A pharmaceutical preparation of a polycyclic carbonylpyridinone derivative

Abstract

The present application provides a kind of polycyclic carbamoyl pyridone derivative pharmaceutical preparation and preparation method thereof, the pharmaceutical preparation includes the compound shown in formula (I) or its pharmaceutically acceptable salt and diluent, wherein the particle size D90 of the compound shown in formula (I) or its pharmaceutically acceptable salt is 0.5-50 μm.The polycyclic carbamoyl pyridone derivative pharmaceutical preparation obtained by the present application has high dissolution rate, good stability, oral absorption is not affected by food, can be used with dairy products, calcium supplement food, good compliance, suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a pharmaceutical formulation of a polycyclic carbamoylpyridinone derivative, and a method for preparing the formulation. Technical Background

[0002] Because the influenza virus genome is small, the synthesis of its required proteins depends on the host cell's translation system. Therefore, the influenza virus's messenger RNA (mRNA) needs to possess both a 5′ cap (CAP) structure and a 3′-poly(A) tail structure that can be recognized by the host cell's translation system. The 5′ cap structure is "snatched" from the 5′ end of the host cell's precursor mRNA by the endonuclease activity of the PA subunit in the influenza virus RNA polymerase complex. This mechanism, known as "CAP-snatching," uses the CAP cap structure of the host mRNA for viral mRNA transcription and is essential for the initiation of influenza virus transcription. Because "CAP-snatching" is a crucial step in the influenza virus replication cycle, and because a similar mechanism and corresponding protease do not exist in the host cell, inhibitors of "CAP-snatching" endonucleases can selectively block the influenza virus transcription process without affecting the host cell. Thus, this mechanism has become a potential target for anti-influenza drugs.

[0003] CN108440564 discloses a polycyclic carbamoylpyridinone derivative as shown in formula (I). The parent compound of the disclosed compound exhibits high inhibitory activity against 5′ cap-dependent endonucleases and high selectivity. The prodrug of the disclosed compound has the following advantages: high oral absorption, good bioavailability, good clearance rate, and high pulmonary metastasis. However, the polycyclic carbamoylpyridinone derivative shown in formula (I) has low in vivo solubility, poor photostability, and poor high-temperature and high-humidity stability, posing a risk of increased side effects.

[0004] In 2021, the NMPA approved the PA inhibitor mabaloxavir for the treatment of uncomplicated influenza in adolescents and adults. Compared to fasting, postprandial administration of mabaloxavir resulted in reductions of 67%, 49%, 42%, and 41% in the Cmax, AUC0–72, AUC0–last, and AUC0–inf of the active metabolite S-033447, respectively. Interprandial administration, compared to fasting, resulted in reductions of 57%, 44%, 36%, and 34% in the Cmax, AUC0–72, AUC0–last, and AUC0–inf of S-033447, respectively.

[0005] Furthermore, the drug's instructions state that mabaloxavir should not be taken concurrently with calcium-fortified drinks or calcium supplements, as this may affect drug exposure, leading to reduced efficacy or even ineffectiveness. However, Chen Shaoren et al. reported in their study "Efficacy Observation of Calcium Supplementation in the Treatment of 192 Cases of Febrile Seizures" that appropriate calcium supplementation after hospitalization in children with febrile seizures may be one of the effective measures to prevent recurrent seizures. Therefore, appropriate calcium supplementation remains necessary for influenza with high fever. The primary user group for calcium-fortified foods or calcium supplements is the elderly over 65 years of age with osteoporosis, and influenza patients over 65 years of age are considered high-risk patients and a key group for anti-influenza drug treatment. Therefore, improving medication adherence to PA inhibitors has significant clinical importance.

[0006]

[0007] Therefore, there is a need for a polycyclic carbamoylpyridinone derivative drug formulation that has a fast in vivo dissolution rate, good bioavailability, stable quality, is easy to prepare, has oral efficacy that is not limited by calcium-fortified beverages and calcium supplements, and has good compliance. Summary of the Invention

[0008] This invention provides a polycyclic carbamoylpyridinone derivative drug formulation with high dissolution, good bioavailability, good stability, oral efficacy not limited by calcium-fortified beverages and calcium supplements, and good patient compliance, as well as its preparation method.

[0009] The present invention provides a pharmaceutical formulation of a polycyclic carbamoylpyridinone derivative as shown in formula (I), the pharmaceutical formulation comprising a polycyclic carbamoylpyridinone derivative or a pharmaceutically acceptable salt thereof and a diluent, wherein the D90 of the polycyclic carbamoylpyridinone derivative or a pharmaceutically acceptable salt thereof is 0.5-50 μm.

[0010]

[0011] in:

[0012] R 1 It is hydrogen or deuterium;

[0013] R 2 It is hydrogen or deuterium;

[0014] R 3 It is hydrogen or deuterium;

[0015] L represents hydrogen, alkyl, -CH2OC(=O)OCH3, -CH2OC(=O)OCD3, -CH2OC(=O)OCD2CD3;

[0016] And R 1 R 2 and R 3 At least one of them is deuterium.

[0017] The polycyclic carbamoylpyridinone derivative of formula (I) is preferably selected from the following compounds: ({(12aR)-12-[(11S)-7,8-difluoro-11-deuterium-6,11-dihydrodibenzo[b,e]-11-thiazolinone]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]-7-triazine}oxy)methyl carbonate (chemical structure as shown in formula (II))

[0018]

[0019] This invention provides a polycyclic carbamoylpyridinone derivative tablet as shown in formula (I) and a method for preparing the same. The polycyclic carbamoylpyridinone derivative tablet comprises a core and a coating.

[0020] The components of the core material are calculated as a percentage by mass as follows:

[0021]

[0022] The coating is a film coating.

[0023] In another technical solution, the polycyclic carbamoylpyridinone derivative tablet contains the active ingredient ({(12aR)-12-[(11S)-7,8-difluoro-11-deuterium-6,11-dihydrodibenzo[b,e]-11-thiazolinone]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]-7-triazine}oxy)methyl carbonate, wherein the preferred mass percentage of the material and each component in the tablet core is:

[0024]

[0025]

[0026] The coating is a film coating premix, with a coating weight gain of 1-10%. The coating premix is ​​a stomach-soluble type, a commercially available product, with components such as: hydroxypropyl methylcellulose, titanium dioxide, talc (representative model: Obadai 03A680006-CN); components such as: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (representative model: Obadai 85F18422-CN); components such as: polyvinyl alcohol, soybean lecithin, talc, titanium dioxide (representative model: Obadai 81W680000-CN).

[0027] In another preferred embodiment, the polycyclic carbamoylpyridinone derivative tablet contains the active ingredient ({(12aR)-12-[(11S)-7,8-difluoro-11-deuterium-6,11-dihydrodibenzo[b,e]-11-thiazolinone]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]-7-triazine}oxy)methyl carbonate, wherein the preferred mass percentage of the tablet core material and each component is:

[0028]

[0029] The percentage of active ingredients by weight of the tablet core is preferably 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 22%, 24%, 26%, or 28%, and more preferably 9%-15%.

[0030] The preferred percentage of microcrystalline cellulose by mass is 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 22%, 24%, 26%, 28%, 30%, 35%, or 40%, and more preferably 10%-15%.

[0031] The preferred percentage of lactose by weight is 35%, 40%, 45%, 50%, 55%, 58%, 60%, 61%, 62%, 64%, 65%, 68%, 69%, or 70%.

[0032] The preferred mass percentages of croscarmellose sodium are 1%, 2%, 3%, 4%, 5%, 5.5%, 6%, 7%, 8%, and 9%.

[0033] The preferred mass percentages of povidone are 2%, 3%, 4%, 5%, 5.5%, 6%, 7%, 8%, and 9%. The preferred mass percentages of sodium stearate fumarate are 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, and 5%.

[0034] More preferably, the active ingredient contains 12.5-14% by weight, more preferably 13-13.5%, microcrystalline cellulose contains 12-13% by weight, lactose contains 61-66% by weight, croscarmellose sodium contains 4.5-5.5% by weight, povidone contains 4.5-5.5% by weight, and sodium stearate fumarate contains 1.2-1.7% by weight.

[0035] The particle size D90 of the active ingredient is preferably 1μm, 2μm, 3μm, 4μm, 5μm, 6μm, 7μm, 8μm, 9μm, 10μm, 12μm, 14μm, 16μm, 18μm, 20μm, 22μm, 25μm, 28μm, 30μm, 35μm, 38μm, 40μm, 45μm, or 48μm.

[0036] The lactose is selected from lactose monohydrate, and the microcrystalline cellulose is selected from microcrystalline cellulose with an average particle size of 40-60 μm, preferably with an average particle size of 45 μm, 50 μm, or 55 μm; and / or selected from microcrystalline cellulose with a bulk density of 0.25-0.32 g / cm³. 3 0.26 g / cm³ is preferred. 3 0.27g / cm 3 0.28g / cm 3 0.29g / cm 3 0.30g / cm 3 0.31g / cm 3 ; and / or preferably microcrystalline cellulose PH101. The povidone is selected from povidone K30 (PVPK30).

[0037] The coating is a film coating premix (gastric-soluble type), with a coating weight gain of 1-6%.

[0038] When the above-mentioned pharmaceutical formulation composition is taken after meals, compared with taking it on an empty stomach, the Cmax, AUC0-72, and / or AUC0-inf of the active metabolite ((R)-12-((S)-7,8-difluoro-11-deuterium-6,11-dihydrodibenzo[b,e]-11-thiazophenone)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione) are reduced by no more than 5%, preferably no more than 4%, 3%, 2%, and 1%, respectively.

[0039] The polycyclic carbamoylpyridinone derivative pharmaceutical formulations of the present invention can be prepared using methods commonly used in the prior art, including wet granulation, dry granulation, and direct tableting. Specifically, the present invention also provides a method for preparing the above-mentioned polycyclic carbamoylpyridinone derivative pharmaceutical formulations, comprising the following steps: pulverizing the polycyclic carbamoylpyridinone derivative, mixing it with microcrystalline cellulose, lactose, croscarmellose sodium, and povidone, then adding water for wet granulation, and finally tableting.

[0040] The preferred method includes the following steps:

[0041] Step 1: Air jet milling of polycyclic carbamoylpyridinone derivative; Step 2: Mixing polycyclic carbamoylpyridinone derivative with microcrystalline cellulose, lactose, croscarmellose sodium and povidone and sieving; Step 3: Wet granulation with water; Step 4: Drying and granulation; Step 5: Adding sodium stearate and mixing; Step 6: Tableting; Step 7: Preparing coating solution with coating premix and coating.

[0042] This invention uses polycyclic carbamoylpyridinone derivatives with a particle size D90 of 0.5-50 μm as the active pharmaceutical ingredient, which can effectively improve the dissolution of poorly soluble drugs, promote absorption and utilization, and exhibit good high temperature and humidity stability and photostability. This pharmaceutical formulation has ideal dissolution effects and advantages such as no decrease in exposure when taken with dairy products or calcium-fortified beverages, greatly improving patient compliance.

[0043] The present invention also provides a method for treating influenza patients with the above-mentioned pharmaceutical composition, wherein the influenza patients also need to receive calcium supplements and dairy products at the same time. While receiving calcium supplements and dairy products, a single dose of 45 mg or 90 mg of the above-mentioned active ingredient is administered once.

[0044] The present invention also provides a method for treating influenza patients with the above-mentioned pharmaceutical composition, wherein the patients are individuals at risk of influenza complicated with osteoporosis and / or febrile seizures, and the patients need to receive calcium supplements and dairy products at the same time. While receiving calcium supplements and dairy products, a single dose of 45 mg or 90 mg of the above-mentioned active ingredient is administered once.

[0045] The present invention also provides the use of the above-described pharmaceutical composition in the preparation of a medicament for treating influenza complicated with osteoporosis and / or the risk of febrile seizures, or the use of a combination product of the pharmaceutical composition of the present invention and calcium supplements and / or dairy products in the preparation of a medicament for treating influenza complicated with osteoporosis and / or the risk of febrile seizures.

[0046] The present invention also provides a method for treating influenza patients with the above-mentioned pharmaceutical composition, wherein the treatment of influenza patients involves taking the medicine with food to reduce gastrointestinal side effects, and administering a single dose of 45 mg or 90 mg of the above-mentioned active ingredient once.

[0047] This invention also provides a method for treating influenza patients with the above-mentioned pharmaceutical composition, administered orally, typically 10-200 mg / dose, once per course of treatment, or 3-5 times per course of treatment; preferably 15-100 mg / dose, once per course of treatment; and the time interval between the first onset of influenza symptoms in the patient is ≤48 hours, and the median time for influenza virus RNA to turn negative is 40-55 hours. The influenza referred to is acute influenza. For adolescents and adults aged 12 years and older, a single oral dose is administered: 45 mg for patients weighing 20 kg ≤ body weight < 80 kg; 90 mg for patients weighing ≥ 80 kg.

[0048] The dosage of the compound tablets of formula (II) of this invention will be adjusted according to the disease state, route of administration, patient age, or weight. For oral administration to adolescents or adults, the usual dosage is 10-200 mg / dose, once per course of treatment, or 3-5 times per course of treatment; preferably, it is 15-100 mg / dose, once per course of treatment. The appropriate dosage of this invention needs to be set considering the patient's age, weight, and condition. In a preferred embodiment of this invention, for adolescents and adult subjects aged 12 years and above, the dosage is based on the patient's weight, with the following dosing regimen: single oral dose, 20 kg ≤ weight < 80 kg: 45 mg; weight ≥ 80 kg: 90 mg.

[0049] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention. Detailed Implementation

[0050] Certain preferred embodiments of the present invention are illustrated in the following non-limiting examples. Experimental methods not specifically described in the following examples are performed according to conventional methods and conditions, or as selected according to the trade instructions. Raw materials may be commercially available, or prepared by methods known in the art, or according to the methods described herein.

[0051] Example 1.

[0052]

[0053]

[0054] Preparation process: The tablet core components were passed through a 30-mesh sieve separately for later use. The prescribed amount of methyl carbonate (particle size D90 of 51.3 μm), microcrystalline cellulose, lactose monohydrate, croscarmellose sodium carboxymethyl cellulose, and povidone K30 were added to a wet granulator and mixed for 10 min. Water was added and stirred for 8 min, kneaded for 2 min, and then wet granulated. The wet granules were then sized using an impeller and a 4.0 mm square-hole sieve. The wet granules were transferred to a fluidized bed for drying, with the inlet air temperature set at 60.0℃. The dried granules were granulated using an impeller and a 1.0mm mesh screen. Sodium stearate fumarate was added and mixed for 5 minutes; 1000 tablets were then compressed. A film-coating premix was used to prepare the coating solution, with a concentration of 10%. During the coating stage, the inlet air temperature was set at 60.0-62.0℃, the inlet air volume at 180 m³ / h, the atomization pressure at 2.5 bar, and the mist pressure at 2.0 bar. The coating parameters were adjusted according to the actual coating conditions. The actual tablet bed temperature was controlled at 37.0-43.6℃, ​​and the coating weight gain ranged from 4%. This yielded the tablet composition of the present invention.

[0055] Example 2.

[0056]

[0057]

[0058] Preparation process: The core components were passed through a 30-mesh sieve separately for later use. The prescribed amount of methyl carbonate (particle size D90 of 4.1 μm), microcrystalline cellulose, lactose monohydrate, croscarmellose sodium carboxymethyl cellulose, and povidone K30 were added to a wet granulator and mixed for 10 min. Water was added and stirred for 8 min, followed by kneading for 2 min, and then wet granulation. The wet granules were then sized using an impeller and a 4.0 mm square-hole sieve. The wet granules were transferred to a fluidized bed for drying, with the inlet air temperature set at 60.0℃. The dried granules were granulated using an impeller and a 1.0mm mesh screen. Sodium stearate fumarate was added and mixed for 5 minutes; 1000 tablets were compressed to obtain uncoated tablets. A film-coating premix was used to prepare the coating solution, with a concentration of 10%. During the coating stage, the inlet air temperature was set at 60.0-62.0℃, the inlet air volume at 180 m³ / h, the atomization pressure at 2.5 bar, and the mist pressure at 2.0 bar. The coating parameters were adjusted according to the actual coating conditions. The actual tablet bed temperature was controlled at 37.0-43.6℃, ​​and the coating weight gain range was 4%. This yielded the film-coated tablets of the present invention.

[0059] Example 3.

[0060]

[0061] Preparation process: The tablet core components were passed through a 30-mesh sieve separately for later use. The prescribed amount of methyl carbonate (particle size D90 of 0.5 μm), microcrystalline cellulose, lactose monohydrate, croscarmellose sodium carboxymethyl cellulose, and povidone K30 were added to a wet granulator and mixed for 10 min. Water was added and stirred for 8 min, kneaded for 2 min, and then wet granulated. The wet granules were then sized using an impeller and a 4.0 mm square-hole sieve. The wet granules were transferred to a fluidized bed for drying, with the inlet air temperature set at 60.0℃. The dried granules were granulated using an impeller and a 1.0mm mesh screen. Sodium stearate fumarate was added and mixed for 5 minutes; 1000 tablets were then compressed. A film-coating premix was used to prepare the coating solution, with a concentration of 10%. During the coating stage, the inlet air temperature was set at 60.0-62.0℃, the inlet air volume at 180 m³ / h, the atomization pressure at 2.5 bar, and the mist pressure at 2.0 bar. The coating parameters were adjusted according to the actual coating conditions. The actual tablet bed temperature was controlled at 37.0-43.6℃, ​​and the coating weight gain ranged from 4%. This yielded the tablet composition of the present invention.

[0062] Example 4.

[0063]

[0064] Preparation process: Refer to the preparation process in Example 1, except that the particle size D90 of the active ingredient is 0.1 μm.

[0065] Example 5.

[0066]

[0067]

[0068] Preparation process: Refer to the preparation process of Example 2, except that 3.5g of sodium dodecyl sulfate is added to the components.

[0069] Example 6.

[0070]

[0071] Preparation process: Refer to the preparation process of Example 2, except that the amount of microcrystalline cellulose used is 80.8g and the amount of lactose monohydrate is 176.6g.

[0072] Example 7.

[0073]

[0074]

[0075] Preparation process: Refer to the preparation process of Example 2, except that component I, water-soluble lactose, is replaced with anhydrous lactose.

[0076] Example 8.

[0077]

[0078] Preparation process: Refer to the preparation process of Example 2, except that component polyvinyl ketone K30 is replaced with polyvinyl ketone K25.

[0079] Example 9.

[0080]

[0081]

[0082] Preparation process: Refer to the preparation process of Example 2, except that the film coating premix (gastric-soluble type) is 85F18422-CN.

[0083] Example 10.

[0084]

[0085] Preparation process: Refer to the preparation process in Example 2, except that the particle size D90 of the active ingredient is 85.8 μm.

[0086] Example 11.

[0087] The prescription dosage is the same as in Example 2, except that 3000 tablets are compressed, i.e., prepared into 15mg tablets.

[0088] Example 12

[0089]

[0090] The preparation process is the same as in Example 2.

[0091] Experimental Example 1: Dissolution Determination

[0092] According to the dissolution test method (Chinese Pharmacopoeia 2020 Edition, Method II, Paddle Method), the dissolution rate (%) of the formulations in Examples 1-10 was determined using 900 ml of pH 6.8 + 0.16% CTAB dissolution medium at a rotation speed of 50 rpm. The results are shown in Table 1 below:

[0093]

[0094]

[0095] Conclusion: The formulations in Examples 1-9 all achieved a dissolution rate of over 85% within 45 minutes and were completely dissolved within 60 minutes. The formulations in Examples 1 and 7 had a dissolution rate below 80% within 30 minutes, while the formulations in Examples 2-6, 8, and 9 all achieved a dissolution rate of approximately 85% or higher within 30 minutes. The formulation in Example 10 had an active ingredient particle size D90 of 85.8 μm, and its dissolution rate was significantly slower, failing to completely dissolve within 60 minutes.

[0096] Experiment Example 2

[0097] Because polycyclic carbamoylpyridinone derivatives have low solubility in vivo and even lower lipophilicity after deuteration, they affect effective dissolution and absorption. To accelerate and improve dissolution, this invention demonstrates that micronizing the active ingredient promotes dissolution. However, micronizing the active ingredient to a D90 particle size of 1-50 μm significantly reduces the material's flowability, thus affecting the flowability of the particles obtained after wet granulation. To examine the flowability of the granules, particles obtained after adding sodium stearate fumarate were tested. Using compressibility as an indicator, this invention employed a powder comprehensive characteristic analyzer to determine the loose density (ρ) of the particles according to the methods for determining loose density and tapped density. b ) and tap density (ρ t The compressibility (Cp) is calculated from the loose density and the tapped density. Compressibility (Cp) = (ρ... t -ρ b )*100% / ρ t The moisture content of the obtained particles was also measured. The specific results are shown in Table 2 below:

[0098] Example 2 1.35 18.76 Example 6 2.11 17.23 Example 7 2.78 27.48 Example 8 1.78 29.61 Example 12 1.89 26.36

[0099] It is generally believed that fluidity is good when the compressibility is below 20%, and fluidity decreases as the compressibility increases. The above results indicate that the formulations using Examples 2 and 6 have superior fluidity.

[0100] When achieving good flowability, the tablet compression performance is affected by various factors such as the composition, particle shape, size, or distribution of the raw materials, which may lead to increased tablet cracking. Therefore, this invention further investigates the elastic recovery rate of granulation and tableting. Tablets were prepared under the same pressure as in the above examples, with a compression time of 10 seconds. After compression, the tablets were placed at 25°C and 20%–30% RH for 24 hours. The thickness of each tablet was then precisely measured using calipers, with three tablets measured for each condition, and the average value was taken.

[0101] Calculate the percentage elastic recovery rate (E) according to the formula.

[0102] E = (H – Hc) / Hc × 100

[0103] Where Hc is the thickness of the tablet when it is ejected from the die; H is the thickness of the tablet after it has been left in the die for 24 hours.

[0104] Example 2 0.24 Example 6 1.82 Example 7 1.65 Example 8 2.67 Example 12 0.58

[0105] The results showed that Example 2 had a lower elastic recovery rate and was less prone to cracking compared to Examples 6-8.

[0106] Stability test in Experiment Example 3

[0107] The stability of formulations 1-9 and 2 tablets was investigated under accelerated conditions of 40±2℃ / 75%±5%RH and 1.2 million lux·hr for 30 days. Appearance and total impurity percentage (%) were recorded. Color difference of the tablet core was observed after removing the coating. Liquid chromatography conditions: UV, 260nm; column: ODS C18, 3.5μm, 3.0X150mm; column temperature: 35℃; flow rate: 1ml / min; mobile phase A: 0.1% TFA / 0.2mM EDTA solution; mobile phase B: acetonitrile. Gradient elution was used, with the gradient as follows:

[0108] 0～5 65 35 5～35 65→20 35→80 35～40 20 80

[0109] Table 3. Results of stability study under accelerated conditions of 40±2℃ / 75%±5%RH

[0110]

[0111]

[0112] Table 4. Stability test results under 1.2 million lux·hr acceleration conditions

[0113]

[0114] Conclusion: Formulas 1-3 and 5-10 in Examples showed stable quality and no visible changes in appearance under accelerated conditions of 40±2℃ / 75%±5%RH. Formulas 4 and 2 in Examples showed a significant increase in impurities, obvious color differences in the tablet core, and a pale yellow or even blackish appearance, with significant hygroscopic and softening phenomena. Formulas 1-3 and 5-10 in Examples showed stable quality and no visible changes in appearance under accelerated conditions of 1.2 million lux·hr. Formulas 4 and 2 in Examples showed a significant increase in impurities, obvious color differences in the tablet core, and a yellowish appearance. The pharmaceutical formulation of this invention, with a particle size D90 of 0.5-50 μm, of methyl carbonate ({(12aR)-12-[(11S)-7,8-difluoro-11-deuterium-6,11-dihydrodibenzo[b,e]-11-thiazolinone]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]-7-triazine}oxy)methyl carbonate has advantages such as stable properties, high dissolution, non-hygroscopicity and non-discoloration under pressure, and more convenient production and storage conditions.

[0115] Experiment Example 4: Effects of Functional Foods

[0116] Twelve male cynomolgus macaques of similar weight and age were divided into three groups of three. Each macaque was given one 45mg tablet of methyl carbonate ({(12aR)-12-[(11S)-7,8-difluoro-11-deuterium-6,11-dihydrodibenzo[b,e]-11-thiazolinone]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]-7-triazine}oxy)methyl carbonate via a feeding device, along with 10mL of calcium lactate oral solution (containing 65mg of calcium, commercially available) and saline solution. Plasma samples were collected from animals at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, 24, and 48 hours after drug administration. The concentration of the active metabolite ((R)-12-((S)-7,8-difluoro-11-deuterium-6,11-dihydrodibenzo[b,e]-11-thiazolinone)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione) (ADC189-I07) in the plasma samples was determined by LC MS / MS. The metabolic parameter C was calculated. max and AUC 0-24h (h*ng / mL). Grouping is as follows:

[0117]

[0118] Table 5. Results of the food impact study

[0119]

[0120] Conclusion: Prescription 2C max and AUC 0-24h (h*ng / mL) When taken with high-calcium foods or dairy products, drug exposure is not affected. When Prescription 10 is taken with calcium lactate oral solution, drug exposure is significantly reduced, by about half. Methyl carbonate of the present invention, with a D90 of 0.5-50 μm, has the advantage that oral absorption is not affected by fortified beverages or calcium supplements, and is a potentially more compliant anti-influenza drug.

[0121] Experimental Example 5: Clinical Trial: Food Impact Assessment

[0122] Inclusion criteria included participants aged 18 to 65 years (inclusive), regardless of gender; a suitable dose of 45 mg (Formula from Example 2, referred to as "ADC189 tablets" in this study) was selected for the study of food effects. A randomized, double-crossover, two-cycle experimental design was employed. A total of 16 qualified participants were enrolled and randomly assigned to groups A and B, with 8 participants in each group. After a 28-day screening period, participants were admitted to the trial center on day -1 (D-1), fasting overnight for at least 10 hours. On day 1 of cycle 1 (D1), participants in group A received an oral dose of Example 2 tablets on an empty stomach, while participants in group B received an oral dose of ADC189 tablets 30 minutes after starting a low-fat meal. PK blood samples were collected and corresponding safety assessments were conducted on day 4 (D4) post-administration. Participants were discharged with the investigator's permission and returned to the research center on days 6, 8, and 15 for PK sample collection and safety assessments. The washout period was tentatively set at 21 days (subject to adjustment based on the PK results in Part 1). After washing out, the second cycle of crossover medication will begin on day 22 or later, with the same procedure as the first cycle. Specifically, subjects in group A will take ADC189 tablets orally 30 minutes after starting a low-fat meal, while subjects in group B will take ADC189 tablets orally on an empty stomach.

[0123] Calculations were performed using SAS statistical analysis software version 9.4 or later. The pharmacokinetics of the active metabolite ((R)-12-((S)-7,8-difluoro-11-deuterium-6,11-dihydrodibenzo[b,e]-11-thiazophenone)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione) were evaluated, specifically the 90% confidence intervals of the geometric mean ratio (postprandial / fasting ratio) of Cmax, AUC0-t, and AUC0-inf for ADC189-I07.

[0124] Results: Food Effects Trial Results

[0125] Following administration of 45 mg ADC189 tablets on an empty stomach and after a meal, the mean Cmax of ADC189-I07 in healthy subjects under fasting conditions was 93.5858 ng / mL, the mean AUC0-t was 4698.6019 h* ng / mL, and the mean AUC0-inf was 5105.0728 h* ng / mL. Under postprandial conditions, the mean Cmax of ADC189-I07 in healthy subjects was 89.5149 ng / mL, the mean AUC0-t was 4776.0369 h* ng / mL, and the mean AUC0-inf was 5217.3465 h* ng / mL.

[0126] in conclusion:

[0127] After administration of ADC189 tablets (45 mg) on ​​an empty stomach and after a meal, the geometric mean ratios of its primary pharmacokinetic parameters (Cmax, AUC0-t, and AUC0-inf) (postprandial vs. fasting) were 95.39%–99.14%. Mixed-effects model results showed that food intake had no significant effect on the primary pharmacokinetic parameters (P>0.05). Oral absorption of ADC189 45 mg (Formulation of Example 2) was not affected by food.

[0128] Experiment Example 6: Clinical Trial: Evaluation of Antiviral Efficacy

[0129] A randomized, double-blind, multicenter, placebo-controlled design was employed. The primary objective was to evaluate the preliminary efficacy of a single tablet dose in adult patients with uncomplicated acute influenza.

[0130] Selection criteria:

[0131] 1) Age between 18 and 65 years old (inclusive), gender not limited;

[0132] 2) Diagnosis of influenza virus infection according to the following criteria: a positive result for rapid influenza antigen test (RAT) on nasopharyngeal or oropharyngeal swabs (rapid influenza virus nucleic acid test or other rapid molecular diagnostic methods are also acceptable); fever (ear temperature ≥37.3℃ or axillary temperature ≥37.2℃), if antipyretics are taken, the ear temperature must be ≥37.3℃ or the axillary temperature ≥37.2℃ >4 hours after taking the medication; and at least one moderate or severe influenza virus infection-related systemic or respiratory symptom: systemic symptoms: headache, fever or chills, muscle or joint aches, fatigue; respiratory symptoms: cough, sore throat, nasal congestion;

[0133] 3) During screening, the time interval between the onset of disease symptoms and the actual time of onset should be ≤48 hours;

[0134] 4) Voluntarily participate in clinical research and sign an informed consent form.

[0135] This phase of the trial included three treatment groups: two investigational drug groups (the 15mg formulation of Example 2 and the 45mg formulation of Example 11, with the 45mg tablets of Example 2 and the 15mg tablets of Example 11 being formulations of equal proportions), and one placebo group. Subjects received either a placebo or a single dose of the investigational drug. In a 2:2:1 ratio, 44, 45, and 24 subjects were enrolled in the three groups, respectively, for a total of 120 subjects.

[0136] Dosage regimen: Single oral dose, administered according to the patient's weight. Dosage regimen: 20kg≤weight<80kg: 45mg; weight≥80kg: 90mg.

[0137] Results: Time to negative conversion of influenza virus RNA

[0138] The median time to seroconversion of influenza virus RNA was 73.400 h in the placebo group (95% CI: 44.167, 117.300), 50.667 h in the 15 mg prescription of Example 2 group (95% CI: 48.350, 92.850), and 45.800 h in the 45 mg prescription of Example 11 group (95% CI: 44.267, 47.033).

[0139] in conclusion:

[0140] The time to negative influenza virus RNA was shorter in both the 15mg and 45mg groups compared to the placebo group, with the 45mg group showing a greater and statistically significant reduction in time (P = 0.0158).

[0141] For those skilled in the art, this disclosure is not limited to the foregoing illustrative embodiments and can be embodied in other specific forms without departing from its essential attributes. Therefore, it is intended that all aspects be considered illustrative rather than restrictive, that references be made to the appended claims rather than the foregoing embodiments, that references be made only to the appended claims and not to the foregoing examples, and that all variations falling within the meaning and scope of claim equivalence are therefore intended to be included herein.

[0142] All patents, patent applications, and references listed in this specification are incorporated herein by reference in their entirety. In case of inconsistencies, this disclosure, including its definitions, will be considered more persuasive.

Claims

1. A pharmaceutical formulation composition of a polycyclic carbamoylpyridinone derivative, characterized in that, The pharmaceutical formulation composition comprises a tablet core and a coating. The particle size D90 of the active ingredient is 0.5-50 μm. The coating is a gastrointestinal soluble film coating premix with a coating weight gain of 1-6%. The povidone is povidone K30 or povidone K25. The mass percentage of the materials and components in the tablet core is as follows: 。 2. The pharmaceutical formulation composition of a polycyclic carbamoylpyridinone derivative as described in claim 1, characterized in that, The tablet core of this pharmaceutical formulation is prepared by wet granulation and compression.

3. The pharmaceutical formulation composition of a polycyclic carbamoylpyridinone derivative as described in claim 2, characterized in that, The ingredients of the gastric-soluble coating premix include: hydroxypropyl methylcellulose, titanium dioxide, and talc.

4. The pharmaceutical formulation composition of a polycyclic carbamoylpyridinone derivative as described in claim 2, characterized in that, The components of the gastric-soluble film-coating premix include: polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide.

5. The use of the pharmaceutical composition according to any one of claims 1-4 in the preparation of a medicament for treating influenza, characterized in that, The flu patients were also taking calcium supplements or dairy products.

6. The application according to claim 5, characterized in that, The administration regimen of the pharmaceutical formulation composition is as follows: a single oral dose of 45 mg of active ingredient for patients weighing ≥20 kg and <80 kg, and 90 mg of active ingredient for patients weighing ≥80 kg.

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