A pharmaceutical composition of a nucleoside-derived compound, its preparation method and uses

Abstract

The present invention provides a pharmaceutical composition of a nucleoside-derived compound, its preparation method and uses, belonging to the field of pharmaceuticals. The pharmaceutical composition comprises compound SHEN26 and pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients include at least one selected from diluents, disintegrants, binders, lubricants and glidants. The pharmaceutical composition has advantages such as high dissolution rate, good compatibility between the active ingredient and excipients, good stability, high bioavailability, etc.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and particularly to a pharmaceutical composition of a nucleoside-derived compound, a preparation method thereof, and uses thereof. Background Art

[0002] The novel coronavirus is an enveloped single-stranded RNA virus belonging to the genus β coronavirus. Similar to SARS and MERS, the SARS-CoV-2 genome encodes non-structural proteins: 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), helicase, and RNA-dependent RNA polymerase (RdRp); structural proteins such as spike glycoprotein and accessory proteins. The spike glycoprotein on the surface of the novel coronavirus binds to the angiotensin-converting enzyme (ACE2) receptor on the surface of human cells, thereby infecting human respiratory epithelial cells. After the virus enters the host cell, it disintegrates, releasing the nucleocapsid and viral RNA into the cytoplasm. The 5′-terminal open reading frame (ORF1a / b) of the viral RNA encodes polyproteins (pp1a and pp1ab), which play an important role in the processing and maturation of enzymes required for virus replication. Pp1a and pp1ab can be cleaved by papain-like protease (PLpro) and 3C-like protease (3CLpro) to produce non-structural proteins, including RNA-dependent RNA polymerase and helicase, etc., which play a key role in the transcription and replication of the novel coronavirus. Currently, the spike glycoprotein on the surface of the coronavirus that recognizes the receptor, and the important proteins 3CLpro, PLpro, and RdRp involved in the replication and transcription processes are four very attractive targets for antiviral drug research and development.

[0003] Remdesivir, as an RdRp inhibitor, has shown anti-novel coronavirus activity at the cellular level. However, clinical trials have shown that remdesivir does not significantly reduce mortality in humans. And since the clinical use dose is already close to the safety dose, some obvious side effects have to be concerned.

[0004] Therefore, there is still a need for a drug for treating the novel coronavirus with good safety, good stability, and good bioavailability. Summary of the Invention

[0005] To solve the above problems, the present invention provides a pharmaceutical composition, a preparation method thereof, and uses thereof.

[0006] In a first aspect, a pharmaceutical composition is provided.

[0007] A pharmaceutical composition comprising compound SHEN26 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient,

[0008]

[0009] The pharmaceutically acceptable excipient may include at least one selected from diluents, disintegrants, binders, lubricants and glidants. In some embodiments, the pharmaceutically acceptable excipient includes a diluent, a disintegrant, a binder and a lubricant.

[0010] The diluent may include at least one selected from microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol; preferably, the diluent is microcrystalline cellulose.

[0011] The disintegrant may include at least one selected from sodium croscarmellose, crospovidone XL-10, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, pregelatinized starch; preferably, the disintegrant is sodium croscarmellose.

[0012] The binder may include at least one selected from hydroxypropyl cellulose, povidone K30, hydroxypropyl methylcellulose, starch; preferably, the binder is hydroxypropyl cellulose.

[0013] The lubricant may include at least one selected from magnesium stearate, sodium stearyl fumarate, stearic acid, talc; preferably, the lubricant is magnesium stearate.

[0014] The composition may further include an external lubricant. The glidant may include colloidal silicon dioxide.

[0015] Calculated based on the total mass of the pharmaceutical composition, the content of compound SHEN26 may be 15 wt% - 70 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of compound SHEN26 is 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 65 wt% or 70 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of compound SHEN26 is 50 wt% - 60 wt%.

[0016] Calculated based on the total mass of the pharmaceutical composition, the content of the diluent may be 20 wt% - 70 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the diluent is 20 wt%, 25 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt% or 70 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the diluent is 30 wt% - 40 wt%.

[0017] Calculated based on the total mass of the pharmaceutical composition, the content of the disintegrant may be 1 wt% - 10 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the disintegrant is 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt% or 10 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the disintegrant is 2 wt% - 4 wt%.

[0018] Calculated based on the total mass of the pharmaceutical composition, the content of the binder may be 1 wt% - 10 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the binder is 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt% or 10 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the binder is 4 wt% - 6 wt%.

[0019] Calculated based on the total mass of the pharmaceutical composition, the content of the lubricant may be 0.1 wt% - 5 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the lubricant is 0.1 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt% or 1 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the lubricant is 0.5 wt% - 1 wt%.

[0020] Calculated based on the total mass of the pharmaceutical composition, the content of the external lubricant may be 0.5 wt% - 5 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the external lubricant is 0.5 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 3.0 wt%, 4.0 wt% or 5 wt%. In some embodiments, calculated based on the total mass of the pharmaceutical composition, the content of the external lubricant is 0.5 wt% - 1.5 wt%.

[0021] In some embodiments, the pharmaceutically acceptable excipients include diluents, disintegrants, binders, lubricants and external lubricants. The diluent is microcrystalline cellulose; the disintegrant is sodium carboxymethylcellulose cross-linked; the binder is hydroxypropylcellulose; the lubricant is magnesium stearate. Calculated based on the total mass of the pharmaceutical composition, the content of the compound SHEN26 is 50 wt% - 60 wt%, the content of the diluent is 30 wt% - 40 wt%, the content of the disintegrant is 2 wt% - 4 wt%, the content of the binder is 4 wt% - 6 wt%, the content of the lubricant is 0.5 wt% - 1 wt%, and the content of the external lubricant is 0.5 wt% - 1.5 wt%.

[0022] In some embodiments, the pharmaceutically acceptable excipients include diluents, disintegrants, binders, lubricants and external lubricants. The diluent is microcrystalline cellulose; the disintegrant is sodium carboxymethylcellulose cross-linked; the binder is hydroxypropylcellulose; the lubricant is magnesium stearate. Calculated based on the total mass of the pharmaceutical composition, the content of the compound SHEN26 is 55.56 wt%, the content of the diluent is 34.94 wt%, the content of the disintegrant is 3 wt%, the content of the binder is 5 wt%, the content of the lubricant is 0.5 wt%, and the content of the external lubricant is 1 wt%.

[0023] The dosage form of the composition can be an oral solid preparation.

[0024] The oral solid preparation can include tablets, granules or capsules.

[0025] The specification of the pharmaceutical composition can be 10 mg - 500 mg. In some embodiments, the specification of the pharmaceutical composition is 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg or 200 mg.

[0026] In a second aspect, a use of the aforementioned pharmaceutical composition is provided.

[0027] In some embodiments of the present invention, a use of the pharmaceutical composition according to the first aspect in the preparation of a product for preventing, alleviating or treating coronavirus infection, or the replication or reproduction of its homologous variant virus and the cytopathic effect produced thereby.

[0028] The infection can include fever, cough, sore throat, pneumonia, acute respiratory tract infection, severe acute respiratory tract infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock.

[0029] In some embodiments of the present invention, there is provided the use of the pharmaceutical composition described in the first aspect in the preparation of a product for detecting a coronavirus or its homologous variant virus.

[0030] The coronavirus may include: MHV-A59, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, murine hepatitis virus, feline infectious peritonitis virus, canine coronavirus, bovine coronavirus, avian infectious bronchitis virus or porcine coronavirus. Preferably, the SARS-CoV-2 includes a mutant strain or a non-mutant strain of SARS-CoV-2; more preferably, the mutant strains of SARS-CoV-2 include SARS-CoV-2 mutant strain B.1, SARS-CoV-2 mutant strain B.1.351, SARS-CoV-2 mutant strain B.1.617.2, SARS-CoV-2 mutant strain C.37, SARS-CoV-2 mutant strain P.1 lineage, SARS-CoV-2 mutant strain B.1.525, SARS-CoV-2 mutant strain B.1.427 or SARS-CoV-2 mutant strain B.1.429.

[0031] The pharmaceutical composition may be applicable to humans or animals; and / or the animals include bovines, equines, ovines, porcines, canines, felines, rodents, primates, avians or fish.

[0032] In a third aspect, there is provided a method for preparing the aforementioned pharmaceutical composition.

[0033] In some preferred embodiments of the present invention, a method for preparing the pharmaceutical composition described in the first aspect includes: mixing the compound SHEN26 and a pharmaceutically acceptable excipient, dry granulating, adding an external lubricant, mixing, and tableting or capsule filling or bagging to obtain the composition.

[0034] In some embodiments of the present invention, a method for preparing the pharmaceutical composition described in the first aspect includes: mixing the compound SHEN26 and a pharmaceutically acceptable excipient, wet granulating, grinding, drying, dry grinding, adding an external lubricant, mixing, and tableting or capsule filling or bagging to obtain the composition.

[0035] In some preferred embodiments of the present invention, a method for preparing the pharmaceutical composition described in the first aspect includes: grinding or pulverizing the compound SHEN26 and then mixing it with a pharmaceutically acceptable excipient, dry granulating, adding an external lubricant, mixing, and tableting or capsule filling or bagging to obtain the composition.

[0036] In some embodiments of the present invention, a method for preparing the pharmaceutical composition described in the first aspect includes: grinding or pulverizing the compound SHEN26 and mixing it with pharmaceutically acceptable excipients, wet granulation, grinding, drying, dry grinding, adding external lubricant, mixing, tableting or capsule filling or bagging to obtain the composition.

[0037] Preferably, the dry granulation method is adopted to prepare the aforementioned pharmaceutical composition in the present invention. Compared with the direct mixing process, the dry granulation method is beneficial to avoid the risk of material stratification and the problem of uneven mixing.

[0038] Beneficial effects

[0039] Compared with the prior art, at least one of the following beneficial technical effects is included in an embodiment of the present invention:

[0040] (1) The pharmaceutical composition provided by the present invention has the advantages of high dissolution rate, fast release rate, good compatibility of raw materials and excipients, good stability, high bioavailability, etc.

[0041] (2) Using the excipients provided by the present invention is beneficial to improve the dissolution rate, release rate, compatibility of raw materials and excipients, and stability of the obtained pharmaceutical composition (the stability includes the stability of properties, content, related substances, humidity gain weight, dissolution rate, release rate, etc.), and is beneficial to improving the material properties during the preparation process of the pharmaceutical composition.

[0042] (3) Using the prescription ratio of the compound SHEN26 and / or the prescription ratio of each excipient provided by the present invention is beneficial to improve the dissolution rate, release rate, compatibility of raw materials and excipients, and stability of the obtained pharmaceutical composition (the stability includes the stability of properties, content, related substances, humidity gain weight, dissolution rate, release rate, etc.), and is beneficial to improving the material properties (viscosity, material formability, particle hardness) during the preparation process of the pharmaceutical composition.

[0043] Term definition:

[0044] In the present invention, "room temperature" refers to the ambient temperature, which can be 10°C - 40°C, can be 20°C - 30°C; in some embodiments, it is 22°C - 28°C; in some embodiments, it is 24°C - 26°C; in some embodiments, it is 25°C.

[0045] The term "specification" refers to the weight of the active ingredient in a unit preparation (single tablet or single capsule). For example, the 50mg specification in the present invention means that each tablet or single capsule contains 50mg of the compound SHEN26.

[0046] The term "D90" refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 90%. Its physical meaning is that 90% of the particles have a particle size smaller than it. For example, "D90 is not greater than 100 μm" means "90% of the particles are not greater than 100 μm". D10 refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 10%; D50 refers to the particle size corresponding to when the cumulative particle size distribution number of a sample reaches 50%.

[0047] The term "open" means that the drug or preparation is placed in an open container without screwing on the cap and sealing, so that the capsule is in contact with the external environment.

[0048] The term "closed" means that after the drug or preparation is placed in the container, the lid is covered and sealed with aluminum foil to isolate the capsule from the external environment.

[0049] In the foregoing of the present invention, whether or not words such as "about" or "approximately" are used, all the numbers disclosed herein are approximate values. Based on the disclosed numbers, the numerical value of each number may have a difference of less than ±10% or a reasonable difference considered by those skilled in the art, such as differences of ±1%, ±2%, ±3%, ±4% or ±5%.

[0050] The "pharmaceutically acceptable salts" used in the present invention refer to the organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reacting with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or these salts can be obtained by other methods described in books and literature such as ion exchange method. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and so on. The salts obtained by appropriate bases include salts of alkali metals, alkaline earth metals, ammonium and N+(C1-4 alkyl)4. The present invention also contemplates quaternary ammonium salts formed by any compound containing N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and so on. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counterbalancing ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates and aromatic sulfonates.

[0051] The terms "optional", "optionally" or "optionally" mean that the subsequent described event or situation may but does not necessarily occur. For example, "optional surfactant" means that the surfactant may or may not be present.

[0052] The term "external lubricant" refers to a substance added after granulation to reduce the friction between the granules obtained by granulation, prevent the raw and auxiliary materials from sticking to the surface of the punch, or reduce the friction between the tablet and the wall of the die hole.

[0053] The term "weight percentage" or "percentage by weight", "wt%", or "w / w%" is defined as the weight of an individual component in a composition divided by the total weight of all components of the composition and then multiplied by 100.

[0054] The term "and / or" shall be understood to mean any one of the alternatives or a combination of any two or more of the alternatives.

[0055] As used herein, the term "treatment" refers to a clinical intervention that is intended to alter the natural course of a disease in an individual being treated. Desired therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of a disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state, and relieving or improving the prognosis.

[0056] "Pharmaceutically acceptable" means a substance or compound that, within the scope of sound medical judgment, is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic response, and the like, and has a reasonable benefit / risk ratio.

[0057] In the description of this specification, descriptions with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples", etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0058] In this application, a "composition" can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. Usually, the composition is prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both.

[0059] In the present invention, "compound SHEN26", "SHEN26", and "SHEN26 compound" all have the same meaning. Detailed Description of the Invention

[0060] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further elaborate on the present invention.

[0061] All the reagents used in the present invention can be purchased from the market or prepared by the methods described in the present invention.

[0062] "#0" represents the capsule shell No. 0. "#4" represents the capsule shell No. 4. "API" represents the active pharmaceutical ingredient, which refers to the compound SHEN26 in the following specific examples. "rpm" represents the rotational speed unit "revolutions per minute".

[0063] Dissolution test method

[0064] Unless otherwise specified, the dissolution test methods used in the formulation research of this product are shown in Table 1.

[0065] Table 1. Dissolution methods

[0066]

[0067] Example 1: Investigation of the preparation process

[0068] (1) Direct mixing process

[0069] Prescription: See Table 2.

[0070] Operation: Directly mix the compound SHEN26 with microcrystalline cellulose 102, mannitol 100SD, croscarmellose sodium and magnesium stearate LIGAMED MF-2-V to obtain a mixed powder, fill the capsules, and obtain the SHEN26 compound capsules.

[0071] Detection of powder properties: Detect the powder properties of the raw material of the compound SHEN26 and the powder properties of the mixed powder after directly mixing the compound SHEN26 with other excipients. The results are shown in Table 3.

[0072] Table 2: Composition of the prescription for the direct mixing process

[0073]

[0074] Table 3: Results of the powder properties of API and the prescription

[0075]

[0076] Result analysis: From the above data, it can be seen that the API has relatively good fluidity. After direct mixing with the excipients, the Carr index is further reduced, and the API particle size is relatively large, resulting in a risk of stratification during the production process. Therefore, the dry granulation process was further investigated.

[0077] (2) Dry granulation process

[0078] Prescription: See Table 4.

[0079] Operation: Mix compound SHEN26 with internal excipients, perform dry granulation, add external excipients, mix, and fill into capsules to obtain the compound SHEN26 capsules.

[0080] Table 4: Prescription composition

[0081]

[0082] Dissolution test: Compare the direct mixing process prescription with the dry granulation process prescription, and the dissolution results are shown in Table 5.

[0083] Table 5: Dissolution results

[0084]

[0085] Result analysis: From the above data, it can be seen that the dissolution of the capsules in both processes meets the requirements. However, the dissolution reaches a relatively high level 30 minutes after filling the capsules by direct mixing, indicating that there may be a risk of stratification in the direct mixing process. Therefore, the dry granulation process is finally determined for prescription development.

[0086] Example 2: Investigation on the amount of binder

[0087] Prescription: See Table 6A, Table 6B, and Table 6C.

[0088] Table 6A: Prescription composition

[0089]

[0090] Table 6B: Prescription composition

[0091]

[0092]

[0093] Table 6C: Prescription composition

[0094]

[0095] Preparation method: Crush compound SHEN26 and mix it with internal excipients, perform dry granulation, add external excipients, mix, and fill into capsules to obtain the compound SHEN26 capsules.

[0096] Phenomenon observation: During the dry granulation process, observe the viscosity, formability, and particle hardness of the material, and the results are shown in Table 7.

[0097] Table 7: Dry granulation phenomenon

[0098]

[0099]

[0100] Result analysis: From the above dry granulation phenomena, it can be seen that in the dry granulation process of Formulations 37167-032A-1 and 37167-032B-1, the ribbon forming property is poor; when the dosage of the binder hydroxypropyl cellulose EXF is 3%, the ribbon forming property of Formulations 37167-032A-2 and 37167-032B-2 is poor and the granules are relatively soft; after adjusting the dosage of the binder hydroxypropyl cellulose EXF to 5%, although there is a slight phenomenon of sticking to the roller in Formulations 37167-032A and 37167-032B, the ribbon forming property is good and the granule hardness is moderate. Therefore, 5% hydroxypropyl cellulose EXF is selected as the binder.

[0101] Example 3: Investigation of the type of filler

[0102] Formulation: See Table 8.

[0103] Table 8: Formulation composition

[0104]

[0105]

[0106] Preparation method: After crushing the compound SHEN26, it is mixed with pharmaceutically acceptable excipients, dry granulated, an external lubricant is added, mixed, and filled into capsules to obtain the compound SHEN26 capsules.

[0107] Phenomenon observation: During the dry granulation process, the viscosity, forming property and granule hardness of the materials are observed, and the results are shown in Table 9.

[0108] Dissolution detection: Take the compound SHEN26 capsules obtained in Example 3 and detect the dissolution rate respectively. The results are shown in Table 10.

[0109] Table 9: Dry granulation phenomena

[0110]

[0111] Table 10: Dissolution rate results

[0112]

[0113] Result analysis: From the above dry granulation phenomena, it can be seen that when the ratio of microcrystalline cellulose 102: mannitol 100SD is 2:1, there is a slight phenomenon of sticking to the roller in the dry granulation process of Formulations 37167-023A and 37167-023B, the ribbon forming property is good and the granule hardness is moderate; when the filler mannitol is removed, there is no phenomenon of sticking to the roller in the dry granulation process of Formulations 37167-036A / B, the ribbon forming property is good and the granule hardness is moderate, and the dissolution rate meets the requirements. Therefore, microcrystalline cellulose 102 is determined to be used as the filler.

[0114] Example 4: Investigation on the particle size of the active pharmaceutical ingredient

[0115] Formulation: See Table 11.

[0116] Table 11: Composition of the formulation

[0117]

[0118]

[0119] Preparation method: The compound SHEN26 was crushed and sieved (through 40-mesh sieve and 60-mesh sieve respectively), mixed with pharmaceutically acceptable excipients, granulated by dry granulation, added with external lubricant, mixed, and filled into capsules to obtain the compound SHEN26 capsules.

[0120] Observation of phenomena: After dry granulation, the powder properties were examined, and the results are shown in Table 12.

[0121] Dissolution test: The compound SHEN26 capsules obtained in Example 4 were taken, and the dissolution degrees were detected respectively. The results are shown in Table 13.

[0122] Table 12: Results of the powder properties of the dry granulation formulation

[0123] Batch number Bulk density (g / ml) Tap density (g / ml) Carr index (%) Angle of repose (°) 37167-045A / B-2 0.5008 0.7033 28.79 39.88

[0124] Table 13: Results of the dissolution degree

[0125]

[0126] From the above results, it can be seen that the final dry granulation formulation has relatively good fluidity, and the particle size D90 of the active pharmaceutical ingredient is in the range of 195.440 μm - 327.667 μm, which will not affect the dissolution behavior of the product. Considering the influence of the large particle size of the active pharmaceutical ingredient on the process, the active pharmaceutical ingredient was crushed and sieved through a 60-mesh sieve before the process investigation.

[0127] Example 5: Preparation of compound SHEN26 capsules

[0128] Formulation: See Table 14.

[0129] Table 14: Composition of the unit dose product of SHEN26 capsules

[0130]

[0131] Remarks: *Gelatin hard capsules, No. 4 opaque white (cap color number: 44.801, body color number: 44.801) and No. 0 opaque white (cap color number: 44.801, body color number: 44.801) - CN, US ingredients are titanium dioxide and gelatin. N / A: Not applicable.

[0132] Preparation method: Grind or pulverize the compound SHEN26 and mix it with pharmaceutically acceptable excipients, granulate by dry granulation, add external lubricant, mix, and fill into capsules to obtain the compound SHEN26 capsules.

[0133] Dissolution test: Take the compound SHEN26 capsules obtained in Example 5 and detect the dissolution degree respectively. The results are shown in Table 15.

[0134] Table 15: Dissolution results

[0135]

[0136] Result analysis: The compound SHEN26 capsules obtained by using the prescription and preparation process provided by the present invention have rapid and complete dissolution and release.

[0137] Example 6: Compatibility of raw materials and excipients

[0138] Operation: Select common excipients for oral solid preparations and mix them with the SHEN26 raw material drug in different proportions. Place them under different conditions and take samples at different time points. Use appearance, increased humidity weight, content and related substances as indicators to judge the compatibility between the raw material drug and the excipients. According to the "Basic Technical Guidelines for the Research of Chemical Pharmaceutical Preparations" and the preparation specifications, for the excipients with larger dosages, the mixture ratio of the main drug to the diluent is set as 1:5; for the excipients with moderate dosages (such as croscarmellose sodium), the mixture ratio of the main drug to the disintegrant is 1:1; for the excipients with smaller dosages (such as magnesium stearate), the mixture ratio of the main drug to the lubricant is 5:1. The information of the raw material drug and excipient manufacturers and the ratio of raw materials and excipients in the compatibility experiment are shown in Table 16.

[0139] Storage conditions: Place the samples under the experimental conditions of high temperature (60 °C), high humidity (25 °C / 90% ± 5% RH), acceleration (40 °C / 75% ± 5% RH), and light (visible light 4500 Lux ± 500 Lux, near ultraviolet light 85 μw / cm 2 ) and take samples for inspection on the 0th day, 10th day, and 30th day. Detect appearance, increased humidity weight, content and related substances.

[0140] Table 16: Investigation on the compatibility of raw materials and excipients

[0141]

[0142] Note: Since the opaque rich yellow component of the gelatin hollow capsule No. 3, except for the pigment, is the same as that of the gelatin hollow capsule No. 4 and the opaque white hollow capsule No. 0, which are both gelatin and titanium dioxide, only the opaque rich yellow capsule shell of the gelatin hollow capsule No. 3 is investigated in this experiment.

[0143] Results: The above excipients are compatible with SHEN26. After 30 days under various storage conditions, there are no significant changes in appearance, increased moisture weight, content, and related substances.

[0144] Example 7: Stability Study

[0145] Operation: Take the SHEN26 capsules of the compounds obtained in Example 5 with batch numbers 37167 - 054A and 37167 - 054B, package them according to the packaging described in Tables 17 and 18, and then place them at 0 day, 10 days, and 30 days under the conditions of light (open), 40°C / 75%RH (open), and 40°C / 75%RH (closed), and detect the dissolution and related substances. The results are shown in Tables 19 and 20.

[0146] Table 17: Packaging Information (Bottled)

[0147]

[0148]

[0149] Table 18: Packaging Information (Double - Aluminum Packaging)

[0150]

[0151] Table 19: Stability Results - Dissolution

[0152]

[0153] Table 20: Stability Results - Related Substances

[0154]

[0155] Result Analysis:

[0156] From the above dissolution data, it can be seen that after 30 days of placement under the conditions of light (open), 40°C / 75%RH (open), and 40°C / 75%RH (closed), the dissolution and related substances of the 50mg - specification and 200mg - specification capsules in bottled or double - aluminum packaging have no obvious changes. The SHEN26 capsules provided by the present invention have good stability.

[0157] The method of the present invention has been described through preferred embodiments. Relevant personnel can obviously make changes or appropriate modifications and combinations to the methods and applications described herein within the content, spirit, and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can draw on the content of this article and appropriately improve the process parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A pharmaceutical composition comprising compound SHEN26 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, ； wherein the pharmaceutically acceptable excipient includes a diluent, a disintegrant, a binder, and a lubricant; the diluent is microcrystalline cellulose; the disintegrant is croscarmellose sodium, the binder is hydroxypropyl cellulose, and the lubricant is magnesium stearate. Calculated based on the total mass of the pharmaceutical composition, the content of compound SHEN26 is 50 wt% - 60 wt%, the content of the diluent is 30 wt% - 40 wt%, the content of the disintegrant is 2 wt% - 4 wt%, the content of the binder is 5 wt% - 6 wt%, and the content of the lubricant is 0.5 wt% - 1 wt%; the pharmaceutical composition further includes an external lubricant; the content of the external lubricant is 0.5 wt% - 5 wt%; The preparation method of the pharmaceutical composition comprises: Mix compound SHEN26 and a pharmaceutically acceptable excipient, perform dry granulation, add the external lubricant, mix, and then perform tabletting, capsule filling, or bagging to obtain the composition; or Grind or pulverize compound SHEN26 and then mix it with a pharmaceutically acceptable excipient, perform dry granulation, add the external lubricant, mix, and then perform tabletting, capsule filling, or bagging to obtain the composition.

2. The pharmaceutical composition according to claim 1, wherein the content of the external lubricant is 0.5 wt% - 1.5 wt%.

3. The pharmaceutical composition according to any one of claims 1 - 2, wherein the dosage form of the composition is an oral solid preparation.

4. The pharmaceutical composition according to claim 3, wherein the oral solid preparation is selected from tablets, granules, or capsules.

5. The pharmaceutical composition according to any one of claims 1 - 2, wherein the specification of the pharmaceutical composition is 10 mg - 500 mg.

6. The pharmaceutical composition according to any one of claims 1 - 2, wherein the specification of the pharmaceutical composition is 50 mg or 200 mg.

7. The pharmaceutical composition according to claim 3, wherein the specification of the pharmaceutical composition is 10 mg - 500 mg.

8. The pharmaceutical composition according to claim 3, wherein the specification of the pharmaceutical composition is 50 mg or 200 mg.

9. The pharmaceutical composition according to claim 4, wherein the specification of the pharmaceutical composition is 10 mg - 500 mg.

10. The pharmaceutical composition according to claim 4, wherein the specification of the pharmaceutical composition is 50 mg or 200 mg.

11. Use of the pharmaceutical composition according to any one of claims 1 - 10 in the preparation of a drug for preventing, alleviating, or treating the replication or reproduction of SARS-CoV-2 coronavirus infection.

12. The use according to claim 11, characterized in that, The pharmaceutical composition is applicable to animals.

13. The use according to claim 12, characterized in that, The animals include bovidae, equidae, ovidae, suidae, canidae, felidae, rodents, primates, avians, or fish.

14. The use according to claim 11, wherein The pharmaceutical composition is applicable to humans.

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