EIDD-1931 sustained-release agent and preparation method thereof

Abstract

The invention provides an EIDD-1931 sustained-release preparation and a preparation method thereof, and belongs to the technical field of medical preparations, and the EIDD-1931 sustained-release preparation is prepared by uniformly mixing EIDD-1931, hydroxypropyl methyl cellulose K15M, polyvinylpyrrolidone K23-27, carbomer, sodium bicarbonate, a flow aid and a filler and tabletting. By preparing the antiviral drug sustained-release agent for cats, the half-life period of EIDD-1931 in plasma of cats is prolonged, the EIDD-1931 only needs to be administered once in one day, the drug feeding difficulty of pet owners is reduced, and the compliance of the pet owners is improved, so that the treatment effect after animal virus infection is improved, the recurrence rate is reduced, and the animal survival treatment and animal welfare are improved.

Description

Technical Field

[0001] This invention relates to the field of medical preparations technology, and in particular to an EIDD-1931 sustained-release agent and its preparation method. Background Technology

[0002] EIDD-1931 (NHC), chemically named N-hydroxycytidine, is an oral medication used to treat feline calicivirus infection. It is considered a promising calicivirus inhibitor, demonstrating a high average IC50 against a variety of viruses. 50 The value is 0.15 μM activity.

[0003] Existing research indicates that when EIDD-1931 is administered to cats at a dose of 10 mg / kg, the average elimination half-life is 0.71 hours, requiring 2-3 doses per day to achieve a therapeutic effect. This suggests that the current EIDD-1931 regimen requires frequent dosing, making administration difficult for pet owners and resulting in poor long-term adherence.

[0004] The present invention aims to prepare an EIDD-1931 sustained-release formulation that only needs to be administered once a day using a gastric floating sustained-release system, so as to reduce the frequency of administration and enhance the pet owner's long-term adherence to administration. Summary of the Invention

[0005] To address the above problems, this invention provides an EIDD-1931 sustained-release agent and its preparation method.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: An EIDD-1931 sustained-release formulation, by weight, is formulated as follows: Main drug: EIDD-1931, 40 doses; Excipients: 39-41 parts of hydroxypropyl methylcellulose K15M, 2-6 parts of polyvinylpyrrolidone K23-27, 9-11 parts of carbomer, 1.9-2.0 parts of sodium bicarbonate, 0.5-0.6 parts of flow aid, and the balance of filler.

[0007] Furthermore, the formulation of the EIDD-1931 sustained-release agent, by weight, is as follows: Main drug: EIDD-1931, 40 doses; Excipients: 40 parts of hydroxypropyl methylcellulose K15M, 2-6 parts of polyvinylpyrrolidone K23-27, 10 parts of carbomer, 2 parts of sodium bicarbonate, 0.5 parts of flow aid, and the remainder of filler.

[0008] Furthermore, the formulation of the EIDD-1931 sustained-release agent, by weight, is as follows: Main drug: EIDD-1931, 40 doses; Excipients: 40 parts hydroxypropyl methylcellulose K15M, 2 parts polyvinylpyrrolidone K23-27, 10 parts carbomer, 2 parts sodium bicarbonate, 0.5 parts flow aid, and the remainder filler.

[0009] Furthermore, the formulation of the EIDD-1931 sustained-release agent, by weight, is as follows: Main drug: EIDD-1931, 40 doses; Excipients: 40 parts hydroxypropyl methylcellulose K15M, 6 parts polyvinylpyrrolidone K23-27, 10 parts carbomer, 2 parts sodium bicarbonate, 0.5 parts flow aid, and the remainder filler.

[0010] Furthermore, the filler is at least one of microcrystalline cellulose, compressible starch, dextrin, and powdered sugar.

[0011] Furthermore, the flow aid is at least one of silica, talc, and magnesium stearate.

[0012] A method for preparing an EIDD-1931 sustained-release formulation, wherein the preparation method is to weigh the active pharmaceutical ingredient and excipients according to the above-mentioned EIDD-1931 sustained-release formulation, mix them evenly, compress them into tablets, and prepare the EIDD-1931 sustained-release formulation.

[0013] Furthermore, the specific process of the preparation method is as follows: take EIDD-1931, hydroxypropyl methylcellulose K15M, polyvinylpyrrolidone K23-27, carbomer, sodium bicarbonate and filler, premix and sieve, add glidant and mix thoroughly, sieve, dry granulate, compress into tablets, and obtain EIDD-1931 sustained-release agent.

[0014] Furthermore, before preparing the EIDD-1931 sustained-release agent, the active pharmaceutical ingredient and each excipient are pulverized and sieved.

[0015] The beneficial effects of the EIDD-1931 sustained-release agent and its preparation method of the present invention are as follows: Since there are currently no new oral veterinary drugs related to EIDD-1931 in China, and compared to the existing raw material drug's half-life of 0.71 hours, this invention prepares a sustained-release antiviral drug for cats, which significantly prolongs the half-life of EIDD-1931 in cat plasma, requiring only one dose per day. This reduces the difficulty of administering the drug to pet owners, improves their compliance, and thus improves the treatment effect after viral infection in animals, reduces the recurrence rate, and enhances animal survival and welfare. The EIDD-1931 sustained-release formulation prepared by this invention has few side effects, and no obvious adverse reactions were observed after administration, demonstrating high safety. Attached Figure Description

[0016] Figure 1 This is a process route diagram for preparing the EIDD-1931 sustained-release agent of the present invention; Figure 2 This is the cumulative release percentage of EIDD-1931 sustained-release tablets with three different HPMC viscosities in Example 1 of this invention; Figure 2 K4M represents EIDD-1931 sustained-release agent made from HPMC with viscosity K4M, K15M represents EIDD-1931 sustained-release agent made from HPMC with viscosity K15M, and K100M represents EIDD-1931 sustained-release agent made from HPMC with viscosity K100M. Figure 3 This is the cumulative release percentage of EIDD-1931 sustained-release tablets made from PVP of different viscosities in Example 1 of this invention; Figure 3 K16-18 represents EIDD-1931 sustained-release tablets made using PVP K16-18, K23-27 represents EIDD-1931 sustained-release tablets made using PVP K23-27, and K29-32 represents EIDD-1931 sustained-release tablets made using PVP K29-32. Figure 4 This represents the cumulative release percentage of sustained-release tablets made with different amounts of carbomer in Example 1 of this invention; Figure 4 10% carbomer means that the sustained-release tablet is made when carbomer accounts for 10% of the total weight; 5% carbomer means that the sustained-release tablet is made when carbomer accounts for 5% of the total weight; 0% carbomer means that the sustained-release tablet is made when carbomer accounts for 0% of the total weight. Figure 5 It is the cumulative release percentage of the sustained-release tablets prepared in the process of "IV. Prescription Optimization: Full Factor Analysis" in Example 1 of this invention; Figure 5 In the table, 1 through 8 represent sustained-release tablets made from prescriptions 1 through 8, respectively. Figure 6 This is a comparison of the sustained-release effects of the optimized formulation (formulation 8) of EIDD-1931 sustained-release tablets prepared in Examples 4, 5, 6, and 7 of this invention with that prepared in Example 1; Figure 6 In the text, 1 represents the EIDD-1931 sustained-release tablet prepared in Example 4, 2 represents the EIDD-1931 sustained-release tablet prepared in Example 6, 3 represents the EIDD-1931 sustained-release tablet prepared in Example 5, 4 represents the EIDD-1931 sustained-release tablet prepared in Example 7, and the optimized final formulation represents the EIDD-1931 sustained-release tablet prepared in Formulation 8 of Example 1. Figure 7 This is the drug-time curve of a cat after a single oral administration of EIDD-1931 sustained-release formulation in Example 8 of this invention; Figure 8 This is the drug-time curve of a cat after a single oral administration of EIDD-1931 active pharmaceutical ingredient in Example 8 of this invention. Detailed Implementation

[0017] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art can make similar extensions without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0018] This invention protects an EIDD-1931 sustained-release agent and its preparation method, wherein the formulation of the EIDD-1931 sustained-release agent, by weight, comprises: ①Main drug: EIDD-1931 40 doses; ② Excipients: 39-41 parts of sustained-release skeleton hydroxypropyl methylcellulose K15M (HPMC K15M), 2-6 parts of binder polyvinylpyrrolidone K23-27 (PVP K23-27), 9-11 parts of sustained-release skeleton carbomer (CP), 1.9-2.1 parts of foaming agent sodium bicarbonate (NaHCO3), 0.4-0.6 parts of flow aid magnesium stearate (MS), and the balance filler microcrystalline cellulose (MCC).

[0019] The preparation method of EIDD-1931 sustained-release formulation is as follows: Figure 1 As shown, it includes the following steps: Take EIDD-1931 and each excipient and pass them through a 50-70 mesh sieve for later use; Weigh out the following amounts according to the prescription: EIDD-1931, HPMC, PVP, MCC, and NaHCO3. MS and carbomer are mixed evenly (i.e., EIDD-1931, HPMC, PVP, MCC, NaHCO3 and carbomer are premixed, sieved, and then the gliding agent MS is added and mixed evenly). The mixture is passed through a 40-mesh sieve, dry granulated, and compressed into EIDD-1931 sustained-release tablets with a diameter of 6 mm and a tablet weight of about 125 mg on a single punch tablet press. Each tablet contains 50 mg of EIDD-1931.

[0020] Example 1: Screening of excipients I. Sustained-release matrix material: Viscosity screening of hydroxymethylpropyl cellulose (HPMC) Using HPMC as the hydrophilic gel backbone material, the effects of HPMC K4M (molecular weight 400,000, viscosity 2700~5040 mPa) on various parameters were investigated. s), HPMC K15M (molecular weight 575,000, viscosity 13,500~25,200 mPa) s), HPMC K100M (molecular weight 1,000,000, viscosity 75,000~140,000 mPa) s) Three types of HPMC with different viscosities were screened, and EIDD-1931 sustained-release agents with three different HPMC viscosities were prepared according to the formulation in Table 1 and the preparation method below. The specific formulations are as follows: Table 1. List of formulations for different HPMC viscosities

[0021] The methods for producing EIDD-1931 sustained-release agents with three different HPMC viscosities are as follows: Take EIDD-1931 and each excipient and pass them through a 60-mesh sieve for later use; Weigh out EIDD-1931 and all excipients according to the prescription, mix them evenly, granulate them by dry granulation through a 40-mesh sieve, and compress them into EIDD-1931 sustained-release tablets with a diameter of 6mm and a tablet weight of about 125mg on a single punch tablet press. Each tablet contains 50mg of EIDD-1931.

[0022] The cumulative release rates of EIDD-1931 sustained-release tablets with three different HPMC viscosities were determined at 0h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h, and release curves were plotted and compared. Specific results are shown in Table 2 and [Table data missing]. Figure 2 The method for determining the cumulative release rate of EIDD-1931 sustained-release tablets with three different HPMC viscosities is as follows: Referring to Method II (slurry method) of Dissolution Determination in Appendix II of the 2020 edition of the Chinese Pharmacopoeia, 500 mL of 0.1 N HCl was selected as the release medium. The temperature was set at 38.5 ± 0.5 °C, and the rotation speed was 50 rpm. 2 mL samples were taken at 0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h, and immediately after each sampling, 2 mL of the same temperature release medium was added to the dissolution system. The sampled liquid was filtered through a 0.45 μm filter membrane, and an appropriate amount of the filtrate was transferred to a sample vial. High-resolution liquid chromatography-mass spectrometry (LC-MS) was used for analysis. The peak area of ​​EIDD-1931 was recorded, and the corresponding concentration was calculated. The cumulative release percentage was then calculated using this concentration.

[0023] Table 2. Cumulative release rates of EIDD-1931 sustained-release tablets with different HPMC viscosities

[0024] Depend on Figure 2As shown in Table 2, the cumulative release rate of EIDD-1931 sustained-release tablets with different HPMC viscosities all reached over 90% after 24 hours, meeting the requirements for sustained-release formulations. HPMC K15M exhibited the lowest release rate in the first 6 hours, but still met the requirement of less than 40% release after 2 hours for sustained-release formulations. The release rates of EIDD-1931 sustained-release tablets with different HPMC viscosities were all too rapid, with almost complete drug release after 12 hours, resulting in poor sustained-release effect.

[0025] Simultaneously, the flocculation properties of EIDD-1931 sustained-release tablets with different HPMC viscosities were measured, and the results are shown in Table 3. The method for measuring flocculation properties is as follows: Each EIDD-1931 sustained-release tablet was placed in 500 mL of hydrochloric acid aqueous solution with pH 1.2 and recorded at 38.5 ± 0.5 °C. (1) Floating Lag Time (FLT): the time required for the tablet to float from the surface of the liquid; (2) Total Floating Duration (TFD): the duration for which the tablet remained floating.

[0026] Table 3. Onset and sustained floating time of EIDD-1931 sustained-release tablets with different HPMC viscosities

[0027] As shown in Table 3, tablets made from HPMC of different viscosities all started to float within 15 minutes, and the floating time was all greater than 12 hours.

[0028] In summary, this invention selects HPMC K15M as the sustained-release skeleton material.

[0029] II. Adhesive: Viscosity screening of polyvinylpyrrolidone (PVP) Using PVP as a binder, three viscosities of PVP (K16-18, K23-27, and K29-32) were screened. Each PVP of different viscosities accounted for 5% of the total weight in its respective formulation (see Table 4 for specific formulations). Following the preparation process used in the HPMC viscosity screening, EIDD-1931 sustained-release tablets with different viscosities were prepared using different PVP formulations. The cumulative release percentage of the EIDD-1931 sustained-release tablets with different formulations was then measured at 0h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h using the same method as in the HPMC viscosity screening. Release curves were plotted and compared. The results are shown in Table 4. Figure 3 See Table 5.

[0030] Table 4. List of formulations for PVP of different viscosities

[0031] Table 5. Cumulative release rates of EIDD-1931 sustained-release tablets made with PVP of different viscosities

[0032] Depend on Figure 3 As shown in Table 5, the cumulative release rate of EIDD-1931 sustained-release tablets made from PVP of different viscosities all reached over 90% after 24 hours, meeting the requirements for sustained-release formulations. PVP K23-27 showed slower release in the first 8 hours. The release rates of EIDD-1931 sustained-release tablets made from PVP of different viscosities were all faster than expected, with almost complete drug release after 12 hours, indicating a poor sustained-release effect.

[0033] Meanwhile, the flocculation properties of EIDD-1931 sustained-release tablets with different formulations were determined according to the determination method in the viscosity screening process of hydroxymethylpropyl cellulose (HPMC), and the results are shown in Table 6.

[0034] Table 6. Onset and sustained floating time of EIDD-1931 sustained-release tablets made with PVP of different viscosities

[0035] As shown in Table 6, EIDD-1931 sustained-release tablets made of PVP with different viscosities all started to float within 15 minutes, and the continuous floating time was greater than 12 hours.

[0036] In summary, this invention selects PVP K23-27 as the adhesive.

[0037] III. Sustained-release matrix: Carbomer Carbomer was selected as the sustained-release matrix, and carbomer at concentrations of 0%, 5%, and 10% was screened. The different carbomer concentrations accounted for 0%, 5%, and 10% of the total weight in their respective formulations, while the contents of other components remained unchanged. The remaining mass was supplemented with microcrystalline cellulose. The specific formulations are shown in Table 7. EIDD-1931 sustained-release tablets with different carbomer concentrations were prepared using the same preparation process as in the HPMC viscosity screening process. The cumulative release percentage of EIDD-1931 sustained-release tablets with different formulations was then measured at 0h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h according to the same determination method as in the HPMC viscosity screening process. Release curves were plotted and compared. The results are shown in Table 7. Figure 4 See Table 8.

[0038] Table 7. List of prescriptions with different carbomer contents

[0039] Table 8. Cumulative Release Rate of EIDD-1931 Extended-Release Tablets with Different Carbomer Contents

[0040] From Table 8 and Figure 4 It can be seen that the cumulative release rate of sustained-release tablets made with different carbomer concentrations all reached over 90% after 24 hours, meeting the requirements for sustained-release formulations. There was no significant difference in the cumulative release rate of sustained-release tablets made with different carbomer concentrations in the first 12 hours, but 10% carbomer showed the slowest release compared to 0% and 5% carbomer in the first 8 hours. The release rate of sustained-release tablets made with different carbomer concentrations was faster than expected, with almost complete drug release after 12 hours, indicating a poor sustained-release effect.

[0041] Meanwhile, the flocculation properties of EIDD-1931 sustained-release tablets with different formulations were determined according to the determination method in the viscosity screening process of hydroxymethylpropyl cellulose (HPMC), and the results are shown in Table 9.

[0042] Table 9. Onset and duration of floatation of EIDD-1931 sustained-release tablets with different carbomer contents

[0043] As shown in Table 9, all sustained-release tablets made with different carbomer contents started to float within 15 minutes, and the continuous floating time was greater than 12 hours.

[0044] Therefore, this invention selects to supplement 10% carbomer as the sustained-release matrix.

[0045] IV. Prescription Optimization: Full Factor Analysis Since the viscosity of HPMC and PVP both affect the drug release rate, after confirming the selection of HPMC K15M as the hydrophilic gel framework and PVP K23-27 as the binder, this invention studies the use of HPMC K15M dosage, PVP K23-27 dosage, and carbomer dosage as three factors in an orthogonal experiment. Each factor is selected at two levels, and the drug release rate is used as the evaluation index. An orthogonal experiment is designed to optimize the formulation. Each formulation maintains EIDD-1931 40%, NaHCO3 2%, MS 0.5%, total mass 125mg, and the remaining mass is MCC. The formulation optimization factors are shown in Table 10.

[0046] Table 10. Proportioning of Various Auxiliary Materials

[0047] Each EIDD-1931 gastric floating sustained-release tablet weighs 125 mg and contains 50 mg of EIDD-1931. The range of excipients is shown in the table above, and the remaining weight is filled with MCC (microcrystalline cellulose). The specific formulation is shown in Table 11.

[0048] Table 11 Summary of Prescriptions

[0049] Then, following the preparation process in the HPMC viscosity screening process, EIDD-1931 gastric floating sustained-release tablets were prepared using different formulations from Table 11. The cumulative release percentages of the different HPMC viscosity screening formulations were then determined at 0h, 2h, 4h, 6h, 8h, 12h, and 24h, and release curves were plotted and compared. The optimization target for the cumulative release of EIDD-1931 gastric floating sustained-release tablets is shown in Table 12, and the cumulative release results for each formulation are shown in Tables 13 and 14. Figure 5 .

[0050] Table 12 Optimization Target Level

[0051] Table 13 Cumulative Release Rate Results for Each Prescription

[0052] From Table 13 and Figure 5 It can be seen that the sustained-release effects of each prescription are different. Among them, prescriptions 6 and 8 have the better sustained-release effects. Therefore, the prescription range of prescriptions 6 and 8 is selected as the final prescription range of the superior prescriptions.

[0053] Example 2: An EIDD-1931 sustained-release agent and its preparation method In this embodiment, EIDD-1931 sustained-release agent was prepared using formulation 6 from Example 1 as one of the optimized formulations. The formulation for preparing EIDD-1931 sustained-release agent, by weight percentage, is: 40% EIDD-1931, 40% HPMC K15M, 2% PVP K23-27, 10% carbomer, 2% NaHCO3, 0.5% MS, and 5.5% MCC.

[0054] The specific preparation method of EIDD-1931 sustained-release agent is as follows: take EIDD-1931 and each excipient and pass them through a 60-mesh sieve for later use; Weigh out the prescribed amounts of EIDD-1931, HPMC, PVP, MCC, NaHCO3, and carbomer, premix and sieve them, then add the gliding agent MS and mix thoroughly. Granulate the mixture dry through a 40-mesh sieve and compress it into EIDD-1931 sustained-release tablets with a diameter of 6 mm and a tablet weight of approximately 125 mg on a single-punch tablet press. These tablets are labeled E1, and each tablet contains 50 mg of EIDD-1931.

[0055] The EIDD-1931 sustained-release formulation prepared in this invention is a sustained-release antiviral drug for cats. It can prolong the half-life of EIDD-1931 in cat plasma, reduce the difficulty of administration to pet owners, improve pet owner compliance, thereby improving the treatment effect after viral infection in animals, reducing the recurrence rate, improving animal survival treatment and animal welfare.

[0056] Example 3: An EIDD-1931 sustained-release agent and its preparation method In this embodiment, EIDD-1931 sustained-release agent was prepared using formulation 8 from Example 1 as one of the optimized formulations. The formulation for preparing EIDD-1931 sustained-release agent, by weight percentage, is: 40% EIDD-1931, 40% HPMC K15M, 6% PVP K23-27, 10% carbomer, 2% NaHCO3, 0.5% MS, and 1.5% MCC.

[0057] The specific preparation method of EIDD-1931 sustained-release agent is as follows: take EIDD-1931 and each excipient and pass them through a 50-mesh sieve for later use; Weigh out the prescribed amounts of EIDD-1931, HPMC, PVP, MCC, NaHCO3, and carbomer, premix and sieve them, then add the gliding agent MS and mix thoroughly. Granulate the mixture dry through a 50-mesh sieve and compress it into EIDD-1931 sustained-release tablets with a diameter of 6 mm and a tablet weight of approximately 125 mg on a single-punch tablet press. Each tablet contains 50 mg of EIDD-1931.

[0058] Example 4: An EIDD-1931 sustained-release agent and its preparation method Based on the optimized formulations of Examples 2-3, this embodiment further explores the formulation range of the EIDD-1931 sustained-release agent that can achieve a better sustained-release effect, and obtains the formulation of the EIDD-1931 sustained-release agent of this embodiment, which, by weight percentage, is: 40% EIDD-1931, 39% HPMC K15M, 5.5% PVP K23-27, 9% carbomer, 1.9% NaHCO3, 0.6% silica and 4% microcrystalline cellulose.

[0059] The specific preparation method of EIDD-1931 sustained-release agent is as follows: take EIDD-1931 and each excipient and pass them through a 70-mesh sieve respectively, and set them aside; Weigh out the prescribed amounts of EIDD-1931, HPMC, PVP, microcrystalline cellulose, NaHCO3, and carbomer, premix and sieve them, then add the glidant silica and mix thoroughly. Granulate the mixture dry through a 30-mesh sieve and compress it into EIDD-1931 sustained-release tablets with a diameter of 6 mm and a tablet weight of approximately 125 mg on a single-punch tablet press. Each tablet contains 50 mg of EIDD-1931.

[0060] Example 5: An EIDD-1931 sustained-release agent and its preparation method Based on the optimized formulations of Examples 2 and 3, this embodiment further explores the formulation range of EIDD-1931 sustained-release agent that can achieve better sustained-release effect, and obtains the formulation of EIDD-1931 sustained-release agent in this embodiment, which, by weight percentage, is: 40% EIDD-1931, 41% HPMC K15M, 5.5% PVP K23-27, 9% carbomer, 1.9% NaHCO3, 0.6% talc and 2% microcrystalline cellulose.

[0061] The specific preparation method of EIDD-1931 sustained-release agent is as follows: take EIDD-1931 and each excipient and pass them through a 60-mesh sieve for later use; Weigh out the prescribed amounts of EIDD-1931, HPMC, PVP, filler, NaHCO3, and carbomer, premix and sieve them, then add the glidant talc powder and mix thoroughly. Granulate by dry method through a 40-mesh sieve and compress into EIDD-1931 sustained-release tablets with a diameter of 6 mm and a tablet weight of approximately 125 mg on a single-punch tablet press. Each tablet contains 50 mg of EIDD-1931.

[0062] Example 6: An EIDD-1931 sustained-release agent and its preparation method Based on the optimized formulations of Examples 2 and 3, this embodiment further explores the formulation range of EIDD-1931 sustained-release agent that can achieve better sustained-release effect, and obtains the formulation of EIDD-1931 sustained-release agent in this embodiment. The formulation for preparing EIDD-1931 sustained-release agent by weight percentage is: 40% EIDD-1931, 39% HPMC K15M, 5.5% PVP K23-27, 11% carbomer, 1.9% NaHCO3, 0.6% MS and 2% MCC.

[0063] The specific preparation method of EIDD-1931 sustained-release agent is as follows: take EIDD-1931 and each excipient and pass them through a 60-mesh sieve for later use; Weigh out the prescribed amounts of EIDD-1931, HPMC, PVP, MCC, NaHCO3, and carbomer, premix and sieve them, then add the gliding agent MS and mix thoroughly. Granulate the mixture using a dry granulation method through a 60-mesh sieve and compress it into EIDD-1931 sustained-release tablets with a diameter of 6 mm and a tablet weight of approximately 125 mg on a single-punch tablet press. Each tablet contains 50 mg of EIDD-1931.

[0064] Example 7: An EIDD-1931 sustained-release agent and its preparation method Based on the optimized formulations of Examples 2 and 3, this embodiment further explores the formulation range of EIDD-1931 sustained-release agent that can achieve better sustained-release effect, and obtains the formulation of EIDD-1931 sustained-release agent in this embodiment. The formulation for preparing EIDD-1931 sustained-release agent by weight percentage is: 40% EIDD-1931, 41% HPMC K15M, 5.5% PVP K23-27, 11% carbomer, 1.9% NaHCO3, and 0.6% MS.

[0065] The specific preparation method of EIDD-1931 sustained-release agent is as follows: take EIDD-1931 and each excipient and pass them through a 60-mesh sieve for later use; Weigh out the prescribed amounts of EIDD-1931, HPMC, PVP, NaHCO3, and carbomer, premix and sieve them, then add the gliding agent MS and mix thoroughly. Granulate the mixture dry through a 60-mesh sieve and compress it into EIDD-1931 sustained-release tablets with a diameter of 6 mm and a tablet weight of approximately 125 mg on a single-punch tablet press. Each tablet contains 50 mg of EIDD-1931.

[0066] The results of the sustained-release effect comparison between Examples 4, 5, 6, and 7 and Formula 8 in Example 1 (i.e., the formula in Example 3) are as follows: Figure 6 .pass Figure 6 It can be seen that the prescriptions of Examples 4 to 7 of the present invention can achieve almost the same sustained-release effect as prescription 8 in Example 1 (i.e., the prescription in Example 3). Therefore, Examples 4 to 7 of the present invention are also protected as the optimized final prescriptions of the present invention.

[0067] Example 8: In vivo release experiment of EIDD-1931 sustained-release agent This invention, referring to the guidelines for in vivo pharmacokinetic studies of oral sustained-release and controlled-release formulations in animals, established a method for determining the in vivo blood concentration of EIDD-1931. The in vivo pharmacokinetic curves of EIDD-1931 sustained-release tablets (E1) prepared in Example 3 were determined in cats under fasting conditions at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, and 24h. The in vivo pharmacokinetic curves of EIDD-1931 raw material were also determined in cats under fasting conditions at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h. Cat 1 was given two E1 sustained-release tablets via oral feeder on an empty stomach; Cat 2 was given 1.5 E1 sustained-release tablets via oral feeder on an empty stomach; Cat 3 was given EIDD-1931 active pharmaceutical ingredient at a dose of 10 mg / kg via oral feeder on an empty stomach; and Cat 4 was given EIDD-1931 active pharmaceutical ingredient at a dose of 7.5 mg / kg via oral feeder on an empty stomach. After administration, 10 mL of water was given via syringe.

[0068] Plasma sample preparation: 200 μL of plasma was placed in a 0.5 mL EP tube, and 300 μL of acetonitrile was added. The mixture was vortexed for 5 min, then centrifuged at 12000 rpm for 20 min at 4 °C. After centrifugation, 300 μL of the supernatant was placed in a 1.5 mL EP tube, and 900 μL of mobile phase (prepared by mixing acetonitrile and 0.05 M phosphate buffer at pH 3.5 at a volume ratio of 24:76) was added. The mixture was then filtered through a 0.22 nm filter and transferred to a sample vial for LC-MS / MS analysis. The specific LC-MS / MS analysis method is as follows: Chromatographic conditions: Separation was performed on an ACQUITY UPLC HSS T3 reversed-phase column (2.1 mm × 50 mm, 1.8 μm). The mobile phase consisted of ultrapure water (A) containing 0.1% formic acid and acetonitrile (B). The flow rate was 0.3 mL / min, the injection volume was 1 μL, and the column temperature was 40 °C. The gradient elution program shown in Table 14 was followed. Under these chromatographic conditions, the retention time of EIDD-1931 was 1.05 min.

[0069] Table 14 Gradient Elution Table

[0070] Mass spectrometry conditions Ion source: Electrospray ionization (ESI); Scanning mode: Multiple Reaction Monitoring (MRM) for mass spectrometry. Desolvent gas removal: 12 mL / min; Nebulizing gas: 1.5 mL / min; Capillary high voltage: 4800V; Backflush air: 1.5 mL / min; Desolvent gas temperature: 400˚C; Polarity: Cation detection; Qualitative analysis of ion pairs: 260.10 m / z → 128.10 m / z; Quantitative analysis of ion pairs: 260.10 m / z → 111.20 m / z; The pharmacokinetic parameters of EIDD-1931 extended-release tablet E1 in cats are shown in Table 15, and the drug-time curves are shown in Table 15. Figure 7 The pharmacokinetic parameters of EIDD-1931 active pharmaceutical ingredient in cats are shown in Table 16, and the drug-time curves are shown in Table 16. Figure 8 .

[0071] Table 15. EIDD-1931 Extended-Release Tablets E1 In Vivo Release Experiment

[0072] Table 16 In vivo release assay of EIDD-1931 active pharmaceutical ingredient

[0073] Note: t 1 / 2λZ To eliminate the half-life, C max For the drug to reach peak concentration, T max Vz / F is the time to peak drug concentration, Vz / F is the volume of distribution (observed value), CL / F is the clearance rate (observed value), and AUC is the peak drug concentration. (0-∞) To calculate the area under the curve (observed value) for drug-time up to positive infinity.

[0074] It should be noted that since EIDD-1931 could not be detected at the 12h sampling point for cats No. 3 and No. 4, the test results data were only retained up to the 8h sampling point.

[0075] From Tables 15-16 and Figures 7-8 It can be seen that the EIDD-1931 sustained-release agent prepared by this invention has a significant sustained-release effect compared with the EIDD-1931 raw material. It is evident that the EIDD-1931 sustained-release agent prepared by this invention has a good sustained-release effect. EIDD-1931 will be phosphorylated into NHC-triphosphate (NHC-TP) in cells, which will continuously affect viral replication.

[0076] Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. An EIDD-1931 sustained-release formulation, characterized in that, The formulation of the EIDD-1931 sustained-release agent, by weight, is as follows: Main drug: EIDD-1931, 40 doses; Excipients: 39-41 parts of hydroxypropyl methylcellulose K15M, 2-6 parts of polyvinylpyrrolidone K23-27, 9-11 parts of carbomer, 1.9-2.0 parts of sodium bicarbonate, 0.5-0.6 parts of flow aid, and the balance of filler.

2. The EIDD-1931 sustained-release agent according to claim 1, characterized in that, The formulation of the EIDD-1931 sustained-release agent, by weight, is as follows: Main drug: EIDD-1931, 40 doses; Excipients: 40 parts of hydroxypropyl methylcellulose K15M, 2-6 parts of polyvinylpyrrolidone K23-27, 10 parts of carbomer, 2 parts of sodium bicarbonate, 0.5 parts of flow aid, and the remainder of filler.

3. The EIDD-1931 sustained-release agent according to claim 1, characterized in that, The formulation of the EIDD-1931 sustained-release agent, by weight, is as follows: Main drug: EIDD-1931, 40 doses; Excipients: 40 parts hydroxypropyl methylcellulose K15M, 2 parts polyvinylpyrrolidone K23-27, 10 parts carbomer, 2 parts sodium bicarbonate, 0.5 parts flow aid, and the remainder filler.

4. The EIDD-1931 sustained-release agent according to claim 1, characterized in that, The formulation of the EIDD-1931 sustained-release agent, by weight, is as follows: Main drug: EIDD-1931, 40 doses; Excipients: 40 parts hydroxypropyl methylcellulose K15M, 6 parts polyvinylpyrrolidone K23-27, 10 parts carbomer, 2 parts sodium bicarbonate, 0.5 parts flow aid, and the remainder filler.

5. The EIDD-1931 sustained-release agent according to any one of claims 1-4, characterized in that, The filler is at least one of microcrystalline cellulose, compressible starch, dextrin, and powdered sugar.

6. The EIDD-1931 sustained-release agent according to any one of claims 1-4, characterized in that, The flow aid is at least one of silica, talc, and magnesium stearate.

7. A method for preparing an EIDD-1931 sustained-release agent, characterized in that, The preparation method is to weigh the active pharmaceutical ingredient and excipients according to the prescription of the EIDD-1931 sustained-release agent according to any one of claims 1-6, mix them evenly, compress them into tablets, and prepare the EIDD-1931 sustained-release agent.

8. The method for preparing the EIDD-1931 sustained-release agent according to claim 7, characterized in that, The specific process of the preparation method is as follows: take EIDD-1931, hydroxypropyl methylcellulose K15M, polyvinylpyrrolidone K23-27, carbomer, sodium bicarbonate and filler, premix and sieve, add glidant and mix thoroughly, sieve, dry granulate, compress into tablets, and obtain EIDD-1931 sustained-release agent.

9. The method for preparing the EIDD-1931 sustained-release agent according to claim 7 or 8, characterized in that, Before preparing the EIDD-1931 sustained-release formulation, the active pharmaceutical ingredient and each excipient were pulverized and sieved.

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