CN112263564A

CN112263564A - Preparation method of Xiyanping dry suspension

Info

Publication number: CN112263564A
Application number: CN202011187109.2A
Authority: CN
Inventors: 司鹏; 付杰; 周世文
Original assignee: Huangshan C King Pharmaceutical Co ltd
Current assignee: Huangshan C King Pharmaceutical Co ltd
Priority date: 2020-10-30
Filing date: 2020-10-30
Publication date: 2021-01-26
Anticipated expiration: 2040-10-30
Also published as: CN112263564B

Abstract

The invention relates to the technical field of medicines, and particularly relates to a preparation method of a Xiyanping dry suspension. The specific technical scheme is as follows: a method for preparing Xiyanping dry suspension comprises sulfonating andrographolide mesoporous silica nanoparticles, precipitating with ethanol, adding lactose and microcrystalline cellulose, ultrasonically homogenizing, filtering, and concentrating to obtain mesoporous silica-loaded andrographolide sulfonate and microcrystalline cellulose; spray granulating the adhesive prepared from sodium dodecyl sulfate and the concentrated product, and drying after granule forming; then, an isolating layer and an enteric coating are sequentially coated on the formed particles, and the Xiyanping dry suspension is obtained. The invention provides a preparation method of a Xiyanping dry suspension, which overcomes the blank of Xiyanping formulation in the current market.

Description

Preparation method of Xiyanping dry suspension

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a preparation method of a Xiyanping dry suspension.

Background

Xiyanping is the sulfonated substance of andrographolide, is easy to dissolve in water, is dissolved in methanol, is slightly soluble in ethanol, has the functions of clearing away heat and toxic materials, is used for treating acute icteric hepatitis, infantile diarrhea and the like in a digestive system, has obvious inhibition effect on more than ten bacteria such as escherichia coli, dysentery bacillus and the like, can inhibit inflammatory reaction, and plays a role in stopping diarrhea.

At present, the Xiyanping preparation on the market is generally injection and dripping pills; however, the injection has poor physicochemical properties and stability, and the quality of the drug is reduced after long-term storage, and impurities are generated, thereby causing toxic and side effects. A large amount of matrix and condensing agent are added in the preparation process of the dripping pill, the condensing agent is generally selected from oily substances, so that the unpleasant odor of the product is increased, and the bioavailability and the effect of the dripping pill are not as good as those of an injection.

Furthermore, since Xiyanping is easily dissolved in water, if it is orally administered, it is dissolved in stomach, so that the drug cannot be absorbed in intestinal tract or is not completely absorbed, resulting in low bioavailability. Thus, there is a need for a dry suspension of Xiyanping for administration in the intestinal tract.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a preparation method of a Xiyanping dry suspension, which overcomes the blank of Xiyanping formulation in the current market.

In order to achieve the purpose, the invention is realized by the following technical scheme:

the invention discloses a preparation method of Xiyanping dry suspension, which comprises the steps of sulfonating andrographolide mesoporous silica nanoparticles, precipitating with ethanol, adding lactose and microcrystalline cellulose, uniformly performing ultrasonic treatment, filtering and concentrating to obtain mesoporous silica-loaded andrographolide sulfonate and microcrystalline cellulose; spray granulating the adhesive prepared from sodium dodecyl sulfate and the concentrated product, and drying after granule forming; then, an isolating layer and an enteric coating are sequentially coated on the formed particles, and the Xiyanping dry suspension is obtained.

Preferably, the method comprises the following steps:

(1) sulfonation and alcohol precipitation of andrographolide mesoporous silica nanoparticles

Mixing andrographolide mesoporous silica nanoparticles with absolute ethyl alcohol, slowly dropwise adding concentrated sulfuric acid under the ice-water bath condition, uniformly mixing, and standing for reaction; then adding absolute ethyl alcohol to quench reaction, and adjusting the pH value to be neutral by using sodium hydroxide; adding absolute ethyl alcohol again, wherein the alcohol content is more than or equal to 85%, standing and filtering;

(2) preparation of granules

Adding lactose and microcrystalline cellulose into the filtrate prepared in the step (1), uniformly mixing under ultrasonic, and then filtering and concentrating to prepare a concentrate for later use; dissolving hydroxypropyl cellulose in 20-95% ethanol water solution, and adding sodium dodecyl sulfate to prepare a solvent with solid content of 3-5% as an adhesive; carrying out spray granulation on the adhesive and the concentrate, and drying after the granules are formed to obtain granules;

(3) wrapping and isolating layer

Dissolving the raw materials of the isolating layer in water or absolute ethyl alcohol to prepare isolating solution; coating the spacer fluid and the particles;

(4) coated with enteric layer

Preparing raw materials of the enteric layer and the plasticizer into enteric coating liquid with the solid content of 3-15% by using purified water or 20-85% ethanol solution, and coating the enteric coating liquid and the product prepared in the step (3) to obtain the Xiyanping enteric-coated granules; and adding a suspending agent and a flavoring agent into the prepared Xiyanping enteric-coated particles to prepare the Xiyanping enteric-coated dry suspension.

Preferably, in the step (1), the mass concentration of the andrographolide mesoporous silica nanoparticles and the absolute ethyl alcohol is 1: 1-2.5; the volume concentration of the concentrated sulfuric acid and the andrographolide mesoporous silica nanoparticles is 1-4: 5; standing and reacting for 50-70 h at 10-25 ℃.

Preferably, the weight gain of the isolating layer is controlled to be 18-50% of the weight of the particles, and the weight gain of the enteric layer is controlled to be 10-50% of the weight of the particles after the isolating layer is coated by the particles.

Preferably, the preparation process of the andrographolide mesoporous silica nanoparticles comprises the following steps: dissolving andrographolide in absolute ethyl alcohol, then adding mesoporous silica, stirring for reaction, filtering and drying to obtain the andrographolide mesoporous silica nanoparticles.

Preferably, the mass ratio of the andrographolide to the mesoporous silica is 1-3: 3-9, the particle size of the mesoporous silica is 80-120 nm, and the pore diameter is 30-50 nm.

Preferably, the enteric layer is one or a mixture of more of cellulose acetate phthalate, acrylic resin II, acrylic resin III, hydroxypropyl methyl cellulose phthalate and polyvinyl alcohol acetate phthalate;

the isolating layer is hydroxypropyl methylcellulose, Opadriamb II,

II. One or more of Opadry 03K19229, Opadry Y-1-7000, Opadry YS-1-7003 and Opadry Y-30-18037;

the plasticizer is one or a mixture of triethyl citrate, dibutyl sebacate, propylene glycol and polyethylene glycol;

the correctant is one or more of aspartame, sodium cyclamate, stevioside, citric acid, orange essence and pineapple essence.

Preferably, the mesoporous silica-loaded andrographolide sulfonate and the microcrystalline cellulose are prepared by a Xiyanping dry suspension reaction device, the reaction device comprises a reaction cylinder with a top cover, a plurality of sliding grooves are formed in the inner wall of the reaction cylinder along the length direction of the reaction cylinder, and a mixing mechanism which slides up and down through the sliding grooves is arranged in the reaction cylinder;

mixing mechanism is including setting up the mixing plate in the reaction cylinder, be provided with the guide post that is located the spout on the mixing plate, be provided with ultrasonic transducer on the lateral wall of the guide post that is located the reaction cylinder, the top of reaction cylinder is stretched out to the guide post to connect fixedly through the connecting rod, be fixed with the output pole of cylinder on the connecting rod.

Preferably, be provided with the several through-hole on the mixing plate, be provided with the apron that can open and shut in the through-hole, it has hoist mechanism to articulate on the apron, hoist mechanism is including setting up the hollow solid fixed cylinder in the center department of mixing plate, gu be provided with the baffle in the week of fixed cylinder, be located the top of baffle, gu be equipped with the sleeve in the week of fixed cylinder, telescopic upwards articulates there is the pull rod in week, the other end of pull rod articulates the top surface of apron.

Preferably, a circle of supporting plate is arranged on the inner wall of the through hole, a separation net is arranged below the supporting plate and in the through hole, the cover plate is placed on the supporting plate, a groove is arranged on the surface of the supporting plate close to the fixed cylinder, fixing parts are respectively fixedly arranged in the groove and at two ends close to the groove, and an arc-shaped hole is formed in the fixing part along the length direction of the fixing part; the side wall of the cover plate corresponding to the groove is fixedly provided with a rotating rod, two ends of the rotating rod respectively penetrate through the arc-shaped holes in the two fixing pieces, two ends of one side of the cover plate, which is provided with the rotating rod, are provided with notches, and the other end portion of each fixing piece is positioned in the notch.

The invention has the following beneficial effects:

the andrographolide sulfonate mesoporous silicon dioxide is prepared by using andrographolide mesoporous silicon dioxide, so that andrographolide sulfonate is loaded in pores of the mesoporous silicon dioxide, and meanwhile, as andrographolide sulfonate is easy to dissolve in water, in the process of preparing andrographolide sulfonate mesoporous silicon dioxide, spherical porous microcrystalline cellulose mixed with different particle sizes is added, so that andrographolide sulfonate in a microcrystalline cellulose adsorption reaction system enters the pores of the mesoporous silicon dioxide under the action of ultrasound, and the obtained mesoporous silicon dioxide simultaneously loads andrographolide sulfonate and microcrystalline cellulose, and the microcrystalline cellulose acts as a disintegrant and can be disintegrated in intestinal tracts, so that drugs can be released in the intestinal tracts.

Drawings

FIG. 1 is a schematic structural view of the present invention;

FIG. 2 is a top view of FIG. 1;

FIG. 3 is a view taken along line A-A of FIG. 1;

FIG. 4 is an enlarged view of a portion A of FIG. 3;

FIG. 5 is a structural schematic of the cover plate;

FIG. 6 is a top view of the mixing plate (from the perspective of FIG. 1);

FIG. 7 is a view from the B-B direction of FIG. 6;

FIG. 8 is an enlarged view of part B of FIG. 7;

in the figure: the device comprises a reaction cylinder 1, a chute 2, a mixing plate 3, a guide post 4, a connecting rod 5, a cylinder 6, a through hole 7, a separation net 8, a cover plate 9, a fixed cylinder 10, a baffle plate 11, a sleeve 12, a pull rod 13, a support plate 14, a groove 15, a fixing part 16, an arc-shaped hole 17, a rotating rod 18 and a notch 19.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Unless otherwise indicated, the technical means used in the examples are conventional means well known to those skilled in the art.

The invention discloses a Xiyanping dry suspension which comprises, by weight, 6-20 parts of andrographolide sulfonate mesoporous silicon dioxide, 3-7 parts of lactose and microcrystalline cellulose in a mass ratio of 1-2: 2-3, 0.01-0.1 part of sodium dodecyl sulfate, 7-25 parts of an enteric layer, 4-12 parts of an isolation layer, 0.05-0.5 part of a plasticizer and 0.01-5 parts of a flavoring agent.

The preparation process of the andrographolide sulfonate mesoporous silicon dioxide is characterized in that the andrographolide sulfonate mesoporous silicon dioxide is prepared by sulfonation reaction of andrographolide mesoporous silicon dioxide, and lactose and microcrystalline cellulose are added in the reaction process to obtain the mesoporous silicon dioxide loaded andrographolide sulfonate and microcrystalline cellulose. The microcrystalline cellulose is spherical porous particles, and the particle size is 3-10 nm. Preferably, the microcrystalline cellulose comprises microcrystalline cellulose with the grain sizes of 3nm, 4-5 nm and 5-7 nm, and the mass ratio of the microcrystalline cellulose to the microcrystalline cellulose is 1: 0.5-0.7: 0.3-0.4.

The preparation process of the andrographolide mesoporous silica comprises the following steps: dissolving andrographolide in absolute ethyl alcohol, then adding mesoporous silica, stirring for reaction, filtering and drying to obtain the andrographolide mesoporous silica nanoparticles. The mass ratio of the andrographolide to the mesoporous silica is 1-3: 3-9, the particle size of the mesoporous silica is 80-120 nm, and the pore diameter is 30-50 nm.

The enteric layer is one or a mixture of more of cellulose acetate phthalate, acrylic resin II, acrylic resin III, hydroxypropyl methyl cellulose phthalate and polyvinyl alcohol acetate phthalate; hydroxypropyl methylcellulose, Opadriamb II, and a separator,

II. One or more of Opadry 03K19229, Opadry Y-1-7000, Opadry YS-1-7003 and Opadry Y-30-18037; the plasticizer is one or a mixture of triethyl citrate, dibutyl sebacate, propylene glycol and polyethylene glycol; the correctant is one or more of aspartame, sodium cyclamate, stevioside, citric acid, orange essence and pineapple essence.

Secondly, a preparation method of Xiyanping dry suspension, which comprises the steps of sulfonating andrographolide mesoporous silica nanoparticles, precipitating with ethanol, adding lactose and microcrystalline cellulose, filtering and concentrating after ultrasonic uniform, carrying out spray granulation on an adhesive prepared from sodium dodecyl sulfate and the concentrated product, and drying after particle forming; then, an isolating layer and an enteric coating are sequentially coated on the formed particles, and the Xiyanping dry suspension is obtained.

The method specifically comprises the following steps:

(1) preparation of andrographolide mesoporous silica nanoparticles

Dissolving Andrographolide (AND) in anhydrous ethanol to make its concentration 20mg/mL, AND dissolving andrographolide under the condition of heating in water bath at 60 deg.C AND stirring; then adding mesoporous silicon dioxide (MSNs), and stirring and reacting for 2 hours at 60 ℃ under a sealed condition; stirring at normal temperature under deblocking conditions, reacting until ethanol is completely volatilized, filtering, AND drying to obtain andrographolide mesoporous silica nanoparticles (MSNs-AND). The mass ratio of the andrographolide to the mesoporous silica is 1-3: 3-9, the particle size of the mesoporous silica is 80-120 nm, and the pore diameter is 30-50 nm.

(2) Sulfonation and alcohol precipitation of andrographolide mesoporous silica nanoparticles

After the andrographolide mesoporous silica nanoparticles are mixed with absolute ethyl alcohol, slowly dripping concentrated sulfuric acid under the condition of ice-water bath, wherein the volume concentration (mL/mg) of the concentrated sulfuric acid and the andrographolide mesoporous silica nanoparticles is 1-4: 5, the dripping speed is 2mL/min, and the fastest dripping speed is not more than 5 mL/min; the dropping process is accompanied with slow stirring, so that concentrated sulfuric acid dropped into the reaction system can be rapidly dispersed and diluted, thereby avoiding the andrographolide from being directly contacted with a large amount of concentrated sulfuric acid to be damaged, and also avoiding the local temperature rise of the reaction system from influencing the quality of the final product andrographolide sulfonate. And after dropwise adding concentrated sulfuric acid, standing and reacting for 50-70 h at 10-25 ℃. Then adding absolute ethyl alcohol with the same amount as andrographolide to carry out quenching reaction, adjusting the pH to be neutral by using 50% sodium hydroxide, and carrying out neutralization under the condition of ice-water bath; adding absolute ethyl alcohol again, keeping the alcohol content to be more than or equal to 85%, standing for 15h, and filtering; the filter residue can be washed with 95% ethanol to colorless, and the washing liquid is mixed with the filtrate. The yield of andrographolide sulfonate in the mixed washing liquid is 65-70% of the content of andrographolide.

The mass concentration (mg/mL) of the andrographolide mesoporous silica nanoparticles and the absolute ethyl alcohol is 1: 1-2.5.

(3) Preparation of granules

Adding lactose and microcrystalline cellulose into the mixed solution prepared in the step (2), wherein the grain size of the microcrystalline cellulose is 3-10 nm, and preferably, the microcrystalline cellulose with the grain sizes of 3nm, 4-5 nm and 5-7 nm is selected for matching use, and the mass ratio of the microcrystalline cellulose to the microcrystalline cellulose is 1: 0.5-0.7: 0.3-0.4. Mixing under ultrasound, filtering, concentrating, and recovering ethanol to obtain concentrate; dissolving hydroxypropyl cellulose in 20-95% ethanol water solution, and adding sodium dodecyl sulfate to prepare a solvent with solid content of 3-5% as an adhesive; carrying out spray granulation on the adhesive and the concentrate, and drying after the granules are formed to obtain granules; spraying granulation is carried out by adopting a coating machine, the spraying speed is 2-15 mL/min, the rotating speed is 100-300 r/min, and the rotation is 10-30 min; the drying temperature is 40 ℃, the drying time is 8-12 h, and the dried particles are sieved by a sieve of 60-100 meshes. It should be noted that: the microcrystalline cellulose is spherical porous particles, can adsorb drug molecules, and has a particle size smaller than that of the mesoporous silicon dioxide. Therefore, in the sulfonation process of andrographolide in the mesoporous two-sample silicon pores, a part of andrographolide sulfonate is separated from the pores, and microcrystalline cellulose adsorbs the part of drug molecules, and the microcrystalline cellulose partially enters the pores of the mesoporous silicon dioxide in an ultrasonic environment, so that the microcrystalline cellulose and the drug molecules can be well loaded in the mesoporous silicon dioxide; and then the surface of the mesoporous silicon dioxide is sealed by the adhesive, so that the andrographolide sulfonate can be well encapsulated, and the drug loss is avoided. Moreover, the microcrystalline cellulose can also play a role in disintegration after the finally prepared Xiyanping dry suspension enters the human body.

(4) Wrapping and isolating layer

Dissolving the raw materials of the isolating layer in water or absolute ethyl alcohol to prepare isolating solution; coating the spacer fluid and the particles; the weight gain of the isolation layer is controlled to be 18-50% of the weight of the particles. Coating the isolation layer in a coating machine, wherein the rotating speed of the coating machine is 100-400 r/min, the coating temperature is 40 +/-5 ℃, the spraying speed is 10-40 mL/min, and the atomization pressure is 0.1-0.4 MPa.

(5) Coated with enteric layer

Preparing raw materials of the enteric layer and the plasticizer into enteric coating liquid with the solid content of 3-15% by using purified water or 20-85% ethanol solution, and coating the enteric coating liquid and the product prepared in the step (3) to obtain the Xiyanping enteric-coated granules; and adding a suspending agent and a flavoring agent into the prepared Xiyanping enteric-coated particles to prepare the Xiyanping enteric-coated dry suspension. The weight gain of the enteric layer is controlled to be 10-50% of the weight of the particles coated with the isolating layer. Coating the enteric coating layer in a coating machine, wherein the rotating speed of the coating machine is 100-400 r/min, the coating temperature is 40 +/-5 ℃, the spraying speed is 10-40 mL/min, and the atomizing pressure is 0.1-0.4 MPa.

The invention is further illustrated below with reference to specific examples.

Example 1

1. According to the preparation method of the andrographolide mesoporous silica nanoparticles in the second method, the andrographolide mesoporous silica nanoparticles are prepared, the specific proportion is shown in table 1 below, wherein the content of andrographolide is measured according to the existing method, the particle size of mesoporous silica is 90nm, and the pore size is 35 nm. The result shows that the content of andrographolide loaded on the mesoporous silica is highest when the mass ratio of andrographolide to mesoporous silica is 1: 3.

TABLE 1 drug loading of andrographolide in mesoporous silica at different ratios

2. When the mass ratio of andrographolide to mesoporous silica is 1:3, the influence of the pore size of the mesoporous silica on the drug loading capacity is shown in table 2 below.

TABLE 2 influence of different pore diameters of mesoporous silica on drug loading

3. Selecting the data in group 3 of table 1 and group c of table 2 to prepare andrographolide mesoporous silica nanoparticles for later use; and then preparing the dry suspension according to the preparation method of the Xiyanping dry suspension in the second method. Wherein the mass concentration of the MSNs-AND AND absolute ethyl alcohol is 1:1.5, the volume concentration of concentrated sulfuric acid AND the MSNs-AND is 3:5, AND the concentrated sulfuric acid is kept stand AND reacts for 68 hours after being dripped; the ratio of lactose to microcrystalline cellulose is 1:2, and the particle size of microcrystalline cellulose is 4 nm. The specific ratio is shown in the following table 3, and the parameters of the coating machine in each step are shown in the table 4.

TABLE 3 raw material proportions (parts by weight)

TABLE 4 Process parameters of the coating machine for the individual steps

4. The Xiyanping dry suspension is prepared by adopting the process parameters in the table 4 and the composition ratios in the table 3, and the weight gain of the isolation layer and the weight gain of the enteric layer are shown in the following table 5 after the isolation layer and the enteric layer are coated.

TABLE 5 weight gain of isolation and enteric layers

Group of	Isolated layer weight gain/%)	Enteric layer weight gain/%)
			1	18	12
2	20	14
			3	19	15
4	22	17
			5	26	18
6	28	20

5. 3g of each Xiyanping dry suspension prepared by the invention is respectively placed in hydrochloric acid solution with the pH value of 1.5 for 2h, then placed in phosphate buffer solution with the pH value of 6.8 for 45min, and the cumulative release degree is respectively measured by sampling in 30min, 60min, 90min, 120min, 135min, 145min, 155min and 165min, and the average value result is shown in the following table 6.

TABLE 6 Xiyanping dry suspension cumulative release results

6. According to the table 6, the mixture ratio of the group 5 in the table 3 is selected, and the microcrystalline cellulose is compounded with different particle sizes, the specific conditions are shown in the following table 7, and the rest processes are the same.

TABLE 7 compounding of microcrystalline cellulose of different particle sizes

7. The cumulative release results for Xiyanping dry suspensions, with different particle size combinations of microcrystalline cellulose, are shown in Table 8 below. The results show that: the microcrystalline cellulose with different grain diameters has better drug release effect in the environment of pH 6.8 after being mixed, and mainly the microcrystalline cellulose plays a good role in disintegration.

TABLE 8 Xiyanping dry suspension cumulative release results

Example 2

In example 1, after the andrographolide mesoporous silica nanoparticles are reacted with concentrated sulfuric acid and other reagents, the yield of andrographolide sulfonate in the final mixed washing liquid is 65-70% of the content of andrographolide, so that 30-35% of andrographolide is not subjected to sulfonation reaction, and the medicine is lost and wasted. Therefore, it is necessary to increase the yield of andrographolide sulfonate with the aid of equipment during sulfonation of andrographolide in andrographolide mesoporous silica.

The whole steps of sulfonation and alcohol precipitation of (2) the andrographolide mesoporous silica nanoparticles in the second method of the embodiment 1 and the step of adding lactose and microcrystalline cellulose in the preparation of the particles into the mixed liquid prepared in the step (2) are carried out in the equipment disclosed by the invention.

The method specifically comprises the following steps: referring to fig. 1-8, the invention discloses a Xiyanping dry suspension reaction device, which comprises a reaction cylinder 1 with a top cover, wherein the reaction cylinder 1 is made of transparent materials, so that the condition inside the reaction cylinder 1 can be observed conveniently, the top cover and the reaction cylinder 1 can be disassembled, a mixing mechanism capable of sliding up and down is arranged in the reaction cylinder 1, a filter screen (not shown in the figure) is arranged at the bottom of the reaction cylinder 1 and used for filtering a reacted product, and the filter screens with different pore sizes can be replaced according to actual conditions.

The method specifically comprises the following steps: a plurality of chutes 2 are arranged on the inner wall of the reaction cylinder 1 along the length direction, and the mixing mechanism slides up and down in the reaction cylinder 1 through the chutes 2. Mixing mechanism is including setting up mixing plate 3 in reaction cylinder 1, be provided with the guide post 4 that is located spout 2 on mixing plate 3, be provided with ultrasonic transducer on the lateral wall of the guide post 4 that is located reaction cylinder 1, can all set up an ultrasonic ring energy ware on every guide post, also can only set up one. The guide post 4 stretches out of the top of the reaction cylinder 1 and is fixedly connected through a connecting rod 5, an output rod of a cylinder 6 is fixedly arranged on the connecting rod 5, and the guide post 4 is driven by the cylinder 6 to drive the mixing plate 3 to slide up and down. Be provided with several through-hole 7 on the mixing plate 3, be provided with in the through-hole 7 and separate net 8, when mixing plate 3 downstream, reaction solution can enter into the top of mixing plate 3 through separating net 8. Therefore, when the mixing plate 3 reciprocates up and down, the reaction solution is uniformly mixed/more sufficiently mixed and reacted with the newly added raw material while reciprocating through the screen 8.

Further, in order to prevent the solids generated during the reaction of the raw materials from depositing on the bottom of the chute 2, the bottom surface of the chute 2 is provided as an inclined surface inclined from the side wall of the chute 2 toward the center of the reaction cylinder 1.

Furthermore, in order to ensure that the raw material components are in a relatively closed environment (not a completely sealed environment) in the reaction process, the ethanol is prevented from volatilizing in the reaction process to cause incomplete reaction, and the safety of personnel in the operation process is ensured. An openable cover plate 9 is arranged in the through hole 7, and a lifting mechanism is hinged on the cover plate 9 to enable the cover plate 9 to be opened and closed under the action of external force. Lifting mechanism is including setting up the hollow solid fixed cylinder 10 of the center department at mixing plate 3, gu be provided with baffle 11 in the circumference of fixed cylinder 10, be located the cover is equipped with sleeve 12 in the circumference of the top of baffle 11, solid fixed cylinder 10, sleeve 12 places on baffle 11, and sleeve 12 and solid fixed cylinder 10 stretch out the top of reaction cylinder 1, gu fixed cylinder 10 stretches out the top of sleeve 12. A pull rod 13 is hinged to the sleeve 12 in the circumferential direction, and the other end of the pull rod 13 is hinged to the top surface of the cover plate 9, preferably to the center of the top surface of the cover plate 9. The hinge joint of the pull rod 13 with the sleeve 12 and the cover plate 9 can realize that the pull rod rotates with the sleeve 12 and the cover plate 9 respectively through the matching of the ear seat and the rotating shaft. The sleeve 12 can be provided with a plurality of hooks, the side wall of the fixed cylinder 10 is provided with a plurality of hanging rings (not shown in the figure) corresponding to the hooks, when the sleeve is lifted, the cover plate 9 is opened, and the hooks hook the hanging rings, so that the cover plate 9 is kept at the same angle. Of course, in order to keep the cover plate 9 immovable at different angles, the hanging ring on the side wall of the fixed cylinder 10 is provided with a plurality of turns along the length direction, and the number of the turns corresponds to the hook.

Further, the specific structure that the cover plate 9 is opened and closed in the through hole is as follows: a circle of supporting plates 14 are arranged on the inner wall of the through hole 7, and the separation net 8 is positioned below the supporting plates 14, preferably: the screen 8 is arranged in the inner bore of the support plate 14, the bottom surface of the support plate 14 being flush with the bottom surface of the mixing plate 3. The cover plate 9 is placed on the support plate 14 and fits into the through hole 7. The plate surface of the supporting plate 14 close to the fixed cylinder 10 is provided with a groove 15, and the groove 15 is arranged along the length direction of the side supporting plate 14. Fixing pieces 16 are fixedly arranged in the groove 15 and at two ends close to the groove 15 respectively, the fixing pieces 16 are arc-shaped, and arc-shaped holes 17 are formed in the fixing pieces 16 along the length direction of the fixing pieces. And a rotating rod 18 is fixed on the side wall of the cover plate 9 which is arranged on the support plate 14 and corresponds to the groove 15, two ends of the rotating rod 18 respectively penetrate through the arc-shaped holes 17 on the two fixing pieces 16, and a baffle plate with the width larger than that of the arc-shaped holes 17 is fixed on the rotating rod 18, so that the rotating rod 18 is prevented from being separated from the fixing pieces 16.

Furthermore, in order to increase the rotation angle of the cover plate 9, the two ends of one side of the cover plate 9, which is provided with the rotating rod 18, are provided with notches 19, the other end of the fixing member 16 is positioned in the notches 19, when the cover plate 9 rotates 90 ° relative to the support plate, the two ends of the rotating rod 18 run along the arc-shaped holes 17 until the rotating rod 19 is positioned in the groove 15, and at this time, one side of the cover plate 9, which is provided with the rotating rod 18, is attached to the support plate 14. It should be noted that: the manner of arranging the cover plate 9 and the through hole 7 disclosed by the invention is suitable for the case that the cover plate 9 and the through hole are square. When the cover plate 9 and the through hole are circular, the cover plate 9 can be hinged only by matching the lug seats with the rotating shaft on the support plate and the cover plate 9, and the hinge point faces the fixed cylinder 10.

Furthermore, in order to avoid the arrangement of the connecting rod 5, the sample adding port at the top of the fixed cylinder 10 is shielded, and reagent and/or raw material is not convenient to add. The middle part of the connecting rod 5 is set into a circular ring shape, the fixed cylinder 10 is positioned at the position below the circular ring shape and can also penetrate through the circular ring shape, and the air cylinder 6 is arranged on the connecting rod 5 and at the position close to the circular ring shape. And the mixing plate 3 is provided with a sample adding hole 20 communicated with the fixed cylinder 10, and the sample adding hole 20 is funnel-shaped, and the diameter of the sample adding hole is gradually reduced towards the bottom of the mixing plate 3 due to the joint of the fixed cylinder 10.

When the andrographolide mesoporous silica nano-particles and absolute ethyl alcohol are used, the andrographolide mesoporous silica nano-particles and the absolute ethyl alcohol are sequentially added into the reaction cylinder 1 through the fixed cylinder 10 in proportion, and before the andrographolide mesoporous silica nano-particles and the absolute ethyl alcohol are added, the mixing plate 3 can be lifted through the air cylinder 6. Then, the sleeve 12 is lifted up to open the cover plate 9 and keep the same angle; starting the air cylinder 6, driving the mixing plate 3 to move up and down at a certain speed, and uniformly mixing the andrographolide mesoporous silica nanoparticles with absolute ethyl alcohol; putting the reaction cylinder 1 in an ice-water bath, dropwise adding concentrated sulfuric acid into the reaction cylinder 1 through the fixed cylinder 10, starting the air cylinder in the dropwise adding process, and enabling the mixing plate 3 to move up and down to rapidly disperse the concentrated sulfuric acid in a reaction system; meanwhile, the ultrasonic transducer is started, and andrographolide in the pores of the mesoporous silica can fully react with concentrated sulfuric acid as far as possible under the action of ultrasonic vibration. After dropwise adding concentrated sulfuric acid, taking the reaction cylinder 1 out of the ice-water bath, putting down the sleeve, covering the through hole 7 by the cover plate 9, attaching or separating the mixing plate 3 to the liquid level of the reaction solution, standing for reaction, wherein in the standing reaction process, the starting time of the ultrasonic transducer is 1/3-1/2 of the standing reaction time. And (3) sequentially adding the reagents into the reaction cylinder 1 through the fixed cylinder 10 according to the adding sequence and the adding time of the reagents in the step (2) of the second method, opening the cover plate 9, and starting the air cylinder 6 to enable the mixing plate 3 to move up and down in the reagent adding process so as to achieve the purpose of mixing. After the reaction is accomplished, filter, when filtering, only need open the valve that sets up the drain pipe in reaction cylinder 1 bottom, filter reaction solution through the filter screen, the filter residue after the filtration carries out washing many times through ethanol, the lotion mixes for subsequent use with filterable filtrating before, and the filter residue after the filtration then reaction cylinder 1 discharges, specifically discharges through the discharge gate that sets up on reaction cylinder 1 lateral wall, when the pH value of test reaction solution, this discharge gate of accessible carries out the sample test. Measuring the yield of andrographolide sulfonate in the mixed solution. And (3) carrying out the reaction of the step (2) according to the steps under the condition of the same consumption of the andrographolide mesoporous silica nanoparticles. The result shows that the yield of the andrographolide sulfonate in the mixed washing liquid is 79-82% of the content of andrographolide, and the yield efficiency of the andrographolide sulfonate is greatly improved.

Then, adding the mixed solution of the filtrate and the washing solution into the reaction cylinder 1 again, adding lactose and microcrystalline cellulose, starting the ultrasonic transducer, and carrying out ultrasonic vibration in the process of stirring and mixing the mixture up and down by driving the mixing plate 3 by the air cylinder 6 so that the microcrystalline cellulose adsorbs drug molecules as much as possible and enters pores of the mesoporous silicon dioxide, wherein the starting time of the ultrasonic transducer is 10-20 min.

The equipment disclosed by the invention is used for preparing the Xiyanping dry suspension, various parameters and raw material ratios corresponding to the group 2a in the table 8 in the step 7 of the embodiment 1 are selected, and the release degree of the finally prepared Xiyanping dry suspension is shown in the table 9. The results show that the amount of drug released by the Xiyanping dry suspension is also higher than in Table 8 with increased andrographolide sulfonate yield.

TABLE 9 Xiyanping dry suspension cumulative release results

In the description of the present invention, it is to be understood that the terms "longitudinal", "lateral", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", and the like, indicate orientations or positional relationships based on those shown in the drawings, are merely for convenience of description of the present invention, and do not indicate or imply that the referenced devices or elements must have a particular orientation, be constructed and operated in a particular orientation, and thus, are not to be construed as limiting the present invention.

The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.

Claims

1. A preparation method of a Xiyanping dry suspension is characterized by comprising the following steps: sulfonating andrographolide mesoporous silica nanoparticles, precipitating with ethanol, adding lactose and microcrystalline cellulose, ultrasonically homogenizing, filtering, and concentrating to obtain mesoporous silica-loaded andrographolide sulfonate and microcrystalline cellulose; spray granulating the adhesive prepared from sodium dodecyl sulfate and the concentrated product, and drying after granule forming; then, an isolating layer and an enteric coating are sequentially coated on the formed particles, and the Xiyanping dry suspension is obtained.

2. The method for preparing a Xiyanping dry suspension as claimed in claim 1, wherein: the method comprises the following steps:

(2) preparation of granules

(3) wrapping and isolating layer

(4) coated with enteric layer

3. The method for preparing a Xiyanping dry suspension as claimed in claim 2, wherein: in the step (1), the mass concentration of the andrographolide mesoporous silica nanoparticles and the absolute ethyl alcohol is 1: 1-2.5; the volume concentration of the concentrated sulfuric acid and the andrographolide mesoporous silica nanoparticles is 1-4: 5; standing and reacting for 50-70 h at 10-25 ℃.

4. The method for preparing a Xiyanping dry suspension as claimed in claim 2, wherein: the weight gain of the isolating layer is controlled to be 18-50% of the weight of the particles, and the weight gain of the enteric layer is controlled to be 10-50% of the weight of the particles after the isolating layer is coated by the particles.

5. The method for preparing a Xiyanping dry suspension as claimed in claim 1, wherein: the preparation process of the andrographolide mesoporous silica nanoparticles comprises the following steps: dissolving andrographolide in absolute ethyl alcohol, then adding mesoporous silica, stirring for reaction, filtering and drying to obtain the andrographolide mesoporous silica nanoparticles.

6. A method of preparing a Xiyanping dry suspension as claimed in claim 5, wherein: the mass ratio of the andrographolide to the mesoporous silica is 1-3: 3-9, the particle size of the mesoporous silica is 80-120 nm, and the pore diameter is 30-50 nm.

7. The method for preparing a Xiyanping dry suspension as claimed in claim 2, wherein: the enteric layer is one or a mixture of more of cellulose acetate phthalate, acrylic resin II, acrylic resin III, hydroxypropyl methyl cellulose phthalate and polyvinyl alcohol acetate phthalate;

the isolating layer is hydroxypropyl methylcellulose, Opadriamb II,

8. The method for preparing a Xiyanping dry suspension as claimed in claim 1, wherein: the mesoporous silica-loaded andrographolide sulfonate and the microcrystalline cellulose are prepared by a Xiyanping dry suspension reaction device, the reaction device comprises a reaction cylinder with a top cover, a plurality of sliding grooves are formed in the inner wall of the reaction cylinder along the length direction of the reaction cylinder, and a mixing mechanism which slides up and down through the sliding grooves is arranged in the reaction cylinder;

9. The method of preparing a Xiyanping dry suspension as claimed in claim 8, wherein: the mixing plate is provided with a plurality of through holes, the through holes are internally provided with openable cover plates, the cover plates are hinged with lifting mechanisms, each lifting mechanism comprises a hollow fixed cylinder arranged at the center of the mixing plate, the fixed cylinders are circumferentially provided with baffle plates, sleeves are sleeved above the baffle plates and circumferentially of the fixed cylinders, pull rods are hinged to the sleeves circumferentially, and the other ends of the pull rods are hinged to the top surfaces of the cover plates.

10. The method of preparing a Xiyanping dry suspension as claimed in claim 9, wherein: a circle of supporting plate is arranged on the inner wall of the through hole, a separation net is arranged below the supporting plate and in the through hole, the cover plate is placed on the supporting plate, a groove is formed in the surface, close to the fixing cylinder, of the supporting plate, fixing parts are fixedly arranged in the groove and at two ends close to the groove respectively, and arc-shaped holes are formed in the fixing parts along the length direction of the fixing parts; the side wall of the cover plate corresponding to the groove is fixedly provided with a rotating rod, two ends of the rotating rod respectively penetrate through the arc-shaped holes in the two fixing pieces, two ends of one side of the cover plate, which is provided with the rotating rod, are provided with notches, and the other end portion of each fixing piece is positioned in the notch.