by precisely measuring a proper amount of the test solution, and adding the diluent to obtain a solution containing about 2 μ g of the test solution per 1 mL.

The chromatographic condition uses octadecylsilane chemically bonded silica as a filler chromatographic column; taking 0.05mol/L sodium perchlorate solution (prepared with diluent) as a mobile phase A, taking methanol as a mobile phase B, and carrying out elution according to the gradient in the following table; the flow rate is 1.2mL per minute, and the detection wavelengths are 270nm and 236nm; the column temperature is 40 ℃; the injection volume is 10. Mu.L.

The measurement method comprises precisely measuring the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording chromatogram.

TABLE 2 degradation study during release of pH1.2 Medium

	Impurity D (%)	Impurity F (%)
			Example 1	0.8	0.9
Example 2	1.1	1.3
			Example 3	1.0	1.1
Example 4	0.8	0.9
			Example 5	1.3	1.8
Comparative example 1	5.9	6.2
			Comparative example 2	0.7	0.8
Comparative example 3	6.8	7.4
			Comparative example 4	1.0	1.2

And (4) conclusion: experiments show that in examples 1-4, the xanthan gum with a specific proportion of dosage is added, so that the medicine can be slowly released in a medium with a pH value of 1.2, the gel protection effect of the xanthan gum reduces the degradation degree of the medicine, the contents of the impurity D and the impurity F are both below 1.5%, more urapidil is ensured to be absorbed in vivo, and the bioavailability is improved. The amount of the impurity D and the impurity F in the example 5 is slightly more than that in the examples 1 to 4, but is below 2.0 percent, which shows that the material temperature in the medicine applying link is too high to cause the increase of degraded impurities, and the material temperature is controlled to be 35-50 ℃, and is more preferably controlled to be 35-45 ℃. Comparative example 1 releases more in the medium with pH1.2, and the degradation impurities are relatively more; comparative example 2 contains sufficient amount of xanthan gum, slowly released in ph1.2 medium, with few degradation impurities; in the formula of the comparative example 3, the consumption of xanthan gum is too small, the xanthan gum is released quickly in a medium with the pH value of 1.2, and impurities D and F are increased obviously; comparative example 4, release was slow in ph1.2 medium with few degrading impurities.

Test example 3 stability study

In order to examine the stability of the products, the samples prepared in examples 1 to 5 and comparative examples 2 to 4 and the commercial product of comparative example 1 were subjected to an accelerated test, each of which was placed under the same package under accelerated conditions (40 ℃. + -. 2 ℃ C., relative humidity 75%. + -. 5%) and sampled at 0 month and 6 months, respectively, to compare the change in the release rate at 3 hours in an aqueous medium with the change in the substance involved, and the results are shown in Table 3:

the release curve detection method comprises the following steps: the experimental device II (paddle method), the rotating speed of 50r/min, the volume of the aqueous medium and the medium of 900ml.

The detection method of the related substances is the same as above.

Table 3 stability study test data

And (4) test conclusion:

according to experimental research, in the aspect of 3h release degree, compared with 0 month and 6 months, in examples 1-4, due to the addition of the xanthan gum with the specific proportion, the xanthan gum can form gel on the surface of the pellet core in an accelerating environment, so that the pellet core is protected, the stability is enhanced, and the change of the release degree is not obvious. In example 5, the drug-loaded pellet core is not smooth in surface and uneven in coating, the release rate is slightly changed under the acceleration condition, the difference of the release rate is slightly larger than that of the reference preparation at 0 month, and the release similarity of the drug-loaded pellet core and the reference preparation is slightly poor. Comparative example 1 release was slightly accelerated after 6 months accelerated testing. Comparative example 2 excessive addition of xanthan gum, although the release change was small after 6 months of acceleration, the difference in the release was too large compared to the reference formulation at 0 months, and the release was not similar to the reference formulation. Comparative example 3 since the amount of added xanthan gum was reduced, the change of the release rate was significant after 6 months of acceleration, and the difference of the release rate was too large compared to the reference formulation at 0 month, which was not similar to the release rate of the reference formulation. Comparative example 4 xanthan gum was changed to guar gum, which became significantly sticky under accelerated high temperature conditions, slowed release at 6 months, and a significant increase in the difference in release at 0 months compared to the reference formulation.

In terms of related substances, the related substances of the examples 1 to 4 and the comparative example 2 are not obviously changed, and the quality is more stable. Comparative example 3 since the amount of xanthan gum added was reduced, the gel forming ability was weakened, moisture was more likely to enter the pellets, and the increase of related substances was significant after 6 months of acceleration. Example 5 during the application, the temperature was slightly higher, which resulted in a slight increase in related substances at 0 month, and after 6 months of acceleration. Comparative example 4 when xanthan gum was changed to guar gum, the product had less impurities at 0 month, but after 6 months of acceleration, the related substances increased significantly and the stability was poor.

Comparative analysis based on the above study data of test examples 1 to 3 revealed that:

in comparative example 2, the mass ratio of xanthan gum, ethyl cellulose and hydroxypropyl methylcellulose phthalate was 1:0.6:1.5, the xanthan gum dosage increased, resulting in a slower release of the formulation in the respective medium. Even if the enteric material hydroxypropyl methyl cellulose phthalate exists, in a medium with pH of 6.8, after the enteric material is dissolved, the dosage of xanthan gum is increased, so that the medicine-carrying part is slowly dissolved, and the ideal slow-release effect cannot be achieved.

In comparative example 3, the mass ratio of xanthan gum, ethyl cellulose and hydroxypropyl methylcellulose phthalate is 1:1.2:2.7, the amount of xanthan gum is reduced, which results in increased impurities in the preparation, poor storage stability and unstable release. Under the conditions that the solubility of the urapidil raw material in a medium with the pH value of 1.2 is larger and is about 37mg/ml, and the consumption of xanthan gum is reduced, the release of the sustained-release material ethyl cellulose and the enteric material hydroxypropyl methyl cellulose phthalate can not be well regulated in the medium with the pH value of 1.2, and the urapidil is degraded in the medium and impurities are increased due to too fast release. Moreover, the slow release effect cannot be achieved even if the dissolution is too fast in a medium with pH 6.8.

Comparative example 4 the xanthan gum in the formula is changed to guar gum, the prepared product has less impurities, but under the condition of accelerated high temperature, the impurities are increased, the stability is poor, and under the condition of accelerated high temperature, the guar gum becomes sticky, the release is slower in 6 months, and the difference from a reference preparation is large; the release can be completed in a medium with pH6.8 for 6 hours, but the release curve is not close to that of a reference preparation, and F2 is too low; due to the slow release at ph1.2, less impurity D and less impurity F are produced.

In conclusion, the urapidil sustained-release capsule disclosed by the invention is stable in vitro release, the release rate can reach more than 100% in 6 hours, the F2 value is more than 75, the sustained-release capsule is consistent with the release behavior of a Japanese reference preparation, the stability of the product is good, the impurity content is low and is less than 0.5% after the acceleration of 6 months, the sustained-release capsule is superior to the reference preparation, and the change of the release behavior after the acceleration test is small. And after the urapidil is released in a hydrochloric acid medium with the pH value of 1.2, the degradation degree of the medicament is low, the contents of impurities D and F are within 2.0 percent when the medicament is released for 0.5 hour, more urapidil is ensured to be absorbed in vivo, and the bioavailability is improved. In addition, the preparation process is simple, the slow-release pellets do not need to be aged, an aqueous solution system is used in the medicine feeding link, the use amount of organic solvents in the production link is reduced, the environment is protected, and the industrial production and application are facilitated.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims

1. An urapidil dispersion sustained-release capsule consists of sustained-release pellets and a capsule shell, wherein the sustained-release pellets comprise blank pellet cores, a medicine feeding layer and a coating layer, the sustained-release pellets are characterized in that the medicine feeding layer comprises urapidil and xanthan gum, and the coating layer comprises sustained-release materials and enteric-coated materials;

wherein the mass ratio of the xanthan gum to the slow-release material to the enteric material is 1:0.7 to 1: 1.7-2.3, and the enteric material is hydroxypropyl methylcellulose phthalate HP50.

2. The urapidil dispersion sustained-release capsule according to claim 1, wherein the sustained-release material is ethyl cellulose.

3. The urapidil dispersion sustained-release capsule according to claim 2, wherein the upper drug layer of the sustained-release pellets further comprises magnesium stearate.

4. The urapidil dispersion sustained-release capsule according to any one of claims 1 to 3, wherein the preparation of the sustained-release pellets comprises the steps of: and (3) feeding the blank pellet core through a fluidized bed to prepare a medicine-feeding pellet, and spraying coating liquid into the medicine-feeding pellet to obtain a slow-release pellet, wherein the temperature of medicine-feeding materials is controlled to be 35-50 ℃ in the fluidized bed medicine-feeding process.

5. The urapidil dispersion sustained-release capsule according to claim 4, wherein the solid content of the coating solution is 7-9%, and/or the solvent of the coating solution is 80% ethanol.

6. The urapidil dispersion sustained-release capsule according to claim 5, wherein the sustained-release pellets comprise the following components in percentage by mass: 16-20% of urapidil, 3.8-4.5% of xanthan gum, 3.2-3.8% of ethyl cellulose, 7.6-9.0% of hydroxypropyl methylcellulose phthalate HP50, 63.3-64.9% of lactose pill core and 1.3-2.7% of magnesium stearate.

7. A method for preparing the urapidil dispersion sustained-release capsule according to claim 6, comprising the steps of:

step a, weighing xanthan gum, urapidil and magnesium stearate in the formula amount, and uniformly mixing to obtain a mixed material;

step c, spraying the suspension onto the surface of a lactose pellet core through a fluidized bed to obtain a medicine-loading pellet; wherein the material temperature controlled by the fluidized bed medicine feeding procedure is 35-50 ℃;

step d, weighing ethyl cellulose and hydroxypropyl methylcellulose phthalate HP50 according to the formula amount, and dissolving the weighed ethyl cellulose and hydroxypropyl methylcellulose phthalate HP50 in 80% ethanol solution to obtain coating liquid; and then spraying the coating solution onto the surfaces of the medicine-feeding pellets through a fluidized bed to obtain the sustained-release pellets, and filling to obtain the urapidil dispersion sustained-release capsule.

8. The method for preparing urapidil dispersion sustained-release capsules according to claim 7, wherein in the step b, the dispersion process is carried out by a high shear dispersion emulsifying machine, the process parameters are 10000-13000 r/min of rotation speed, and the stirring time is set to be 8-15min.

9. The method for preparing urapidil dispersion sustained-release capsules according to claim 8, wherein in step c, the fluidized bed process parameters are as follows: the air inlet temperature of the fluidized bed is 40-55 ℃, and the atomization pressure is 1.0-1.5bar.

10. The method for preparing urapidil dispersion sustained-release capsules according to claim 9, wherein in step d, the fluidized bed process parameters are as follows: the air inlet temperature of the fluidized bed is 35-45 ℃, the material temperature is controlled at 30-40 ℃, and the atomization pressure is 1.3-1.8bar.