3CL protease inhibitor preparation and preparation method thereof

Abstract

The invention relates to process development of a preparation prescription of a coronavirus 3CL protease inhibitor compound Iscartrevir and a preparation method of the coronavirus 3CL protease inhibitor compound Iscartrevir. By strictly screening and optimizing the formula, the preparation with a specific prescription ratio is obtained. According to the preparation, the medicine stability is improved, through the overall synergistic effect of the dry granulation step, in the preparation process of the medicine components, the flowing property of totally mixed materials is good, and the sticking problem is further solved. Meanwhile, the preparation is simple in production process, short in production period, energy-saving, efficient, low in cost and suitable for industrial mass production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a preparation containing 3CL protease inhibitor N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)isoquinoline-4-carboxamide or a pharmaceutically acceptable salt thereof and a preparation method thereof. BACKGROUND

[0002] Coronavirus, in English, is abbreviated as CoV, and its full name is Coronavirus: Corona (crown) + Virus (virus) = coronavirus. Coronavirus particles look like a crown under an electron microscope, hence the name coronavirus. It is a class of RNA viruses that can cause diseases in mammals and birds, causing mild to severe respiratory infections, including SARS, MERS, and SARS-CoV-2 (COVID-19) and other fatal diseases. 3CLpro (3C-like protease, also known as 3C-like protease) is a major protease produced by coronavirus, which can hydrolyze viral polyproteins pp1a and pp1ab, thereby producing functional proteins required for viral replication. Therefore, 3C-like protease is essential for viral replication, and inhibition of 3CLpro activity can effectively inhibit viral replication and infection.

[0003] A coronavirus 3CLPro non-covalent binding inhibitor is disclosed in WO2022150962A1, wherein the compound (N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)isoquinoline-4-carboxamide) has good inhibitory activity on SARS-CoV-2 3CLpro protease, and exhibits significant antiviral activity in various cell models and in ACE2 transgenic mice. Research papers (ACS Cent. Sci. 2023, 9, 217-227) systematically introduce that the compound has high exposure and bioavailability, and good safety. The compound has been approved for clinical research (NCT06205329; NCT06205329; NCT06205329) since September 2022, further proving its safety and effectiveness in treating coronavirus infection, and is expected to be developed into a clinical drug. The compound has obtained the WHO International Nonproprietary Name (INN) of Iscartrelvir (CAS: 2921711-74-0). Iscartrelvir is a 3CLpro non-covalent binding inhibitor independently developed by West Lake Pharmaceuticals (Hangzhou) Co., Ltd. SUMMARY

[0004] The object of the present invention is to provide a formulation containing a 3CL protease inhibitor, which is N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)isoquinoline-4-carboxamide (Iscartrelvir) or a pharmaceutically acceptable salt thereof, and a process for preparing the same.

[0005] The present invention can be described from different aspects, which are independent of each other and are associated with each other, and together constitute the content of the present invention.

[0006] In a first aspect of the present invention, a solid formulation containing a drug substance is provided, wherein the active ingredient of the drug substance is Compound 1 or a pharmaceutically acceptable salt thereof:

[0007]

[0008] In some embodiments, the solid formulation of the present invention comprises Compound 1 or a pharmaceutically acceptable salt thereof, and an excipient.

[0009] In some embodiments, the solid formulation of the present invention comprises Compound 1 or a pharmaceutically acceptable salt thereof, and an excipient.

[0010] In some embodiments, the drug substance in the solid formulation of the present invention is a pharmaceutically acceptable salt of Compound 1.

[0011] In some embodiments, the drug substance in the solid formulation of the present invention is a hydrochloride salt of Compound 1.

[0012] In some embodiments, the solid formulation of the present invention is a tablet.

[0013] In some embodiments, the solid formulation of the present invention comprises a coating.

[0014] In some embodiments, the excipient in the solid formulation of the present invention comprises a filler, a binder, a surface active agent, a disintegrant, a glidant, a pH buffering agent, a lubricant, and a coating powder.

[0015] In some embodiments, the excipient in the solid formulation of the present invention comprises a filler, a binder, a disintegrant, a lubricant, and a coating powder.

[0016] In some embodiments, the excipient in the solid formulation of the present invention comprises a filler, a binder, a disintegrant, and a lubricant.

[0017] In some embodiments, the filler in the solid formulation of the present invention is selected from the group consisting of one or more of microcrystalline cellulose, mannitol, and lactose.

[0018] In some embodiments, the filler in the solid formulation of the present application comprises microcrystalline cellulose and mannitol.

[0019] In some embodiments, the filler in the solid formulation of the present application comprises microcrystalline cellulose and mannitol in a weight ratio of about 2:1.

[0020] In some embodiments, the binder in the solid formulation of the present application is selected from the group consisting of hypromellose.

[0021] In some embodiments, the disintegrant in the solid formulation of the present application is selected from the group consisting of one or more of a combination of crospovidone, croscarmellose sodium.

[0022] In some embodiments, the lubricant in the solid formulation of the present application is selected from the group consisting of one or more of a combination of magnesium stearate, sodium stearyl fumarate.

[0023] In some embodiments, the coating powder in the solid formulation of the present application is selected from the group consisting of one or more of a combination of Opadry® film coating preblend 85F18422-CN, 88A170005-CN Beige, 85F270011 Beige.

[0024] In some embodiments, the solid formulation of the present application is an oral tablet.

[0025] In some embodiments, the solid formulation of the present application comprises intragranular ingredients and extragranular ingredients.

[0026] In some embodiments, the solid formulation of the present application comprises intragranular ingredients and extragranular ingredients, wherein the intragranular ingredients comprise the drug substance, the filler, the disintegrant, the binder, and the lubricant; and the extragranular ingredients comprise the lubricant.

[0027] In some embodiments, the intragranular ingredients of the solid formulation of the present application comprise the drug substance, microcrystalline cellulose, mannitol, hypromellose, croscarmellose sodium, and magnesium stearate; and the extragranular ingredients comprise magnesium stearate.

[0028] In some embodiments, the solid formulation of the present application is prepared by a direct compression process or a dry granulation process; preferably, by a dry granulation process.

[0029] In some embodiments, the content of the drug substance in the solid formulation of the present application is about 30-40% by weight.

[0030] In some embodiments, the content of the filler in the solid formulation of the present application is about 43-63% by weight.

[0031] In some embodiments, the content of the disintegrant in the solid formulation of the present application is about 3% by weight.

[0032] In some embodiments, the content of the binder in the solid formulation of the present application is about 3% by weight.

[0033] In some embodiments, the content of the lubricant in the solid formulation of the present application is about 0.5-1.5% by weight.

[0034] In some embodiments, the solid formulation of the present application comprises, by weight: about 30-40% of the drug substance; about 35-42% of microcrystalline cellulose; about 17 -21 % of mannitol; about 3% of hypromellose; about 3% of croscarmellose sodium; and about 0.5-1.5% of magnesium stearate.

[0035] In some embodiments, the solid formulation of the present application comprises, by weight: about 40% of the drug substance; about 35.33% of microcrystalline cellulose; about 17.67% of mannitol; about 3% of hypromellose; about 3% of croscarmellose sodium; and about 0.5-1.5% of magnesium stearate.

[0036] In some embodiments, the solid formulation of the present application comprises, by weight: about 35% of the drug substance; about 38.67% of microcrystalline cellulose; about 19.33% of mannitol; about 3% of hypromellose; about 3% of croscarmellose sodium; and about 0.5-1.5% of magnesium stearate.

[0037] In some embodiments, the solid formulation of the present application comprises, by weight: about 31.25% of the drug substance; about 40.83% of microcrystalline cellulose; about 20.42% of mannitol; about 3% of hypromellose; about 3% of croscarmellose sodium; and about 0.5-1.5% of magnesium stearate.

[0038] In some embodiments, the solid formulation of the present application comprises, by weight: about 33.41% of the drug substance; about 39.39% of microcrystalline cellulose; about 19.70% of mannitol; about 3% of hypromellose; about 3% of croscarmellose sodium; and about 0.5-1.5% of magnesium stearate.

[0039] In some embodiments, the solid formulation of the present application comprises, by weight: about 30-40% of the drug substance; about 35-42% of microcrystalline cellulose; about 17 -21 % of mannitol; about 3% of hypromellose; about 3% of croscarmellose sodium; and about 0.5-1.5% of magnesium stearate.

[0040] In some embodiments, the solid formulation of the present application comprises, by weight: about 40% of the drug substance; about 35.33% of microcrystalline cellulose; about 17.67% of mannitol; about 3% of hypromellose; about 3% of croscarmellose sodium; and about 0.5-1.5% of magnesium stearate.

[0041] In some embodiments, the solid preparation of the present application comprises, by weight: 35% of the drug substance; 38.67% of microcrystalline cellulose; 19.33% of mannitol; 3% of hypromellose; 3% of croscarmellose sodium; and 0.5-1.5% of magnesium stearate;

[0042] In some embodiments, the solid preparation of the present application comprises, by weight: 31.25% of the drug substance; 40.83% of microcrystalline cellulose; 20.42% of mannitol; 3% of hypromellose; 3% of croscarmellose sodium; and 0.5-1.5% of magnesium stearate;

[0043] In some embodiments, the solid preparation of the present application comprises, by weight: 33.41% of the drug substance; 39.39% of microcrystalline cellulose; 19.70% of mannitol; 3% of hypromellose; 3% of croscarmellose sodium; and 0.5-1.5% of magnesium stearate.

[0044] In some embodiments, the solid preparation of the present application contains about 5 mg-500 mg of the active ingredient of the drug substance, and preferably 50 mg-200 mg of the active ingredient of the drug substance. In some embodiments, the active ingredient of the drug substance contained is 5 mg, 10 mg, 20 mg, 25 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg or 500 mg of the active ingredient of the drug substance.

[0045] In a second aspect, the present application provides a method for preparing a solid preparation containing a drug substance, wherein the active ingredient of the drug substance is Compound 1 or a pharmaceutically acceptable salt thereof:

[0046]

[0047] In some embodiments, the method for preparing the solid preparation of the present application comprises the steps of feeding, premixing, lubricating, granulating and tabletting.

[0048] In some embodiments, the method for preparing the solid preparation of the present application further comprises the step of total mixing after granulation.

[0049] In some embodiments, the method for preparing the solid preparation of the present application further comprises the step of coating after tabletting.

[0050] In some embodiments, the step of feeding in the method for preparing the solid preparation of the present application comprises the step of weighing the drug substance, the filler, the disintegrant, the binder, the lubricant and the coating powder.

[0051] In some embodiments, the step of feeding in the method for preparing the solid preparation of the present application further comprises the step of sieving the drug substance and the lubricant.

[0052] In some embodiments, the sieving step of the solid preparation method of the present application uses a 20-90 mesh sieve; preferably, a 60 mesh sieve is used.

[0053] In some embodiments, the premixing step of the solid preparation method of the present application comprises mixing the raw material drug, the filler, the disintegrant and the binder in a mixing bucket. Preferably, the mixing is performed at 20 rpm.

[0054] In some embodiments, the lubricating step of the solid preparation method of the present application comprises adding the intragranular lubricant to the premixed mixing bucket and mixing again. Preferably, the mixing is performed at 20 rpm.

[0055] In some embodiments, the granulating step of the solid preparation method of the present application comprises adding the lubricated mixture to a dry granulator to obtain granules.

[0056] In some embodiments, the granulating step of the solid preparation method of the present application comprises sampling and testing at least one of the bulk density, the tap density, the particle size distribution and the loss on drying.

[0057] In some embodiments, the total mixing step of the solid preparation method of the present application comprises adding the extragranular lubricant and the granules obtained from the granulating step to a mixing bucket and mixing. Preferably, the mixing is performed at 20 rpm.

[0058] In some embodiments, the total mixing step of the solid preparation method of the present application comprises sampling and testing the mixing uniformity.

[0059] In some embodiments, the tabletting step of the solid preparation method of the present application comprises tabletting the granules obtained from the granulating step using a rotary tablet press to obtain a tablet core.

[0060] In some embodiments, the tabletting step of the solid preparation method of the present application comprises tabletting the mixture obtained from the total mixing step using a rotary tablet press to obtain a tablet core.

[0061] In some embodiments, the tabletting step of the solid preparation method of the present application comprises sampling and testing at least one of the appearance, the tablet weight, the thickness and the hardness.

[0062] In some embodiments, the coating step of the solid preparation method of the present application comprises preparing a coating solution using a coating powder and purified water, and coating the tablet core.

[0063] In some embodiments, the coating step of the solid preparation method of the present application controls the air inlet temperature to be 65°C, sprays the coating to a weight gain of 3.0%-5.0%, and after the target weight gain is reached, the tablet is discharged after drying and cooling.

[0064] In some embodiments, the solid preparation preparation method of the present application comprises the following steps:

[0065] Step 1: material delivery

[0066] The raw drug, microcrystalline cellulose, mannitol, hydroxypropyl methyl cellulose, sodium croscarmellose and magnesium stearate are weighed respectively, and the raw drug and magnesium stearate are sieved;

[0067] Step 2: premixing

[0068] The raw drug, microcrystalline cellulose, mannitol, hydroxypropyl methyl cellulose and sodium croscarmellose are added into a mixing barrel and rotated to mix;

[0069] Step 3: lubrication

[0070] The intragranular magnesium stearate is added into the mixing barrel of step 2 and the rotation is continued to mix, to obtain a mixture;

[0071] Step 4: dry granulation

[0072] The mixture obtained in step 3 is added into a dry granulator to granulate, to obtain granules;

[0073] Step 5: total mixing

[0074] The extragranular magnesium stearate and the granules obtained in step 4 are added into a mixing barrel;

[0075] Step 6: tabletting

[0076] The tabletting is performed by using a rotary tablet press, to obtain the solid preparation.

[0077] The solid preparation provided by the present application has good drug stability. The inventors have also solved the sticking problem in the preparation process through further research. Meanwhile, the solid preparation obtained by the preparation method of the present application has simple production process, short production cycle, high energy efficiency, low cost and is suitable for industrialized mass production. BRIEF DESCRIPTION OF DRAWINGS

[0078] In order to make the content of the present application more easily understood, the present application will be further described in detail below according to specific embodiments of the present application and in combination with the drawings, in which

[0079] Figure 1 XRPD comparison atlas in the tablet feasibility study of Example 2;

[0080] Figure 2 Comparison atlas of dissolution results in the 200mg specification dry granulation prescription investigation in the tablet feasibility study of Example 2;

[0081] Figure 3Figure 2 shows dissolution profile comparison of dry granulation formulation for 50 mg strength in Example 2;

[0082] Figure 4 Figure 3 shows dissolution profile comparison of WIAS-T22050102C-1 and WIAS- T22050102C-2 lots (50 mg and 200 mg strengths) in Example 3.

[0083] Figure 5 Figure 4 shows the chemical structure of Iscartrelvir. DETAILED DESCRIPTION

[0084] DEFINITIONS

[0085] As used herein, "pharmaceutically acceptable salt" means a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / risk ratio, and includes but is not limited to those disclosed in S.M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0086] As used herein, "about" when used in reference to a numerical value, means within 10% of the value stated; preferably, within 5% of the value stated; further preferably, within 2% of the value stated; most preferably, within 1% of the value stated. When "about" is used in reference to a range of values, it is meant that both the upper value and the lower value of the range of values can be increased or decreased by up to 10% of the upper value or the lower value, respectively; preferably, by up to 5% of the upper value or the lower value, respectively; further preferably, by up to 2% of the upper value or the lower value, respectively; most preferably, by up to 1% of the upper value or the lower value, respectively.

[0087] As used herein, "oral tablet" means a single dose solid dosage form for oral administration. The tablet can be produced by conventional granulation methods, such as dry or wet granulation, etc. The tablet can include intragranular and extragranular ingredients, and can or can not be coated.

[0088] As used herein, "filler" is a concept known in the art, and suitable fillers include, but are not limited to, one or more of microcrystalline cellulose, starch, lactitol, lactose, suitable inorganic calcium salts, sucrose, dextrose, mannitol, silica.

[0089] The binders in the present application are known concepts in the art, suitable binders include, but are not limited to, one or more of a combination of starch, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, povidone or polyethylene glycol.

[0090] The disintegrants in the present application are known concepts in the art, suitable disintegrants include, but are not limited to, one or more of a combination of agar, calcium carbonate, dry starch, alginic acid, certain silicates, sodium carbonate, crospovidone, PVP or polyvinylpyrrolidone, sodium carboxymethyl starch, croscarmellose sodium, pregelatinized starch, microcrystalline starch, insoluble starch, sodium starch glycolate, polacrillin potassium, sodium alginate, calcium carboxymethyl cellulose, magnesium aluminum silicate.

[0091] The lubricants in the present application are known concepts in the art, suitable lubricants include, but are not limited to, one or more of a combination of stearate, sodium stearyl fumarate, magnesium stearate and magnesium stearate.

[0092] The lubricants in the present application can be used in the intragranular component and / or the extragranular component. The lubricants in the intragranular component and the extragranular component can be the same or different.

[0093] Examples

[0094] The tablet technical solution of the present application containing 3CL protease inhibitor composition is clearly and completely illustrated by the following examples and the accompanying drawings in the inventive examples, and the described examples are only a part of the examples of the present application, which do not constitute any limitation on the present application.

[0095] Example 1: Compatibility test of raw and auxiliary materials

[0096] Through the compatibility test of raw and auxiliary materials, whether the salt of Iscartrelvir (API), the filler, the binder, the surfactant, the disintegrant, the glidant, the pH buffer, the lubricant and the coating powder have a significant effect on the degradation of the API content under the condition of three influencing factors is explored.

[0097] The compatibility test of raw and auxiliary materials is designed to refer to the Basic Technical Guidelines for Chemical Drug Preparation Research, and different auxiliary materials for oral solid preparations are selected to study the raw material, the binary mixture of the raw material and the auxiliary material and the original prescription. Placed in different temperature, humidity and light conditions, such as high temperature 60℃, high humidity 92.5% RH, light (total illumination not less than 1.2×10 6 lux·hr, near ultraviolet energy not less than 200w·hr / m 2 ); respectively at different time points (10 days, 72 days, 1xICH), after taking out, detection is carried out, and the compatibility of the raw material and the auxiliary material is evaluated.

[0098] Reference sample of raw material: API of Iscartrelvir hydrochloride.

[0099] Binary mixture: Accurately weigh 10 mg of Iscartrelvir hydrochloride and the corresponding amount of excipient into a 40 mL glass bottle, vortex for 10 minutes with a vortex, gently knock the bottom of the bottle on the table to make the sample flat on the bottom of the bottle to ensure that the raw material and excipient are in full contact. This sample is binary mixture 1-12, the ingredients, ratio and function of the binary mixture are shown in Table 1 as follows:

[0100] Table 1 Excipient compatibility test-binary mixture

[0101]

[0102] Prototype formula: Accurately weigh all excipients in the prototype formula scaled by the same proportion into a 40 mL glass bottle, and vortex for 10 minutes with a vortex. This sample is labeled as placebo. Then, accurately weigh about 10 mg of Iscartrelvir hydrochloride and the corresponding amount of placebo into a 40 mL glass bottle, and vortex for 10 minutes with a vortex. Gently knock the bottom of the bottle on the table to make the sample flat on the bottom of the bottle to ensure that the raw material and placebo are in full contact. The results are shown in Table 2 as follows:

[0103] Table 2 Excipient compatibility test-prototype formula

[0104]

[0105]

[0106] In the warm reading, humidity test, all samples were placed under different temperature and humidity conditions, and samples were taken at different time points. For the raw material control and prototype formula, three replicates were performed in parallel, two for analysis and one as a backup. For binary mixtures, two replicates were performed in parallel, one for analysis and one as a backup. For pure excipients, only one sample was prepared for each condition except for the initial point analysis, and analysis was only performed when degradation occurred in the binary mixture sample. For light stability samples, four replicates were performed in parallel, all exposed to 1200 klux-hrs of visible light and 200 W-hrs / m 2 of ultraviolet light, two wrapped in aluminum foil to avoid light as light control samples, one for analysis and one as a backup. The other two were exposed to light as light samples, one for analysis and one as a backup. Samples were taken at 0 days, 10 days and 72 days, the appearance of the product was recorded, the content and related substances of the sample were determined, and the results are shown in Table 3 as follows:

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] The conclusions of the compatibility test of the excipients are as follows:

[0113] Appearance: All samples did not change in appearance under high temperature and high humidity conditions for 72 days and under light conditions, and were orange yellow powders.

[0114] Related substances: Minor degradation was detected in the binary mixture 12 film coating premix, and no significant impurity changes were observed in the other excipients. Under light conditions, the impurity (RRT = 0.80) in microcrystalline cellulose PH-112, mannitol 100 SD and lactose SD FAST FLO 316 increased by 0.05%. The total impurity change of the prototype prescription 2 was about 0.1%, which was presumably caused by the film coating premix 85F18422-CN (white) and fumaric acid. Based on the above test results, it can be determined that there is no risk of compatibility problems for all excipients during further formulation development and formulation storage. Since it was found during the small-scale study that the API is a yellow to orange solid, the placebo tablets are yellowish, and the two tablets will have different colors when coated with the film coating premix 85F18422-CN (white), the film coating premix (gastroresistant type) 85F270011 Beige was adjusted to coat the two tablets.

[0115] The excipients selected in the final formulation include microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, croscarmellose sodium, magnesium stearate and film coating premix (gastroresistant type) 85F270011 Beige.

[0116] Example Two: Further formulation screening and optimization of Iscartrelvir hydrochloride tablets:

[0117] By screening the types of fillers, binders, disintegrants and lubricants, the hardness, friability, dissolution, powder properties and content uniformity of different formulations were investigated.

[0118] 1. Tablet feasibility study (placebo - direct compression)

[0119] Using the excipient direct compression process, an attempt was made to compress placebo tablets (two specifications were initially proposed with tablet weights of 125 mg and 500 mg) to investigate the feasibility of tablet compression, and the punch, hardness, etc. were studied. The placebo formulation is shown in Table 4 below:

[0120] Table 4 Formulation design for tablet feasibility study (placebo - direct compression)

[0121]

[0122]

[0123] Tensile strength (TS) is better (>2Mpa) when the tablet hardness is 13kp for tablets with a tablet weight of 125mg; Tensile strength is better (>2Mpa) when the tablet hardness is 20kp for tablets with a tablet weight of 500mg. In addition, the tensile strength should not be too high, which may affect the disintegration and dissolution, therefore 13kp and 20kp are respectively selected as the hardness target values for 50mg and 200mg products in subsequent experiments. Since the shape of the tablet punched by 12.0mm round punch is too large, which is not conducive to the patient to swallow, and the shape of the tablet punched by special-shaped punch is better and the size is appropriate. Therefore, special-shaped punch is selected for subsequent large-scale tablet compression. The specific experimental results are shown in Table 5 below:

[0124] Table 5 Tablet feasibility study (placebo - direct compression) experimental results

[0125]

[0126] 2. Tablet feasibility study (Iscartrelvir hydrochloride tablet - direct compression)

[0127] The tablet feasibility study was carried out by adding the raw material drug Iscartrelvir hydrochloride to the placebo prescription, and the prescription in Table 6 was compressed by direct compression process and XRPD test was carried out to investigate the influence of tablet compression on the crystal form of the raw material drug. Figure 1 The XRPD comparison chart of Iscartrelvir hydrochloride, prescription 2, prescription 3 and blank excipients. The results show that the tablet compression process does not cause the crystal form of API to change, so it is planned to develop Iscartrelvir hydrochloride tablets.

[0128] Table 6 Tablet feasibility prescription investigation

[0129]

[0130]

[0131] 3. Direct compression tablet prescription research

[0132] Using direct compression process, the influence of tablet drug loading, filler ratio, adhesive amount and type, lubricant type and addition of colloidal silicon dioxide on the final tablet compression results was investigated, and the prescription information is shown in Table 7 below:

[0133] Table 7 Direct compression tablet prescription design

[0134]

[0135] The tabletting results are shown in Table 8 below:

[0136] Table 8 Direct Compression Tabletting Prescription Investigation Results

[0137]

[0138]

[0139] * : "+" represents the degree of sticking and the more "+" signs, the greater the degree of sticking.

[0140] From the results analysis can be seen:

[0141] 1) The effect of drug loading

[0142] Comparing the results of prescription 3, prescription 4 and prescription 5, it can be seen that the prescription with 50% drug loading has relatively serious sticking, and the difference in sticking degree between 30% and 40% drug loading is not large. Considering the tablet weight and volume of the tablet compressed by 30% drug loading, there will be problems such as patient compliance in terms of difficulty in swallowing and too many tablets to be taken by the patient in the 200 mg specification tablet. Therefore, 40% drug loading is preliminarily selected for subsequent prescription process investigation.

[0143] 2) The effect of filler ratio

[0144] Comparing the results of prescription 3 and prescription 6, it can be seen that the sticking degree is smaller when the ratio of microcrystalline cellulose: mannitol is 2:1. Therefore, the prescription with a mass ratio of microcrystalline cellulose: mannitol of 2:1 is selected for subsequent prescription process investigation.

[0145] 3) The effect of binder amount

[0146] Comparing the results of prescription 3 and prescription 7, it can be seen that the sticking degree is smaller when the amount of binder is 3%. Therefore, the prescription with 3% binder amount is selected for subsequent prescription process investigation.

[0147] 4) The effect of binder type

[0148] Comparing the results of prescription 3 and prescription 10, it can be seen that the sticking degree is larger when the binder is replaced by S-630. Therefore, the prescription with hydroxypropyl methyl cellulose E5 LV is selected for subsequent prescription process investigation.

[0149] 5) The effect of lubricant type

[0150] Comparing the results of prescription 3 and prescription 8, it can be seen that the sticking degree is smaller and the ejection force is significantly reduced when the lubricant is replaced by magnesium stearate. Therefore, magnesium stearate is selected as the lubricant for subsequent prescription process investigation.

[0151] 6) The effect of adding colloidal silicon dioxide to the prescription

[0152] From the comparison of prescription 3 and prescription 9, the addition of colloidal silicon dioxide cannot significantly improve the sticking situation, although it can significantly reduce the tablet ejection force, but has no significant effect on tablet weight, hardness, thickness, disintegration time, TS, and combined with the results of prescription 8, the subsequent prescription does not consider adding colloidal silicon dioxide.

[0153] In summary, the appearance of each prescription tablet has no cover, overlapping, cracking, breaking, and edge knocking, but has different degrees of sticking phenomenon. From the three aspects of sticking degree, ejection force and TS value, the compression results of prescription 8 are better, so the subsequent prescription optimization is based on prescription 8.

[0154] 4. Dry granulation prescription research

[0155] Due to the poor flowability of the mixed powder in the direct compression process, the tablet weight difference is large, and there is always a sticking phenomenon, so the dry granulation compression process is considered. In the previous experimental process, it was found that the higher the API ratio, the more obvious the sticking phenomenon. In order to reduce the sticking situation, the API ratio in the prescription is appropriately reduced, and the prescriptions 11 and 12 are designed as shown in Table 9:

[0156] Table 9 Dry granulation prescription design

[0157] Material name Formulation 11 (ratio %) Formulation 12 (ratio %) Iscartrelvir hydrochloride 35.00 31.25 Microcrystalline cellulose PH-112 38.67 40.83 Mannitol 200 SD 19.33 20.42 Croscarmellose sodium SD-711 3.00 3.00 Hydroxypropyl methylcellulose E5 Premium LV 3.00 3.00 Magnesium stearate (internal) LIGAMED MF-2-V 0.50 0.50 Magnesium stearate (external) LIGAMED MF-2-V 0.50 1.00 Total 100.00 100.00

[0158] The particle size results, tablet compression results and dissolution results of dry granulation are shown in Tables 10, 11 and 12:

[0159] Table 10 Dry granulation prescription inspection results-1

[0160]

[0161] Table 11 Dry granulation prescription inspection results-2

[0162]

[0163] Table 12 Dry granulation prescription inspection results-3

[0164]

[0165] Results analysis:

[0166] The granules prepared by prescription 11 have large particle size, and the 200 mg tablet has large ejection force. During the dry granulation and tabletting process, the roller is sticky and there is a slight sticking phenomenon. Therefore, prescription 12 continues to reduce the API proportion, the API proportion is reduced, the tablet weight is increased to 160 mg and 640 mg target tablet weight (corresponding to 50 mg and 200 mg specifications), and in order to reduce the tablet thickness and improve the sticking phenomenon, a suitable punch is selected, and the amount of additional lubricant (magnesium stearate) is increased.

[0167] Compared with prescription 11, prescription 12 has less large particle size granules, and the granules have good flowability. The 200 mg ejection force is significantly reduced, and there is no sticking phenomenon during the tabletting process. The dissolution results of prescription 12 and prescription 11 are not significantly different. Therefore, the dry granulation process is scaled up based on prescription 12.

[0168] 5. Dry granulation prescription scale-up

[0169] The small-scale expansion of prescription 12 is carried out, and the batch is expanded from 250 g to 500 g. The particle size results, tabletting results and dissolution results are shown in Tables 13, 14 and 15:

[0170] Table 13 Dry granulation prescription scale-up results-1

[0171]

[0172] Table 14 Dry granulation prescription scale-up results-2

[0173]

[0174] Table 15 Dry granulation prescription scale-up results-3

[0175]

[0176] In summary, after the dry granulation process of prescription 12 is scaled up, the TS of the 50 mg and 200 mg tablets prepared by prescription 11 and prescription 12 is similar, and the ejection force is small, Figure 2 and Figure 3 respectively, 200 mg specification dry granulation prescription dissolution results comparison and 50 mg specification dry granulation prescription dissolution results comparison. The dissolution results are highly similar, so the dry granulation scale-up process of prescription 12 is preferred for subsequent production.

[0177] 6. Selection of coating material

[0178] Three types of gastric soluble film coating materials (85F18422-CN, 88A170005-CN Beige and 85F270011 Beige) were selected for coating, and it was found that the color difference between the active tablets and placebo blank tablets after coating with 85F18422-CN white type was obvious, there were gun blockage and slight sticking during coating with 88A170005-CN Beige type, and the coating effect of 85F270011 Beige type was better, so it was selected as the coating material for Iscartrelvir hydrochloride tablets 50mg and 200mg.

[0179] 7. Determined prescription composition

[0180] Final prescription

[0181] The final prescription of Iscartrelvir hydrochloride tablets is shown in Table 16 as follows:

[0182] Table 16 Final prescription of Iscartrelvir hydrochloride tablets 50mg and 200mg

[0183]

[0184] The percentage is the weight percentage.

[0185] Example Three: Preparation method of final prescription

[0186] Step 1: Material issue

[0187] According to the batch prescription amount, Iscartrelvir raw material, microcrystalline cellulose PH-112, mannitol, hydroxypropyl methyl cellulose (LV), cross-linked sodium carboxymethyl cellulose SD-711, magnesium stearate and film coating premix (gastric soluble type) were weighed and issued respectively, and the Iscartrelvir raw material and magnesium stearate were sieved through a 60 mesh sieve.

[0188] Step 2: Premixing

[0189] The Iscartrelvir raw material, microcrystalline cellulose PH-112, mannitol, hydroxypropyl methyl cellulose (LV) and cross-linked sodium carboxymethyl cellulose SD-711 were added to a 50L mixing barrel and mixed at 20rpm.

[0190] Step 3: Lubrication

[0191] The magnesium stearate (internal addition) was added to the mixing barrel of step 2 and mixed at 20rpm again.

[0192] Step 4: Granulation

[0193] The mixture obtained in Step 3 was added to a dry granulator for granulation, and the bulk density, tap density, particle size distribution (PSD), and loss on drying (LOD) were determined by sampling.

[0194] Step 5: Total mixing

[0195] The sieved magnesium stearate (extragranular) and the granules obtained in Step 4 were added to a 50 L mixing tank. Mixing was performed at 20 rpm. The mixing uniformity was determined by sampling.

[0196] Step 6: Compression

[0197] Tablet compression was performed using a rotary tablet press, and the appearance, tablet weight, thickness, and hardness were determined by sampling.

[0198] Step 7: Coating

[0199] The Iscartrelvir tablets were coated with a coating liquid prepared by mixing the coating powder and purified water, the inlet air temperature was controlled at 65°C, and the spray coating was performed until the coating weight gain reached 3.0%-5.0%, and after the target weight gain was reached, the tablets were discharged after drying and cooling.

[0200] Example Four: Formulation-related properties - dissolution

[0201] The dissolution test was performed using the paddle method at a rotation speed of 75 rpm (the rotation speed was increased to 250 rpm after 60 min), and the dissolution medium was 0.01 mol / L hydrochloric acid with a volume of 900 ml. The dissolution results of the Iscartrelvir hydrochloride tablets according to the final prescription in the example were investigated for a research and development batch of more than ten thousand tablets and a clinical batch under GMP conditions, and the dissolution results could well meet the quality standards. The dissolution results of the research and development batch are shown in Table 17 below:

[0202] Table 17 Dissolution results of Iscartrelvir hydrochloride tablets (research and development batch)

[0203]

[0204]

[0205] Figure 4 The results are the dissolution curve comparison chart of different batches of 50 mg and 200 mg specifications of WIAS-T22050102C-1 and WIAS-T22050102C-2, and the dissolution results are similar.

[0206] Example Five: Stability investigation of Iscartrelvir hydrochloride tablets:

[0207] The stability study conditions and methods of Iscartrelvir hydrochloride tablets were carried out according to the “Guiding Principles of Stability Testing of Drug and Pharmaceutical Products in China (2020 Edition, Volume 4)”, the “Technical Guidelines for Stability Study of Chemical Drugs (API and Formulation) ” issued by CDE, “ICH Q1 (R2) Guideline on Stability Testing of New Drug Substances and Products” and “ICH Q1B Guideline on Stability Testing: Photostability Testing of New Drug Substances and Products”. The influence factors (high temperature, high humidity, light) of Iscartrelvir hydrochloride tablets (batch number: CT-22C124) prepared by the preferred prescription 12 of the application in a GMP system for more than 10,000 tablets were investigated, and the long-term (temperature: 25℃±2℃, relative humidity (RH): 60%±5%) and accelerated (temperature: 40℃±2℃, relative humidity (RH): 75%±5%) stability investigations were carried out. According to the characteristics of the product, the key investigation contents in the stability study were formulated as shown in Table 18,

[0208] Table 18. Routine stability investigation scheme (CT-22C124 batch)

[0209]

[0210]

[0211] *1 : Light 0.5xICH, equivalent to total illumination not less than 0.6x10 6 Lux·hr, near ultraviolet energy not less than 100w·hr / m 2 ; Light 1xICH, equivalent to total illumination not less than 1.2x10 6 Lux·hr, near ultraviolet energy not less than 200w·hr / m 2 .

[0212] *2 : Selective test.

[0213] *3 : Test at 6 months of acceleration, 12 months and 24 months of long-term.

[0214]

[0215]

[0216]

[0217]

[0218]

[0219] Routine stability test results conclusion

[0220] High temperature test: Iscartrelvir hydrochloride tablets were placed at high temperature of 60℃±2℃ for 30 days, and there were no obvious changes in appearance, content, related substances, dissolution, and moisture, and they were all within the limit range, proving that the product has good thermal stability at 60℃±2℃.

[0221] High humidity test: Iscartrelvir hydrochloride tablets were placed at 25℃±2℃ / 90%±5% RH for 30 days, black mold spots appeared on the surface of the tablets, the moisture increased beyond the limit, the content fluctuated more than ±5%, the dissolution was much lower than the limit (80%), and the related substances had no obvious change, proving that it is unstable under high humidity conditions.

[0222] Light test: Iscartrelvir hydrochloride tablets were placed under 1x ICH light, and there were no obvious changes in appearance, content, related substances, dissolution, and moisture, proving that it has good light stability.

[0223] Accelerated test: Iscartrelvir hydrochloride tablets were placed under accelerated conditions for 6 months, and there were no obvious changes in appearance, content, related substances, dissolution, moisture, enantiomeric impurities, and microbial limit, and they were all within the limit range, and the quality was stable.

[0224] Long-term test: Iscartrelvir hydrochloride tablets were placed under long-term conditions for 12 months, and there were no obvious changes in appearance, content, related substances, dissolution, moisture, and enantiomeric impurities, and they were all within the limit range, and the quality was stable.

[0225] After the influence factor sampling, the dissolution behavior of prescription 12-Iscartrelvir hydrochloride tablets was similar to that before sampling, and there was no big difference. The results further illustrate the rationality and feasibility of the prescription and process design of Iscartrelvir hydrochloride tablets. The active ingredient content of Iscartrelvir hydrochloride tablets is high, the impurity content is low, and the impurity content does not increase basically in the accelerated test and long-term test, and the stability is high, the dissolution is fast, and the pharmacokinetic effect is good.

[0226] The above is only the preferred specific embodiment of the present application, but the protection scope of the present application is not limited thereto, any skilled person in the art can make equivalent replacement or change according to the technical scheme and inventive concept of the present application within the technical range disclosed by the present application, which should be covered within the protection scope of the present application.

Claims

1. A solid dosage form comprising: Active pharmaceutical ingredient, microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, croscarmellose sodium cellulose, and magnesium stearate; Its characteristic is that the active pharmaceutical ingredient is compound 1 or a pharmaceutically acceptable salt thereof.

2. The solid dosage form as described in claim 1, characterized in that, By weight, it includes the following components: 30-40% raw materials; 35-42% microcrystalline cellulose; 17-21% mannitol; Approximately 3% hydroxypropyl methylcellulose; Approximately 3% cross-linked sodium carboxymethyl cellulose; and 0.5-1.5% magnesium stearate.

3. The solid dosage form as described in claim 1, characterized in that, By weight, it includes components selected from one of the following groups: a) 40% of the raw materials; 35.33% microcrystalline cellulose; 17.67% mannitol; 3% hydroxypropyl methylcellulose; 3% crosslinked sodium carboxymethyl cellulose; and 0.5-1.5% magnesium stearate; b) 35% of the active pharmaceutical ingredient; 38.67% microcrystalline cellulose; 19.33% mannitol; 3% hydroxypropyl methylcellulose; 3% crosslinked sodium carboxymethyl cellulose; and 0.5-1.5% magnesium stearate; c) 31.25% of the active pharmaceutical ingredient; 40.83% microcrystalline cellulose; 20.42% mannitol; 3% hydroxypropyl methylcellulose; 3% crosslinked sodium carboxymethyl cellulose; and 0.5-1.5% magnesium stearate; d) 33.41% of the active pharmaceutical ingredient; 39.39% microcrystalline cellulose; 19.70% mannitol; 3% hydroxypropyl methylcellulose; 3% crosslinked sodium carboxymethyl cellulose; and 0.5-1.5% magnesium stearate.

4. The solid dosage form according to any one of claims 1-3, characterized in that, The pharmaceutically acceptable salt of the compound of Formula I is its hydrochloride salt.

5. The solid dosage form according to any one of claims 1-3, characterized in that, The solid dosage form is an oral tablet.

6. The solid dosage form according to any one of claims 1-3, characterized in that, The solid dosage form is prepared by direct tableting or dry granulation. Preferably, it is prepared by a dry granulation process.

7. The solid dosage form according to any one of claims 1-3, characterized in that, The solid dosage form includes in-particle and out-of-particle components; wherein the in-particle components include active pharmaceutical ingredient, microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate, and the out-of-particle components include magnesium stearate.

8. The solid dosage form according to claim 7, characterized in that, The magnesium stearate content in the components outside the granules is approximately 1%.

9. The solid dosage form according to any one of claims 1-3, characterized in that, The solid dosage form also includes coating.

10. The solid dosage form according to claim 9, characterized in that, The coating comprises a gastrosoluble film coating material; preferably, the coating comprises 85F270011Beige type coating material.

11. The method for preparing the solid dosage form according to any one of claims 1-10, characterized in that: The active pharmaceutical ingredient, microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, and croscarmellose sodium are premixed, then magnesium stearate is added for lubrication, followed by dry granulation, and then magnesium stearate is added to the final mixture before tableting to obtain the solid dosage form.

12. The preparation method according to claim 11, characterized in that: After obtaining the solid dosage form, a coating step is also included.

13. The method for preparing solid dosage forms according to any one of claims 1-10, characterized in that: Includes the following steps: Step 1: Feeding the ingredients Weigh out the raw material, microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, croscarmellose sodium cellulose, and magnesium stearate respectively, and sieve the raw material and magnesium stearate. Step 2: Premixing Add the active pharmaceutical ingredient, microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, and croscarmellose sodium to a mixing tank and mix by rotation. Step 3: Lubrication Add the magnesium stearate particles into the mixing tank of step 2 and continue to rotate and mix to obtain a mixture; Step 4: Dry granulation The mixture obtained in step 3 is added to a dry granulator for granulation to obtain granules; Step 5: Total Mixing Add the granulated magnesium stearate and the granules obtained in step 4 to the mixing tank; Step 6: Tableting The solid formulation was obtained by compression using a rotary tablet press.

14. The preparation method according to claim 12, characterized in that: In the coating step, a coating solution prepared by mixing a stomach-soluble film coating premix with purified water is used to coat the uncoated tablets. The inlet air temperature is controlled at 65°C, and the coating is spray-coated until the weight gain is 3.0%-5.0%. After the formulation reaches the target weight gain, it is dried, cooled, and then dispensed as tablets.

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