A combination tablet of nematamide and ritonavir and its preparation method

Abstract

This invention provides a nematidine and ritonavir combination tablet and its preparation method. The nematidine and ritonavir combination tablet is prepared by double-layer compression of materials corresponding to the ritonavir layer and the nematidine layer. The nematidine layer is composed of the following raw materials: 280-320 parts of nematidine, 200-250 parts of compound dispersant, 60-100 parts of filler, 20-50 parts of disintegrant, 10-25 parts of binder, and 2-3 parts of lubricant. The ritonavir layer is composed of 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 binder. The nematamide and ritonavir combination tablets of the present invention have small initial dissolution fluctuations, stable onset time and efficacy; at the same time, the excipients adsorb less of the active ingredients, resulting in high drug recovery rate, good efficacy and good stability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and more specifically, to a nematradivir / ritonavir compound tablet and its preparation method. Background Technology

[0002] Coronaviruses are a large family of viruses that began affecting humans in 1965; they have since caused three major epidemics: Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and the novel coronavirus infection COVID-19.

[0003] Gilead's remdesivir, a small-molecule broad-spectrum antiviral drug, was officially approved for marketing in October 2020 as the first treatment for COVID-19; Merck's Molnupiravir and Pfizer's Paxlovid followed suit in November 2021. Paxlovid has reportedly reduced the risk of hospitalization or death in patients with mild to moderate COVID-19 by approximately 89%, attracting significant attention within the industry.

[0004] Paxlovid is a combination formulation of nelmatvir film-coated immediate-release tablets and ritonavir tablets. Ritonavir is an HIV-1 protease inhibitor that helps slow the metabolism or breakdown of nelmatvir. The combination enhances nelmatvir's antiviral activity tenfold. The recommended dose is 300 mg nelmatvir (150 mg x 2 tablets) combined with 100 mg ritonavir (100 mg x 1 tablet), orally every 12 hours for 5 days. However, Paxlovid requires simultaneous administration of both drugs, which can be difficult for patients to take and increases the risk of missed or incorrect doses, affecting efficacy. To address this, Chinese Patent Application No. 202210200071.0 discloses a compound bilayer tablet containing ritonavir microspheres for the treatment of novel coronavirus. The tablet is a bilayer compound tablet containing microspheres, and the active ingredients are ritonavir and Nirmatrelvir. This approach can increase the convenience of drug carrying and taking, and improve patient compliance. However, it also has shortcomings such as poor initial dissolution uniformity and low dissolution rate, resulting in an unsatisfactory antiviral effect.

[0005] In view of this, the present invention is hereby proposed. Summary of the Invention

[0006] The problem solved by this invention is that the initial dissolution rate of ritonavir in existing nematradivir / ritonavir combination tablets fluctuates greatly and the total dissolution rate needs to be improved.

[0007] To address the aforementioned problems, this invention provides a nematidine and ritonavir combination tablet, which is prepared by double-layer compression of materials corresponding to the ritonavir layer and the nematidine layer. The nematidine layer is composed of the following raw materials: 280-320 parts of nematidine, 200-250 parts of a compound dispersant, 60-100 parts of a filler, 20-50 parts of a disintegrant, 10-25 parts of a binder, and 2-3 parts of a lubricant. The ritonavir layer is composed of 90-110 parts of ritonavir, 30-60 parts of a filler, 6-10 parts of a coating material, 40-100 parts of a filler, 3-5 parts of a lubricant, and 200-300 parts of a binder.

[0008] Preferably, the nematevir layer is composed of the following raw materials: 300 parts nematevir, 240 parts composite dispersant, 90 parts filler, 20 parts disintegrant, 25 parts binder, and 2 parts lubricant; and the ritonavir layer is composed of 100 parts ritonavir, 60 parts filler, 7 parts coating material, 40 parts filler, 5 parts lubricant, and 240 parts binder.

[0009] Preferably, the composite dispersant 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.

[0010] Preferably, the weak acid is at least one selected from tartaric acid, fumaric acid, boric acid, aspartic acid, glutamic acid, and phenol. Preferably, the weak acid is either aspartic acid or glutamic acid.

[0011] Preferably, the binder in the ritonavir layer is at least one selected from povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, calcium silicate, calcium carbonate, ethyl cellulose, and gum arabic. Preferably, the binder consists of 1 part ethyl cellulose and 1.5 parts gum arabic.

[0012] Preferably, the preparation method of nematvir / ritonavir combination tablets includes:

[0013] S1. The material obtained by modification, coating, and mixing of the Nematote layer;

[0014] S2. The material of ritonavir layer is obtained by porousing treatment, dry granulation and total mixing;

[0015] S3. Add the ritonavir granules after mixing the layers to the No. 1 feed port of the double-layer tableting machine, and add the namatevir granules after mixing the layers to the No. 2 feed port for double-layer tableting.

[0016] S4. Coat the double-layer film.

[0017] Preferably, the modification method in S1 is as follows:

[0018] S11. Dissolve the prescribed amount of ritonavir in an organic solvent to obtain solution A;

[0019] S12. Add pore-forming agent to the filler and lubricant in the prescribed amount at a ratio of 4-10g:1g to obtain mixture B; S13. Dissolve mixture B in deionized water to obtain solution C; Add solution C to solution A and stir at high speed for 6-15 minutes to form an emulsion;

[0020] S14. Spray drying, controlling the feed flow rate at 8-14 ml / min and the gas flow rate at 40-60 m / min. 3 / h, with an outlet temperature of 40-50℃, microparticles D are obtained.

[0021] Preferably, the particle size D of the particle D is... 90 <200μm.

[0022] Preferably, the pore-forming agent is ammonium bicarbonate.

[0023] Preferably, the coating and mixing operations in step S1 are as follows:

[0024] S15. Place the particles D into a fluidized bed granulation pot, preheat it, and when the material temperature reaches 40-42℃, spray it with slurry, and control the flow rate of the coating liquid with a mass concentration of 10-12% to 40-60 g / min to obtain microcapsules containing ritonavir.

[0025] S16. Mix the micro-pellets with the filler, lubricant and binder to obtain the final product.

[0026] Preferably, step S2 includes the following steps:

[0027] S21. Pass the prescribed amount of compound dispersant through an 80-mesh sieve, add it to acetic acid solution at a ratio of 1g:30-50ml, heat to 65-75℃, then add the prescribed amount of nematidine and stir for 20-50 minutes to fully dissolve it, vacuum dry and grind it through an 80-mesh sieve to obtain the modified intermediate;

[0028] S22. Mix the modified intermediate with the filler and disintegrant evenly, perform dry granulation, and then granulate through an 18-mesh sieve.

[0029] S23. Mix the dry-granulated granules with the added binder and lubricant until homogeneous to obtain the final product.

[0030] Compared with the prior art, the nematidine and ritonavir compound tablets and their preparation method described in this invention have the following beneficial effects: 1) Adding a pore-forming agent to ritonavir for porous treatment and coating, and controlling the dissolution rate by the coating material, dosage, and binder, reduces the adverse effect of ritonavir's low solubility on the initial dissolution, while controlling the particle size to further reduce the fluctuation of the initial dissolution, thereby ensuring the onset time and efficacy stability of the oral solid dosage form; 2) Adding a specific combination of non-hydrophilic binders can reduce the adsorption of ritonavir, resulting in high drug recovery rate and good efficacy; 3) Adding a dispersant keeps nematidine in an amorphous state, which is beneficial for dissolution; and adding a weak acid, especially an acidic amino acid, can further improve the stability of nematidine in the compound tablets. Detailed Implementation

[0031] The present invention will be described below through specific embodiments to make the technical solutions of the present invention easier to understand and master, but the present invention is not limited thereto. Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods; the equipment, reagents, and materials described are all commercially available unless otherwise specified. The technical features of each embodiment in the present invention can be combined accordingly without mutual conflict.

[0032] Dissolution homogeneity is used to examine the variability in the rate and extent of product dissolution. Controlling dissolution homogeneity helps reduce differences in dissolution rate and extent among different products, thereby reducing variations in drug absorption rate caused by formulation factors. This is crucial for ensuring stable onset time of oral solid dosage forms. Some excipients interact with the active pharmaceutical ingredient (API), such as adsorbing the API, leading to incomplete dissolution and thus affecting efficacy. Based on the above issues, the applicant proposes the following solution:

[0033] Example 1

[0034] Litonavir layer:

[0035]

[0036]

[0037] Its preparation method is as follows:

[0038] 1) Dissolve the prescribed amount of ritonavir in butyl acetate at a ratio of 1g:50ml to obtain solution A; add the prescribed amount of lactose to ammonium bicarbonate at a ratio of 12g:1g to obtain mixture B; dissolve mixture B in deionized water at a ratio of 1g:10ml to obtain solution C; add solution C to solution A and stir at 12000rpm for 4min; spray dry the obtained emulsion to obtain microparticles D, with a feed flow rate of 12ml / min, a gas flow rate of 55m3 / h, and an outlet temperature of 42℃, controlling the average particle size D of microparticles D. 90 =195μm.

[0039] 2) Prepare a coating solution with a concentration of 18%, put the particles D into a fluidized bed granulation pot, preheat it, and when the material temperature reaches 40°C, spray the granules, control the material temperature to be about 40°C, and the flow rate of the coating solution to be 40 g / min to obtain microcapsules containing ritonavir.

[0040] 3) Mix the micro-pellets with pregelatinized starch, talc, and ethyl cellulose in a mixer until homogeneous to obtain the total mixed granules.

[0041] Naimatwe Layer:

[0042]

[0043] Its preparation method is as follows:

[0044] 1) After passing the prescribed amount of nematidine and the compound dispersant through a 90-mesh sieve, the compound dispersant, which is composed of aspartic acid, lecithin and polyvinylpyrrolidone in a weight ratio of 4:2:5, was added to a dimethyl sulfoxide solution at a ratio of 1g:60ml. The mixture was heated to 70℃ and then the prescribed amount of nematidine was added and stirred for 40min to dissolve it completely. The mixture was then vacuum dried at 50℃ for 48h and finely ground through an 80-mesh sieve to obtain the modified intermediate.

[0045] 2) After the modified intermediate is mixed evenly with microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, it is dry granulated and then granulated through an 18-mesh sieve.

[0046] 3) Mix the dry-granulated granules with the added cross-linked sodium carboxymethyl cellulose and magnesium stearate evenly to obtain the total mixed granules.

[0047] Bilayer wafer fabrication process:

[0048] 1) Add the ritonavir granules after mixing the layers to the No. 1 feed port of the double-layer tableting machine, and add the namatevir granules after mixing the layers to the No. 2 feed port for double-layer tableting;

[0049] 2) Prepare a 12% coating solution using cellulose acetate phthalate (CAP), place the double-layer tablets into a coating pan, preheat, and spray the solution when the tablet bed temperature reaches 40°C to obtain compound double-layer coated tablets.

[0050] Example 2

[0051] Litonavir layer:

[0052]

[0053]

[0054] Its preparation method is as follows:

[0055] 1) Dissolve the prescribed amount of ritonavir in ethyl acetate at a ratio of 1 g: 40 ml to obtain solution A; add the prescribed amount of pregelatinized starch to ammonium bicarbonate at a ratio of 8 g: 1 g to obtain mixture B; dissolve mixture B in deionized water at a ratio of 1 g: 12 ml to obtain solution C; add solution C to solution A and stir at 9000 rpm for 6 min; spray dry the obtained emulsion to obtain microparticles D at a feed flow rate of 10 ml / min and a gas flow rate of 52 m / s. 3 / h, outlet temperature is 44℃, control the average particle size D of particles D 90 It is 180μm.

[0056] 2) Prepare a 15% coating solution, put the particles D into a fluidized bed granulation pot, preheat, and spray the material when the material temperature reaches 41°C. Control the material temperature to be about 41°C and the coating solution flow rate to be 45 g / min to obtain microparticles containing ritonavir.

[0057] 4) Mix the micro-pellets with microcrystalline cellulose, sodium fumarate stearate, and polyvinylpyrrolidone in a mixer until homogeneous to obtain the total mixed granules.

[0058] Naimatwe Layer:

[0059]

[0060] Its preparation method is as follows:

[0061] 1) After passing the prescribed amount of the compound dispersant through a 90-mesh sieve, the compound dispersant, which consists of glutamic acid, lecithin and polyvinylpyrrolidone in a weight ratio of 5:2:9, is added to an acetic acid solution at a ratio of 1g:50ml. After heating to 72℃, the prescribed amount of nermatimivir is added and stirred for 30min to dissolve it completely. Then, it is vacuum dried at 48℃ for 45h, finely ground and passed through an 80-mesh sieve to obtain the modified intermediate.

[0062] 4) After the modified intermediate is mixed evenly with calcium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, it is dry granulated and then granulated through an 18-mesh sieve.

[0063] 5) Mix the dry-granulated granules with the added hydroxypropyl methylcellulose and sodium stearate fumarate evenly to obtain the total mixed granules.

[0064] Bilayer wafer fabrication process:

[0065] 1) Add the ritonavir granules after mixing the layers to the No. 1 feed port of the double-layer tableting machine, and add the namatevir granules after mixing the layers to the No. 2 feed port for double-layer tableting;

[0066] 2) Prepare a 12% coating solution using hydroxypropyl methylcellulose phthalate (HPMCP), place the double-layer tablets into a coating pan, preheat, and spray the solution when the tablet bed temperature reaches 40°C to obtain compound double-layer coated tablets.

[0067] Example 3

[0068] Litonavir layer:

[0069]

[0070]

[0071] Its preparation method is as follows:

[0072] 1) Dissolve the prescribed amount of ritonavir in ethyl acetate at a ratio of 1g:40ml to obtain solution A; add the prescribed amount of sorbitol and lubricant to ammonium bicarbonate at a ratio of 6g:1g to obtain mixture B; dissolve mixture B in deionized water at a ratio of 1g:8ml to obtain solution C; add solution C to solution A and stir at 10000rpm for 8min; spray dry the obtained emulsion to obtain microparticles D at a feed flow rate of 9ml / min and a gas flow rate of 50m. 3 / h, outlet temperature is 42℃, control the average particle size D of particles D 90 It is 200μm.

[0073] 2) Prepare a 12% coating solution, put the particles D into a fluidized bed granulation pot, preheat it, and when the material temperature reaches 41°C, spray the granules, control the material temperature to about 41°C, and the coating solution flow rate to 48 g / min to obtain microcapsules containing ritonavir.

[0074] 5) Mix the micro-pellets with lactitol, gum arabic, ethyl cellulose and the remaining polyethylene glycol in a mixer until homogeneous to obtain the total mixed granules.

[0075] Naimatwe Layer:

[0076]

[0077]

[0078] Its preparation method is as follows:

[0079] 1) After passing the prescribed amount of the compound dispersant through a 90-mesh sieve, the compound dispersant, which consists of glutamic acid, lecithin and polyvinylpyrrolidone in a weight ratio of 3:5:12, is added to an acetic acid solution at a ratio of 1g:30ml. After heating to 72℃, the prescribed amount of nermatimivir is added and stirred for 30min to fully dissolve it. Then, it is vacuum dried at 48℃ for 45h, finely ground and passed through an 80-mesh sieve to obtain the modified intermediate.

[0080] 2) After the modified intermediate is mixed evenly with pregelatinized starch and low-substituted hydroxypropyl cellulose, it is dry granulated and then granulated through an 18-mesh sieve.

[0081] 3) Mix the dry-granulated granules with added povidone K30 and magnesium stearate evenly to obtain the total mixed granules.

[0082] Bilayer wafer fabrication process:

[0083] 1) Add the ritonavir granules after mixing the layers to the No. 1 feed port of the double-layer tableting machine, and add the namatevir granules after mixing the layers to the No. 2 feed port for double-layer tableting;

[0084] 2) Prepare a 12% coating solution using hydroxypropyl cellulose (HPC), place the double-layer tablets into a coating pan, preheat, and spray the solution when the tablet bed temperature reaches 40°C to obtain compound double-layer coated tablets.

[0085] Comparative Example 1

[0086] The compound bilayer tablets were prepared using the method described in Example 1 of Publication No. CN114668737A.

[0087] Comparative Example 2

[0088] The ritonavir tablets were prepared using the process method of Example 1, with the only difference being that ammonium bicarbonate was not added in step 1).

[0089] Comparative Example 3

[0090] The ritonavir tablets were prepared using the process described in Example 1, with the only difference being the particle size D of the microparticles D in step 1). 90 It is 400μm.

[0091] Experimental Example 1: Effect of Different Adhesives on the Adsorption Rate of Ritonavir

[0092] Take the adhesives listed in Table 1 and prepare the ritonavir layer mixture according to the method in Example 1 as the test samples; accurately weigh an appropriate amount of the test sample, place it in a 50 ml volumetric flask, dissolve it in pH 6.8 water for 60 min; dilute to the mark, shake well, filter, and determine by high performance liquid chromatography. Calculate the ritonavir content by peak area according to the external standard method. Set up three parallels for each group and take the average value.

[0093] Table 1. Effect of different adhesives on ritonavir adsorption rate

[0094]

[0095] Table 1 shows that when non-hydrophilic binders such as povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and calcium carbonate were used to prepare the nitrazepam layer, the recovery rate of ritonavir was below 93.5%. However, when non-hydrophilic binders ethyl cellulose and gum arabic were used, the recovery rates of ritonavir were 93.4% and 94.8%, respectively. When the two were mixed in a 1:1.5 ratio, the recovery rate of nitrazepam was 98.3%, significantly higher than the other groups. Data analysis indicates that hydrophilic binders have a certain adsorption effect on the active pharmaceutical ingredient, resulting in insufficient recovery rates. In contrast, using non-hydrophilic binders in specific proportions effectively avoids adsorption of the active pharmaceutical ingredient, leading to high recovery rates and better efficacy.

[0096] Experimental Example 2: Nematoves Forced Decomposition Test

[0097] Accurately weigh 100 mg of nematvir (96.3% purity) and place it in a 200 mL flask. Add 100 mL of distilled water to the flask to dissolve it. Add 5 mL of pH adjuster or distilled water according to Table 2, and place the flask in a 75°C oven for 2 hours to allow the reaction to proceed. Then adjust the pH to neutral and detect the active pharmaceutical ingredient content using ultraviolet light.

[0098] Table 2 Effect of pH adjuster on the stability of nematidine

[0099] Group additive % of main drug content Group 1 distilled water 92.1％ 2 groups 0.1N HCl 93.6％ 3 groups 0.001N HCl 98.9％ 4 groups 0.1N NaOH 75.4％ 5 groups 0.001N NaOH 86.7％

[0100] Table 2 shows that nematevir is relatively stable under acidic conditions, but unstable and decomposes under neutral to alkaline pH conditions. This confirms that nematevir is most stable under weakly acidic pH conditions.

[0101] Based on this, a composite dispersant was prepared using the weak acid listed in the table below, and a nematribine layer was prepared according to the method in Example 1. The nematribine content was determined after being placed at 60℃ / 75%RH for 10 days. Pfizer PAXLOVID nematribine tablets were used as a control. Three parallels were set up for each group and the average value was taken. The results are shown in Table 3.

[0102] Table 3. Effects of different weak acids on the stability of nematidine

[0103] type % of main drug content type % of main drug content tartaric acid 97.6 boric acid 98.2 fumaric acid 96.9 Aspartic acid 98.9 phenol 97.3 glutamic acid 99.0 Comparison 95.6 - -

[0104] As shown in Table 3, glutamic acid and aspartic acid, as weak acids, can further improve the stability of nematidine. The possible reason is that glutamic acid and aspartic acid, as acidic amino acids, contain carboxyl groups that can provide a weakly acidic environment for the active ingredient; at the same time, their amino groups can protect nematidine, an amine substance, and further improve its stability.

[0105] Experimental Example 3 Initial Dissolution Detection

[0106] Ritonavir mixtures from Examples 1, 1, and 2 were compressed into tablets, as well as commercially available PAXLOVID ritonavir tablets. Dissolution was determined according to the method described in Appendix XC, Method 2 of the 2010 edition of the Chinese Pharmacopoeia, Part II. A 0.06 mol / L polyoxyethylene 10-dodecyl ether solution (37.54 g of polyoxyethylene 10-dodecyl ether was added to 900 ml of water, heated, stirred until completely dissolved, cooled to room temperature, and then water was added to 1000 ml) was used as the dissolution medium, with a rotation speed of 75 rpm. After 15 min, 30 min, 60 min, and 120 min, appropriate amounts of the solution were taken, filtered through a 0.45 μm filter membrane, and the dissolution rate was determined by high-performance liquid chromatography (HPLC). Five replicates were set up for each group, and the average value was calculated. The results are shown in Table 4.

[0107] Table 4 Dissolution test results for different samples

[0108]

[0109]

[0110] As shown in Table 4, compared with Comparative Example 1 and PAXLOVID, the ritonavir tablets prepared in Example 1 of this application exhibit good uniformity in initial dissolution. On one hand, this application reduces the impact of ritonavir's low solubility on dissolution by adding ammonium bicarbonate, which decomposes thermally during spray drying to form a porous structure. Subsequently, the porous structure is coated, and the relative standard deviation of the initial dissolution is controlled by the amount of coating material, thickness, and binder used (see Comparative Example 2). Compared with Comparative Example 3, controlling the pretreated particle size D90 < 200 μm further reduces fluctuations in initial dissolution.

[0111] Stability analysis

[0112] Nematovir and ritonavir bilayer tablets prepared in Examples 1-3 and Comparative Example 1, as well as Pfizer's PAXLOVID, were placed at 60°C and 75% humidity for 30 days for accelerated testing. Related substances in the samples were measured on days 0 and 30. The results are shown in Table 5.

[0113] Table 5. Results of impurity determination at different times

[0114]

[0115]

[0116] As shown in Table 5, compared to Comparative Example 1 and commercially available PAXLOVID, the nelmatidine layer in the bilayer tablets prepared in this application exhibits good stability due to modification of nelmatidine. Specifically, this application utilizes a modifier composed of acidic amino acids, lecithin, and polyvinylpyrrolidone to disperse the lipid-soluble nelmatidine in an amorphous state, forming a uniform dispersion. Simultaneously, the added lecithin effectively inhibits the aggregation tendency of nelmatidine particles, maintaining them in an amorphous state with a large specific surface area, ensuring controllable dissolution consistent with the reference standard. Furthermore, the addition of acidic amino acids enhances stability, effectively guaranteeing long-term drug storage.

[0117] While the present invention has been disclosed above, it is not limited thereto. Any person skilled in the art can make various modifications and alterations without departing from the spirit and scope of the invention; therefore, the scope of protection of the present invention should be determined by the scope defined in the claims.

Claims

1. A compound tablet of nirmatrelvir and ritonavir, which is prepared by double-layer compression of a material corresponding to a ritonavir layer and a nirmatrelvir layer, characterized in that, The nematevir layer is composed of the following raw materials in parts by weight: 280-320 parts nematevir, 200-250 parts composite dispersant, 60-100 parts filler, 20-50 parts disintegrant, 10-25 parts binder, and 2-3 parts lubricant; the ritonavir layer is composed of 90-110 parts ritonavir, 30-60 parts filler, 6-10 parts coating material, 40-100 parts filler, 3-5 parts lubricant, and 200-300 parts binder. The composite dispersant 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; The weak acid is either aspartic acid or glutamic acid. The adhesive for the ritonavir layer is composed of ethyl cellulose and gum arabic in a weight ratio of 1:1.

5. The preparation method of the nematradivir and ritonavir combination tablets includes: S1. Obtaining the Nematofil layer material through modification, dry granulation, and total mixing; Step S1 includes the following steps: S11. Pass the prescribed amount of compound dispersant through an 80-mesh sieve, add it to acetic acid solution at a ratio of 1g:30-50ml, heat to 65-75℃, then add the prescribed amount of nermatimivir and stir for 20-50 minutes to fully dissolve it. Vacuum dry and grind it into a fine powder, passing it through an 80-mesh sieve to obtain the modified intermediate. S12. Mix the modified intermediate with the filler and disintegrant evenly, perform dry granulation, and then granulate through an 18-mesh sieve. S13. Mix the dry-granulated granules with the added binder and lubricant until homogeneous to obtain the final product. S2. The material obtained by porousing, coating and mixing to obtain the ritonavir layer; S3. Add the ritonavir granules after mixing the layers to the No. 1 feed port of the double-layer tableting machine, and add the namatevir granules after mixing the layers to the No. 2 feed port for double-layer tableting. S4. Coating the double-layer film; The method for the porousification process in S2 is as follows: S21. Dissolve the prescribed amount of ritonavir in an organic solvent to obtain solution A; S22. Add a pore-forming agent, which is ammonium bicarbonate, to the filler and lubricant in the prescription amount at a ratio of 4-10g:1g to obtain mixture B; S23. Dissolve mixture B in deionized water to obtain solution C; add solution C to solution A and stir at high speed for 6-15 minutes to form an emulsion; S24. Spray drying, controlling the feed flow rate to 8-14 ml / min, the gas flow rate to 40-60 m3 / h, and the outlet temperature to 40-50℃ to obtain particulate D; The particle size D90 of the particle D is less than 200 μm.

2. The nematamide and ritonavir combination tablets according to claim 1, characterized in that, The coating and mixing procedures in step S2 are as follows: S25. Place the particles D into a fluidized bed granulation pot, preheat it, and when the material temperature reaches 40-42℃, spray it with slurry, and control the flow rate of the coating liquid with a mass concentration of 10-12% to 40-60 g / min to obtain microcapsules containing ritonavir. S26. Mix the micro-pellets with fillers, lubricants and binders to obtain the final product.

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