CN116832004A - Nemactevir and ritonavir compound tablet and preparation method thereof - Google Patents

Abstract

The invention provides a nematvir and ritonavir compound tablet and a preparation method thereof. The nematvir and ritonavir compound tablet is made of materials corresponding to the ritonavir layer and the nematvir layer. Prepared by double-layer compression tablets, the nematvir layer is composed of the following raw materials: 280-320 parts of nematvir, 200-250 parts of composite dispersant, 60-100 parts of filler, and 20-50 parts of disintegrant , 10-25 parts of adhesive, and 2-3 parts of lubricant. The ritonavir layer consists of 90-110 parts of ritonavir, 30-60 parts of filler, 6-10 parts of coating material, and filler Composed of 40-100 parts, 3-5 parts of lubricant, and 200-300 parts of adhesive. The nematvir and ritonavir compound tablets of the present invention have small initial dissolution fluctuations, and the preparation onset time and drug effect are stable; at the same time, the auxiliary materials have little adsorption of active ingredients, the recovery rate of the main drug is high, and the drug effect is good and Has good stability.

Description

Nemactevir and ritonavir compound tablet and preparation method thereof

Technical Field

The application relates to the technical field of pharmaceutical preparations, in particular to a Nemactevir and ritonavir compound tablet and a preparation method thereof.

Background

Coronaviruses are a large virus family and the attack on humans was initiated in 1965; three more serious epidemic diseases, middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) and novel coronavirus infection covd-19, have been initiated.

A small molecule broad-spectrum antiviral drug, adefovir (remdesivir), developed by gilider, was officially approved for the first drug to treat covd-19 for 2020.10 months; whereas Molnupiravir, splendid, paxlovid, merck, was marketed in the 11 th year 2021. Paxlovid has been reported to reduce the risk of hospitalization or mortality of mild or moderate COVID-19 patients by about 89%, and has attracted great attention in the industry.

Paxlovid is a compound preparation of a combination package of a Nemactetavir film-coated quick-release tablet and a ritonavir tablet, wherein ritonavir is an HIV-1 protease inhibitor, and is helpful for slowing down the metabolism or decomposition of Nemactetavir, and the combination of the two enhances the antiviral activity of the Matevir by 10 times. The recommended dose is 300mg (150 mg. Times.2 tablets) of Nemactrevir combined with 100mg (100 mg. Times.1 tablets) of ritonavir, administered orally every 12h1 for 5 days. However, paxlovid requires that both drugs be taken simultaneously, and patients are difficult to take the drugs and are prone to missed and misadministration, which affects the efficacy. Therefore, the Chinese patent of application number 202210200071.0 discloses a compound double-layer tablet containing ritonavir pellets for treating novel coronaviruses, wherein the tablet is a double-layer compound tablet containing pellets, and active ingredients are ritonavir and Nirmatrelvir, and the scheme can increase the convenience of carrying and taking medicines and improve the medication compliance of patients; however, the initial dissolution uniformity is poor, the dissolution rate is low, and the like are insufficient, so that the antiviral effect is still not ideal.

In view of this, the present application has been made.

Disclosure of Invention

The application solves the problems that the initial dissolution rate of ritonavir in the existing Nemacleavir and ritonavir compound tablet fluctuates greatly and the total dissolution rate needs to be improved.

In order to solve the problems, the application provides a Nemactetvir and ritonavir compound tablet, which is prepared by double-layer tabletting of a ritonavir layer and materials corresponding to the Nemactetvir layer, wherein the Nemactetvir layer is prepared from the following raw materials: 280-320 parts of Nemadavir, 200-250 parts of composite dispersing agent, 60-100 parts of filler, 20-50 parts of disintegrating agent, 10-25 parts of adhesive and 2-3 parts of lubricant, wherein ritonavir Wei Ceng comprises 90-110 parts of ritonavir, 30-60 parts of filler, 6-10 parts of coating material, 40-100 parts of filler, 3-5 parts of lubricant and 200-300 parts of adhesive.

Preferably, the nemaltevir layer is composed of the following raw materials: 300 parts of Nemactetavir, 240 parts of composite dispersing agent, 90 parts of filler, 20 parts of disintegrating agent, 25 parts of adhesive and 2 parts of lubricant, wherein ritonavir Wei Ceng consists of 100 parts of ritonavir, 60 parts of filler, 7 parts of coating material, 40 parts of filler, 5 parts of lubricant and 240 parts of adhesive.

Preferably, the composite dispersing agent comprises the following raw materials in parts by weight: 3-5 parts of weak acid, 2-5 parts of lecithin and 5-12 parts of polyvinylpyrrolidone.

Preferably, the weak acid is at least one of tartaric acid, fumaric acid, boric acid, aspartic acid, glutamic acid and phenol. Preferably, the weak acid is any one of aspartic acid and glutamic acid.

Preferably, the binder in the ritonavir layer is at least one of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, calcium silicate, calcium carbonate, ethylcellulose, and gum arabic. Preferably, the binder consists of 1 part of ethylcellulose and 1.5 parts of gum arabic.

Preferably, the preparation method of the Nemactevir and ritonavir compound tablet comprises the following steps:

s1, modifying, coating and mixing to obtain a material of a Nemactetvir layer;

s2, obtaining a ritonavir layer material through porosification treatment, dry granulation and total mixing;

s3, adding particles after total mixing of ritonavir layers into a No. 1 feed inlet of a double-layer tablet press, adding particles after total mixing of nemat Wei Ceng into a No. 2 feed inlet, and tabletting the double-layer tablet;

s4, coating the double-layer tablet.

Preferably, the modification operation method in S1 is as follows:

s11, dissolving a prescription amount of ritonavir in an organic solvent to obtain a solution A;

s12, adding pore-forming agent into filling agent and lubricant according to the ratio of 4-10g to 1g to obtain a mixture B; s13, dissolving the mixture B in deionized water to obtain a solution C; adding the solution C into the solution A, and stirring at high speed for 6-15min to form emulsion;

s14, spray drying, wherein the feeding flow is controlled to be 8-14ml/min, and the gas flow rate is controlled to be 40-60m ³ And/h, obtaining the particles D at the outlet temperature of 40-50 ℃.

Preferably, the particle diameter D of the fine particles D ₉₀ ＜200μm。

Preferably, the pore-forming agent is ammonium bicarbonate.

Preferably, the coating and total mixing operation in step S1 is as follows:

s15, placing the particles D into a fluidized bed granulating pot, preheating, spraying slurry when the temperature of the materials reaches 40-42 ℃, and controlling the flow rate of coating liquid with the mass concentration of 10-12% to be 40-60g/min to obtain pellets containing ritonavir;

s16, uniformly mixing the pellets with the filler, the lubricant and the adhesive.

Preferably, the step S2 includes the steps of:

s21, sieving the compound dispersing agent with a 80-mesh sieve according to the prescription amount, wherein the weight of the compound dispersing agent is 1g: adding 30-50ml of acetic acid solution, heating to 65-75 ℃, adding the amount of the nemortevir, stirring for 20-50min to fully dissolve, vacuum drying, grinding and sieving with a 80-mesh sieve to obtain a modified intermediate;

s22, uniformly mixing the modified intermediate, the filler and the disintegrating agent, performing dry granulation, and finishing granules by a 18-mesh screen after granulating;

s23, uniformly mixing the granules after dry granulation with an external adhesive and a lubricant to obtain the composite material.

Compared with the prior art, the Nemaclear and ritonavir compound tablet and the preparation method thereof have the following beneficial effects: 1) The ritonavir is subjected to porosification treatment and coating by adding a pore-forming agent, the dissolution rate is controlled by a coating material, the dosage and an adhesive, the adverse effect of low solubility of ritonavir on the initial dissolution rate is reduced, and the fluctuation of the initial dissolution rate is further reduced by controlling the particle size of particles, so that the onset time and the stable drug effect of the oral solid preparation are ensured; 2) The adsorption of ritonavir can be reduced by adding the non-hydrophilic adhesive with specific combination, so that the recovery rate of the main medicine is high, and the medicine effect is good; 3) The dispersing agent is added to ensure that the Nemactetvir is always in an amorphous state, thereby being beneficial to dissolution; meanwhile, the stability of the nemaltevir in the compound tablet can be further improved by adding weak acid, especially acidic amino acid.

Detailed Description

The present application will be described by way of specific examples, to facilitate understanding and grasping of the technical solution of the present application, but the present application is not limited thereto. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the devices, reagents and materials described, unless otherwise specified, are all commercially available. The technical features of the embodiments of the present application can be combined correspondingly without mutual conflict.

The dissolution uniformity was used to examine the variability of the dissolution rate and extent of the product. Controlling the dissolution uniformity is beneficial to reducing the difference of dissolution speed and degree of different products, thereby reducing the change of the drug absorption speed caused by the preparation factors, and having important significance for guaranteeing the stable acting time of the oral solid preparation; part of auxiliary materials and the main medicine have interaction, for example, the main medicine is adsorbed to cause incomplete dissolution, thereby affecting the medicine effect. The applicant proposes the following solutions based on the above problems:

example 1

Ritonavir layer:

the preparation method comprises the following steps:

1) Dissolving a prescription amount of ritonavir in butyl acetate according to a ratio of 1g to 50ml to obtain a solution A; adding lactose with a prescription amount into ammonium bicarbonate according to a ratio of 12g to 1g to obtain a mixture B, and dissolving the mixture B into deionized water according to a ratio of 1g to 10ml to obtain a solution C; adding the solution C into the solution A and stirring at 12000rpm for 4min; spray drying the obtained emulsion to obtain particles D, controlling the average particle diameter D of the particles D, wherein the feeding flow is 12ml/min, the gas flow rate is 55m3/h, the outlet temperature is 42 DEG C ₉₀ ＝195μm。

2) Preparing coating solution with concentration of 18%, placing the particles D into a fluidized bed granulating pot, preheating, spraying slurry when the material temperature reaches 40 ℃, controlling the material temperature to be about 40 ℃ and the flow rate of the coating solution to be 40g/min to obtain the micropill containing ritonavir.

3) Mixing the pellets with pregelatinized starch, talcum powder and ethyl cellulose in a mixer uniformly to obtain the total mixed particles.

Layer of nemaltevir:

the preparation method comprises the following steps:

1) After the prescription amount of the nemaltevir and the compound dispersing agent are sieved by a 90-mesh sieve, the weight ratio of the compound dispersing agent is 4:2:5, lecithin and polyvinylpyrrolidone, according to 1g: adding dimethyl sulfoxide solution 60ml, heating to 70deg.C, adding the required amount of nematolide Wei Jiaoban min to dissolve thoroughly, vacuum drying at 50deg.C for 48 hr, grinding, and sieving with 80 mesh sieve to obtain modified intermediate;

2) Uniformly mixing the modified intermediate with microcrystalline cellulose and croscarmellose sodium, granulating by a dry method, and finishing granules by a 18-mesh screen after granulating;

3) And uniformly mixing the dry granulated particles with externally-added crosslinked sodium carboxymethyl cellulose and magnesium stearate to obtain the total mixed particles.

The preparation process of the double-layer tablet comprises the following steps:

1) Adding ritonavir layer total mixed particles into a No. 1 feed inlet of a double-layer tablet press, adding nemat Wei Ceng total mixed particles into a No. 2 feed inlet, and tabletting the double-layer tablet;

2) Preparing a coating solution with the concentration of 12% by using Cellulose Acetate Phthalate (CAP), putting the double-layer tablet into a coating pot, preheating, and spraying slurry when the temperature of a tablet bed reaches 40 ℃ to obtain the compound double-layer coated tablet.

Example 2

Ritonavir layer:

the preparation method comprises the following steps:

1) Dissolving a prescription amount of ritonavir in ethyl acetate according to a ratio of 1g to 40ml to obtain a solution A; adding 8g of pregelatinized starch into 1g of ammonium bicarbonate to obtain a mixture B, and dissolving the mixture B into deionized water according to 1g of pregelatinized starch to 12ml to obtain a solution C; adding the solution C into the solution A and stirring at 9000rpm for 6min; spray drying the obtained emulsion to obtain particles D with a feed flow rate of 10ml/min and a gas flow rate of 52m ³ And/h, controlling the average particle diameter D of the particles D, wherein the outlet temperature is 44 DEG C ₉₀ 180 μm.

2) Preparing coating liquid with the concentration of 15%, placing the particles D into a fluidized bed granulating pot, preheating, spraying slurry when the material temperature reaches 41 ℃, controlling the material temperature to be about 41 ℃ and controlling the flow rate of the coating liquid to be 45g/min to obtain the micropill containing ritonavir.

4) Mixing the micropill with microcrystalline cellulose, sodium stearate, and polyvinylpyrrolidone in a mixer to obtain the granule.

Layer of nemaltevir:

the preparation method comprises the following steps:

1) After passing the prescribed amount of the compound dispersing agent through a 90-mesh sieve, the weight ratio of the compound dispersing agent is 5:2:9, glutamic acid, lecithin and polyvinylpyrrolidone according to 1g: adding 50ml of acetic acid solution, heating to 72 ℃, adding the prescription amount of nematolide Wei Jiaoban min to fully dissolve, then vacuum drying at 48 ℃ for 45h, grinding and sieving with a 80-mesh sieve to obtain a modified intermediate;

4) Uniformly mixing the modified intermediate with calcium carboxymethyl cellulose and crosslinked polyvinylpyrrolidone, performing dry granulation, and granulating with a 18-mesh screen;

5) And uniformly mixing the dry granulated particles with the added hypromellose and the sodium stearyl fumarate to obtain the total mixed particles.

The preparation process of the double-layer tablet comprises the following steps:

1) Adding ritonavir layer total mixed particles into a No. 1 feed inlet of a double-layer tablet press, adding nemat Wei Ceng total mixed particles into a No. 2 feed inlet, and tabletting the double-layer tablet;

2) Preparing 12% coating solution with hypromellose phthalate (HPMCP), placing the bilayer tablet into a coating pan, preheating, and spraying slurry when the temperature of tablet bed reaches 40deg.C to obtain compound bilayer coated tablet.

Example 3

Ritonavir layer:

the preparation method comprises the following steps:

1) Dissolving a prescription amount of ritonavir in ethyl acetate according to a ratio of 1g to 40ml to obtain a solution A; adding 6g of total weight of sorbitol and lubricant into 1g of ammonium bicarbonate to obtain a mixture B, and dissolving the mixture B into deionized water according to 1g of total weight of sorbitol and lubricant to 8ml of total weight to obtain a solution C; adding the solution C into the solution A and stirring at 10000rpm for 8min; spray drying the obtained emulsion to obtain particles D with a feed flow of 9ml/min and a gas flow rate of 50m ³ And/h, controlling the average particle diameter D of the particles D, wherein the outlet temperature is 42 DEG C ₉₀ 200 μm.

2) Preparing coating liquid with the concentration of 12%, placing the particles D into a fluidized bed granulating pot, preheating, spraying slurry when the material temperature reaches 41 ℃, controlling the material temperature to be about 41 ℃ and controlling the flow rate of the coating liquid to be 48g/min to obtain the micropill containing ritonavir.

5) Mixing the pellets with lactitol, gum arabic, ethyl cellulose and the rest polyethylene glycol in a mixer uniformly to obtain the total mixed particles.

Layer of nemaltevir:

the preparation method comprises the following steps:

1) After passing the prescribed amount of the compound dispersing agent through a 90-mesh sieve, the weight ratio of the compound dispersing agent is 3:5:12, glutamic acid, lecithin and polyvinylpyrrolidone according to 1g: adding 30ml of acetic acid solution, heating to 72 ℃, adding the prescription amount of nematolide Wei Jiaoban min to fully dissolve, then vacuum drying at 48 ℃ for 45h, grinding and sieving with a 80-mesh sieve to obtain a modified intermediate;

2) Uniformly mixing the modified intermediate with pregelatinized starch and low-substituted hydroxypropyl cellulose, performing dry granulation, and granulating with a 18-mesh screen;

3) And uniformly mixing the dry granulated particles with additional povidone K30 and magnesium stearate to obtain the total mixed particles.

The preparation process of the double-layer tablet comprises the following steps:

1) Adding ritonavir layer total mixed particles into a No. 1 feed inlet of a double-layer tablet press, adding nemat Wei Ceng total mixed particles into a No. 2 feed inlet, and tabletting the double-layer tablet;

2) Preparing 12% coating solution with hydroxypropyl cellulose (HPC), placing the bilayer tablet into a coating pan, preheating, and spraying slurry when the temperature of tablet bed reaches 40deg.C to obtain compound bilayer coated tablet.

Comparative example 1

A compound bilayer tablet prepared using the method of example 1 in publication No. CN114668737 a.

Comparative example 2

Ritonavir tablet layer total blend material was prepared using the process of example 1, the only difference being: no ammonium bicarbonate is added in step 1).

Comparative example 3

Ritonavir tablet layer total blend material was prepared using the process of example 1, the only difference being: particle diameter D of the particles D in step 1) ₉₀ 400 μm.

Experimental example 1 Effect of different binders on ritonavir adsorption Rate

Taking the adhesives listed in table 1 respectively, preparing a nemat Wei Ceng total mixture material according to the method of example 1 and taking the mixture material as a sample to be tested; precisely weighing a proper amount of sample to be measured, placing the sample into a 50ml measuring flask, and dissolving the sample in water with pH of 6.8 for 60min; diluting to scale, shaking, filtering, measuring by high performance liquid chromatography, calculating according to external standard method with peak area to obtain ritonavir content, and averaging three parallel groups.

TABLE 1 Effect of different binders on ritonavir adsorption Rate

As can be seen from table 1, when non-hydrophilic binders such as povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, calcium carbonate were used to prepare nematode Wei Ceng, the recovery of ritonavir was less than 93.5%; whereas the non-hydrophilic binder ethylcellulose, gum arabic, was used to prepare ritonavir layers, the recovery rates of ritonavir were 93.4% and 94.8%, respectively; when the ratio of the two is 1:1.5, the recovery rate of the Nemactetvir is 98.3 percent, which is obviously higher than that of other groups. Through data analysis, the hydrophilic adhesive has a certain adsorption effect on the main medicine, the recovery rate can not meet the requirement, and the adsorption on the main medicine can be effectively avoided when the non-hydrophilic adhesive is used and the specific proportion is combined, so that the recovery rate of the active ingredients is high, and the medicine effect is good.

Experimental example 2 Nemactetvir forced decomposition test

100mg of Nemactetvir (purity 96.3%) was accurately weighed out and placed in a 200 mL-volume flask, and 100mL of distilled water was added to the flask and dissolved. 5ml of pH adjustor or distilled water was added according to Table 2, and the mixture was left in an oven at 75℃for 2 hours to react, after which the pH was adjusted to neutral, and the content of the main drug was measured by ultraviolet rays.

Table 2 Effect of pH modulators on Nemactetvir stability

Group of	Additive agent	The content of the main medicine is%
			Group 1	Distilled water	92.1％
Group 2	0.1N HCl	93.6％
			Group 3	0.001N HCl	98.9％
Group 4	0.1N NaOH	75.4％
			Group 5	0.001N NaOH	86.7％

From table 2, it can be seen that nemaltevir is relatively stable under acidic conditions and unstable to decompose under neutral to alkaline pH conditions. It was confirmed that the nemaltevir was most stable at weakly acidic pH conditions.

Based on this, a composite dispersant was prepared according to the weak acid of the following table, and a nemortevir layer was prepared according to the method of example 1, and the content of nemortevir was measured by standing for 10 days at 60 ℃/75% RH, while setting three parallel average values for each group using nemortevir tablets of the pyroxalovid as a control, and the results are shown in Table 3.

TABLE 3 influence of different weak acids on Nemactetvir stability

Species of type	The content of the main medicine is%	Species of type	The content of the main medicine is%
				Tartaric acid	97.6	Boric acid	98.2
Fumaric acid	96.9	Aspartic acid	98.9
				Phenol (P)	97.3	Glutamic acid	99.0
Control	95.6	-	-

As can be seen from table 3, glutamic acid and aspartic acid as weak acids can further improve the stability of the nemaltevir; the possible reasons for this are: glutamic acid and aspartic acid as acidic amino acids, wherein the carboxyl group of the glutamic acid and aspartic acid can provide weak acidic environment for the active ingredient; meanwhile, the amino contained in the compound can form protection for the Namalite Wei Zheyi amine substances, so that the stability of the compound is further improved.

Experimental example 3 initial dissolution test

Tabletting ritonavir layer mixtures of example 1 and comparative examples 1 and 2 and ritonavir tablets sold in PAXLOVID respectively, heating and stirring 0.06mol/L polyoxyethylene 10 dodecyl ether solution (37.54 g to 900ml of polyoxyethylene 10 dodecyl ether) in water according to a dissolution rate measurement method (second method of second annex X C of 2010 edition), cooling to room temperature, adding water to 1000 ml) and controlling 900ml as a dissolution medium, wherein the rotation speed is 75rpm; filtering with 0.45 μm filter membrane at 15min, 30min, 60min, and 120min, and measuring dissolution rate by high performance liquid chromatography, wherein each group has 5 parallel averaging values, and the results are shown in Table 4.

TABLE 4 dissolution testing of different samples

As can be seen from table 4, the ritonavir sheet prepared in example 1 of the present application had good uniformity of initial dissolution relative to comparative example 1 and PAXLOVID. On one hand, the ammonium bicarbonate is added, so that the ammonium bicarbonate is heated and decomposed in the spray drying process to form a porous structure, and the influence of low solubility of ritonavir on dissolution is reduced; then coating the porous structure, and controlling the relative standard deviation of the initial dissolution degree by the coating material, the thickness and the using amount of the adhesive, wherein the comparative example 2; by controlling the particle diameter D90 < 200 μm after pretreatment, the fluctuation of the initial dissolution rate can be further reduced as compared with comparative example 3.

Stability analysis

The nemaltevir, ritonavir double-layer tablets prepared in examples 1-3 and comparative example 1 and the pamxlovid of the gabion were taken and placed at 60 ℃ and 75% humidity for 30 days for accelerated test, and the related substances of the samples were measured at the 0 th and 30 th months, and the results are shown in table 5.

TABLE 5 results of different time impurity determinations

As is clear from Table 5, the nemalt Wei Ceng in the bilayer tablet prepared in the present application had good stability by modifying the nemalt-West, relative to comparative example 1, commercially available PAXLOVID. Specifically, the application can lead the fat-soluble Nemactetvir to be dispersed in an amorphous state by adding the modifier consisting of the acidic amino acid, lecithin and polyvinylpyrrolidone to form a uniform dispersion; meanwhile, the added lecithin can effectively inhibit the aggregation trend of the Nemalide Wei Lizi, so that the Nemalide Wei Lizi is kept in an amorphous state with large specific surface area, and the dissolution rate of the Nemalide Wei Lizi is controllable and is consistent with that of a reference substance; meanwhile, the stability of the medicine is improved by adding acidic amino acid, so that the medicine can be effectively ensured to be stored for a long time.

Although the present application is disclosed above, the present application is not limited thereto. Various changes and modifications may be made by one skilled in the art without departing from the spirit and scope of the application, and the scope of the application should be assessed accordingly to that of the appended claims.

Claims (10)

1. The compound tablet of the Nemactetvir and the ritonavir is prepared by double-layer tabletting of materials corresponding to a Nemactetvir layer and a Nemactetvir layer, and is characterized in that the Nemactetvir layer is composed of the following raw materials: 280-320 parts of Nemadavir, 200-250 parts of composite dispersing agent, 60-100 parts of filler, 20-50 parts of disintegrating agent, 10-25 parts of adhesive and 2-3 parts of lubricant, wherein ritonavir Wei Ceng comprises 90-110 parts of ritonavir, 30-60 parts of filler, 6-10 parts of coating material, 40-100 parts of filler, 3-5 parts of lubricant and 200-300 parts of adhesive.

2. The Nemactevir and ritonavir compound tablet according to claim 1, wherein the compound dispersing agent is composed of the following raw materials in parts by weight: 3-5 parts of weak acid, 2-5 parts of lecithin and 5-12 parts of polyvinylpyrrolidone.

3. The compound tablet of nemaltavir and ritonavir according to claim 2, wherein the weak acid is at least one of tartaric acid, fumaric acid, boric acid, aspartic acid, glutamic acid and phenol.

4. The compound tablet of nemaltvir and ritonavir according to claim 1, wherein the binder in the ritonavir layer is at least one of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, calcium silicate, calcium carbonate, ethylcellulose, and gum arabic.

5. The preparation method of the compound tablet of nemaltevir and ritonavir as claimed in any one of claims 1 to 4, which is characterized by comprising the following steps:

s1, modifying, coating and mixing to obtain a material of a Nemactetvir layer;

s2, obtaining a ritonavir layer material through porosification treatment, dry granulation and total mixing;

s3, adding particles after total mixing of ritonavir layers into a No. 1 feed inlet of a double-layer tablet press, adding particles after total mixing of nemat Wei Ceng into a No. 2 feed inlet, and tabletting the double-layer tablet;

s4, coating the double-layer tablet.

6. The preparation method of the Nemactevir and ritonavir compound tablet according to claim 5, wherein the modification operation method in S1 is as follows:

s11, dissolving a prescription amount of ritonavir in an organic solvent to obtain a solution A;

s12, adding pore-forming agent into filling agent and lubricant according to the ratio of 4-10g to 1g to obtain a mixture B; s13, dissolving the mixture B in deionized water to obtain a solution C; adding the solution C into the solution A, and stirring at high speed for 6-15min to form emulsion;

s14, spray drying, wherein the feeding flow is controlled to be 8-14ml/min, and the gas flow rate is controlled to be 40-60m ³ And/h, obtaining the particles D at the outlet temperature of 40-50 ℃.

7. The preparation method of the Nemactevir and ritonavir compound tablet according to claim 6, wherein the particle diameter D of the particles D ₉₀ ＜200μm。

8. The method for preparing the compound tablet of Nemactevir and ritonavir as set forth in claim 6, wherein said pore-forming agent is ammonium bicarbonate.

9. The preparation method of the Nemactevir and ritonavir compound tablet according to claim 6, wherein the coating and total mixing operation method in the step S1 is as follows:

s15, placing the particles D into a fluidized bed granulating pot, preheating, spraying slurry when the temperature of the materials reaches 40-42 ℃, and controlling the flow rate of coating liquid with the mass concentration of 10-12% to be 40-60g/min to obtain pellets containing ritonavir;

s16, uniformly mixing the pellets with the filler, the lubricant and the adhesive.

10. The method for preparing the compound tablet of nemaltavir and ritonavir according to claim 5, wherein the step S2 comprises the following steps:

s21, sieving the compound dispersing agent with a 80-mesh sieve according to the prescription amount, wherein the weight of the compound dispersing agent is 1g: adding 30-50ml of acetic acid solution, heating to 65-75 ℃, adding the amount of the nemortevir, stirring for 20-50min to fully dissolve, vacuum drying, grinding and sieving with a 80-mesh sieve to obtain a modified intermediate;

s22, uniformly mixing the modified intermediate, the filler and the disintegrating agent, performing dry granulation, and finishing granules by a 18-mesh screen after granulating;

s23, uniformly mixing the granules after dry granulation with an external adhesive and a lubricant to obtain the composite material.