Mabloxvir directly-taken granules and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to macloxvir direct granules and a preparation method thereof. The taste is improved by adding the flavoring agent and a multi-layer coating technology, and the effect of direct swallowing is realized; by controlling the particle size of the raw materials and the variety and dosage of the auxiliary materials, the obtained macloxvir direct-taking granules are excellent in dissolution performance; and the stabilizer is added, so that the obtained macloxvir direct-taking granules are excellent in stability. In addition to providing a product which can be divided into doses and can be directly swallowed, the macloxvir directly-taken granules disclosed by the invention are stable and controllable in prescription process, excellent in dissolution performance, relatively good in mouth feel, taste masking effect and stability, suitable for large-scale production and good in market prospect.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to mabaloxavir direct-take granules and a preparation method thereof. Background Art

[0002] Influenza (flu) is an acute respiratory infectious disease caused by influenza viruses. Influenza viruses are divided into four types: A, B, C, and D. Currently, influenza A and B viruses are the main ones that infect humans. Among them, influenza A virus is the most contagious and most prone to mutation, and can cause a global pandemic. Influenza has an acute onset. Although most influenza patients can recover on their own, some patients may develop severe cases due to complications such as pneumonia, encephalitis, or myocarditis, or due to worsening of underlying diseases. In a few cases, the disease progresses rapidly and complications may occur, leading to death. Severe influenza mainly occurs in high-risk groups such as the elderly, young children, obese people, pregnant women, and those with chronic underlying diseases, but it can also occur in the general population.

[0003] Baloxavir, the active metabolite of mabaloxavir, is an innovative cap-dependent endonuclease inhibitor and the first and only single-dose oral drug approved for the treatment of influenza A and B. Its mechanism of action differs from existing antiviral therapies in that it blocks the endonuclease enzyme within viral cells, rendering the virus unable to replicate. A single dose can halt viral shedding within 24 hours, shortening the infectious period and significantly reducing the duration of flu symptoms.

[0004] Currently available mabaloxavir dosage forms primarily include tablets and dry suspensions. Considering that both tablets and dry suspensions are inconvenient for children, the elderly, bedridden patients, those with dysphagia, and those with difficulty accessing water, Chinese patent CN113069423A discloses a method for preparing orally disintegrating mabaloxavir tablets, aiming to improve the compliance of special patients while addressing the high cost and poor taste of most orally disintegrating tablets. However, orally disintegrating tablets still have issues such as easy moisture absorption and inconvenience in adjusting dosage. Direct-dose granules, a type of granule, mask the taste of the active pharmaceutical ingredient through multi-layer coating technology, enabling direct swallowing without water. This improves patient compliance while also offering advantages such as flexibility in dosage design and administration. After investigation, Chinese patent CN116785245A discloses a heat-clearing and detoxifying granule that can be swallowed directly. This invention masks the bitterness and astringency by coating, and the prepared granules can be swallowed directly orally, improving the compliance of special patients while maintaining a stable and controllable process and improving the stability of the product.

[0005] Chinese patents CN119700715A and CN119564645A also disclose a method for preparing an orally disintegrating film of mabaloxavir, which offers advantages such as portability and ease of administration (no water required). This method also addresses the shortcomings of most orally disintegrating films, such as low drug loading and high process costs. This present invention compares the two formulations in terms of taste and stability, and the results show that the direct-take granules prepared by this invention exhibit better palatability and stability than the orally disintegrating film.

[0006] This product can be swallowed directly without the need for additional water, and has almost no dissolution in the mouth and no unpleasant taste, greatly improving patient compliance. However, there are few studies on mabaloxavir direct-take granules. Therefore, there is an urgent need to develop mabaloxavir direct-take granules and a preparation method thereof to make up for the shortcomings in this field. Summary of the Invention

[0007] Based on the deficiencies of the prior art, the present invention aims to provide mabaloxavir direct-take granules and a preparation method thereof.

[0008] To achieve the above-mentioned object, the technical solution adopted by the present invention is as follows: A mabaloxavir direct-take granule comprises a drug-loaded pill core, an isolation layer, a taste-masking layer and a smoothing layer, wherein the drug-loaded pill core comprises mabaloxavir, a blank pill core, a binder, a stabilizer and an anti-adherent agent; the isolation layer comprises a coating material and an anti-adherent agent; the taste-masking layer comprises a taste-masking agent, a flavoring agent, an anti-adherent agent and a plasticizer; the smoothing layer comprises a binder, a gelling agent and an anti-adherent agent, and the weight ratio of the active ingredient to the blank pill core is 1:5 to 1:15, preferably 1:5 to 1:8; the usage ratio of the isolation layer to the drug-loaded pill core is 1:5 to 1:15, preferably 1:8 to 1:12; the usage ratio of the taste-masking layer to the drug-loaded pill core is 1:5 to 1:17, preferably 1:5 to 1:9; the usage ratio of the smoothing layer to the drug-loaded pill core is 1:10 to 1:30, preferably 1:15-1:20.

[0009] In some embodiments, the blank pellet core in the drug-loaded pellet core is a sucrose pellet core, a microcrystalline cellulose pellet core, a lactose pellet core, a mannitol pellet core, etc., preferably a mannitol pellet core.

[0010] In some embodiments, the binder in the drug-loaded pellet core is hypromellose, hydroxyethyl cellulose, polyvinyl pyrrolidone, preferably hypromellose; the anti-adhesive agent is talc, colloidal silicon dioxide, magnesium stearate, preferably talc; and the stabilizer is fumaric acid or ascorbic acid, preferably ascorbic acid.

[0011] In some embodiments, the coating material in the isolation layer is selected from one or more of hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, or polyethylene glycol 6000, preferably hypromellose and polyethylene glycol 6000.

[0012] In some embodiments, the anti-sticking agent in the isolation layer is talc, colloidal silicon dioxide, magnesium stearate, preferably talc.

[0013] In some embodiments, the taste masking agent in the taste masking layer is ethylcellulose, Eudragit E100, Eudragit EPO, Eudragit S100, preferably Eudragit EPO.

[0014] In some embodiments, the flavoring agents in the taste masking layer are sucralose and strawberry flavor.

[0015] In some embodiments, the anti-sticking agent in the taste-masking layer is talc, colloidal silicon dioxide, magnesium stearate, preferably talc; and the plasticizer is triethyl citrate.

[0016] In some embodiments, the binder in the smooth layer is hypromellose, and the gelling agent is xanthan gum, carbomer, or agar, preferably carbomer; the weight percentage of the gelling agent in the smooth layer is 20%-60%, preferably 35%-45%.

[0017] In some embodiments, the mabaloxavir direct-dose granules include the following ingredients in parts by weight:

[0018]

[0019]

[0020] A second object of the present invention is to provide a method for preparing the above-mentioned mabaloxavir direct-dose granules, comprising the following steps:

[0021] Step 1) Preparation of drug-loaded pill cores: Dissolve hydropropyl methylcellulose in water and stir until completely dissolved, then add mabaloxavir and other excipients to prepare a suspension solution, use mannitol pill cores as blank pill cores, and apply the drug by fluidized bed spraying to prepare mabaloxavir-loaded pill cores;

[0022] Step 2) Seal layer coating: Hydroxypropyl methylcellulose and polyethylene glycol 6000 are dissolved in a mixed solvent of ethanol and water, stirred until completely dissolved, and talc is added to prepare a suspension solution. The drug-loaded pellet cores of step 1) are coated using a fluidized bed, and dried after coating.

[0023] Step 3) Taste-masking layer coating: Dissolve Eudragit EPO, sucralose, and strawberry essence in a mixed solvent of ethanol and water, stir until completely dissolved, add talc and triethyl citrate to prepare a suspension, and apply a taste-masking layer coating to the product obtained in step 2) using fluidized bed coating technology, and dry after coating.

[0024] Step 4) Smoothing layer coating: Prepare the various smoothing layer ingredients into a suspension, and use fluidized bed coating technology to coat the product obtained in step 3) with a smoothing layer. After coating, dry the product.

[0025] The present invention has the following beneficial effects: The present invention improves the mouthfeel and enables direct swallowing by adding flavoring agents and using multi-layer coating technology; controls the particle size of the raw materials and the type and amount of the excipients to achieve excellent dissolution performance for the resulting mabaloxavir direct-take granules; and adds a stabilizer to achieve excellent stability for the resulting mabaloxavir direct-take granules. In addition to providing a product that can be directly swallowed in divided doses, the mabaloxavir direct-take granules of the present invention have a stable and controllable formulation process, excellent dissolution performance, good mouthfeel, taste-masking effect, and stability, are suitable for large-scale production, and have promising market prospects. DETAILED DESCRIPTION

[0026] The following examples may enable those skilled in the art to more fully understand the present invention, but the present invention is not limited to the scope of the examples.

[0027] Example 1

[0028] Mabaloxavir direct-dose granules were prepared according to the following prescription:

[0029]

[0030] Preparation method:

[0031] (1) Preparation of drug-loaded pellet cores:

[0032] (1.1) Raw material pretreatment: First, Mabaloxavir is air-grinded to D 90 ≤20μm;

[0033] (1.2) Preparation of drug solution: Dissolve Hydroxypropyl Methylcellulose E5 in purified water, stir until completely dissolved, add the prescribed amount of Mabaloxavir, ascorbic acid, and talc, stir for more than 30 minutes, and pass through a 100-mesh sieve for later use.

[0034] (1.3) Drug Coating: Set the inlet air temperature to 50-60°C. Place the mannitol pellets into the fluidized bed for preheating. Coating begins when the material temperature is ≥40°C. During the coating process, maintain the material temperature within the range of 40±5°C. After coating, begin drying, maintaining the material temperature at ≤50°C for 20 minutes.

[0035] (2) Isolation layer coating

[0036] (2.1) Preparation of isolation layer coating solution: Dissolve Hydroxypropyl Methylcellulose E5 and Polyethylene Glycol 6000 in a mixed solvent of ethanol and water, stir until completely dissolved, add talcum powder and stir for more than 30 minutes to prepare a suspension, and pass through a 100-mesh sieve for later use.

[0037] (2.2) Isolation Coating: Set the inlet air temperature to 50-60°C and control the material temperature within the range of 40±5°C during the coating process. Stop spraying after the weight gain reaches 10% and start drying. Control the material temperature to ≤50°C and dry for 20 minutes.

[0038] (3) Taste-masking coating

[0039] (3.1) Preparation of taste masking coating solution: Dissolve Eudragit EPO, sucralose, and strawberry essence in a mixed solvent of ethanol and water. Stir until completely dissolved. Add talcum powder and triethyl citrate to prepare a suspension. Pass through a 100-mesh sieve and set aside.

[0040] (3.2) Taste-masking coating: Set the inlet air temperature to 50-60°C and control the material temperature within the range of 38±5°C during the coating process. After coating, begin drying, controlling the material temperature to ≤45°C for 20 minutes.

[0041] (4) Smooth layer coating

[0042] (4.1) Preparation of the smooth layer coating solution: Add hydropropyl methylcellulose to anhydrous ethanol and stir until completely dissolved to obtain solution A. Add carbomer and talc to anhydrous ethanol and high-shear to obtain solution B. Pour solution B into solution A to form a suspension, and pass through a 100-mesh sieve for later use.

[0043] (4.2) Smooth layer coating: Set the inlet air temperature to 45-55°C and control the material temperature within the range of 35±5°C during the coating process. After coating, start drying and control the material temperature to ≤40°C for 20 minutes.

[0044] Results: The dissolution rate, salivary dissolution rate and taste evaluation of the prescription were carried out. The results are as follows: the taste evaluation of this product is ≥50 points, which shows that the product has good palatability; the salivary dissolution rate is ≤10% in 5 minutes, which shows that the product has a good taste masking effect; the dissolution rate in standard medium is ≥85% in 15 minutes, which shows excellent dissolution performance.

[0045]

[0046] Example 2

[0047] Referring to the prescription composition and preparation method in Example 1, the particle size of the mabaloxavir API was changed. The experimental results are as follows:

[0048]

[0049] The results show that when the baloxavir raw material D 90 When the particle size does not exceed 30 μm, the dissolution amount of the preparation in 15 minutes is greater than 85%, which is rapid dissolution. 90 When the particle size does not exceed 20 μm, the dissolution amount of the preparation in 15 minutes is greater than 90%, and the dissolution platform can reach about 100%, indicating better dissolution performance.

[0050] Example 3

[0051] Referring to the formulation and preparation method in Example 1, ascorbic acid was replaced with fumaric acid and vitamin E. The stability results of the finished product are as follows:

[0052]

[0053]

[0054] It can be seen from the results that the formulation with ascorbic acid as the stabilizer has the best stability under high temperature and accelerated conditions, and the growth of various impurities is not obvious, and all are within the limit; the formulation with fumaric acid as the stabilizer has slight growth of various impurities under high temperature and accelerated conditions, but all are within the limit; the formulation with vitamin E as the stabilizer has obvious growth of various impurities under high temperature and accelerated conditions, and impurity B exceeds the limit. Therefore, the stabilizer for this product can be selected from ascorbic acid and fumaric acid, with ascorbic acid being preferred.

[0055] Comparative Examples 1-3

[0056] Mabaloxavir orally disintegrating film-forming agent was prepared by referring to the method described in patent CN119700715A. The specific formulation composition is as follows:

[0057]

[0058] Preparation method:

[0059] (1) Weigh the active ingredient, film-forming material, plasticizer, flavoring agent, colorant, and purified water according to the stated proportions and set aside;

[0060] (2) The active ingredient, colorant, and plasticizer were added to purified water, stirred thoroughly, and then homogenized and emulsified at an emulsification parameter of 5.5 krpm for 20 min to obtain solution B;

[0061] (3) Adding Hydroxypropyl Methylcellulose E15 to Solution B, and continuing the homogenization and emulsification operation at an emulsification parameter of 6.5 krpm and an emulsification time of 20 min to obtain Solution C;

[0062] (4) Add the remaining excipients to solution C and stir at 900 rpm for 30 min to obtain solution D;

[0063] (5) The solution D obtained in step (4) was allowed to stand for defoaming, and the bubble-free adhesive was coated on a high-temperature resistant PET tape, dried at a drying temperature of 60° C., and then removed from the film;

[0064] (6) Cut and package the rolled film to obtain the finished product.

[0065] Comparative Example 4

[0066] Mabaloxavir orally disintegrating film-forming agent was prepared by referring to the method described in patent CN119564645A. The specific formulation composition is as follows:

[0067]

[0068] Preparation: Weigh the prescribed amount of mabaloxavir and add it to purified water. Stir and disperse evenly. Then, weigh the prescribed amount of citric acid, sucralose, croscarmellose sodium, and glycerin and add them to purified water. Stir and disperse evenly. Weigh the prescribed amount of hypromellose and add it to the dispersed solution. Stir and dissolve thoroughly to form a glue solution. Degas the glue solution by vacuum centrifugation. Pour the glue solution into a coating machine and apply film. Cut according to specifications and package.

[0069] Test case stability

[0070]

[0071] The results showed that Example 1 was superior to Comparative Examples 1 to 4 in both taste and stability.

[0072] The mabaloxavir direct-dose granules prepared in Example 1 were stored at 40°C ± 2°C and 75% RH ± 10% RH for 6 months and at 25°C ± 2°C and 60% RH ± 10% RH for 36 months. The solubility (medium: pH 6.8 phosphate buffer (containing 0.16% cetyltrimethylammonium bromide (CTAB)) and sampling was performed every 15 minutes), the saliva solubility (artificial saliva and sampling was performed every 5 minutes), the related substances and the mouthfeel were measured. The specific data are shown in the following table:

[0073]

[0074] As can be seen from the above table, the levels of related substances, dissolution, saliva dissolution and mouthfeel of the sample of Example 1 did not change significantly under accelerated conditions and long-term conditions (inspected for up to 36 months), while the samples of Comparative Examples 1-4 had poor stability under accelerated conditions and reduced mouthfeel.

Claims

1. A mabaloxavir direct-take granule, comprising a drug-loaded pill core, an isolation layer, a taste-masking layer, and a smoothing layer, wherein the drug-loaded pill core comprises mabaloxavir, a blank pill core, a binder, a stabilizer, and an anti-adherent; the isolation layer comprises a coating material and an anti-adherent; the taste-masking layer comprises a taste-masking agent, a flavoring agent, an anti-adherent, and a plasticizer; the smoothing layer comprises a binder, a gelling agent, and an anti-adherent, wherein the weight ratio of the active ingredient to the blank pill core is 1:5 to 1:8; the amount ratio of the isolation layer to the drug-loaded pill core is 1:8 to 1:12; the amount ratio of the taste-masking layer to the drug-loaded pill core is 1:5 to 1:9; and the amount ratio of the smoothing layer to the drug-loaded pill core is 1:15 to 1:

20.

2. The mabaloxavir direct-take granules according to claim 1, characterized in that The weight ratio of the active ingredient to the blank pill core is 1:7 to 1:8; the dosage ratio of the isolation layer to the drug-loaded pill core is 1:10 to 1:11; the dosage ratio of the taste-masking layer to the drug-loaded pill core is 1:7 to 1:8; and the dosage ratio of the smooth layer to the drug-loaded pill core is 1:17 to 1:

18.

3. The mabaloxavir direct-take granules according to claim 1, characterized in that: The blank pill cores in the drug-loaded pill cores are sucrose pill cores, microcrystalline cellulose pill cores, lactose pill cores and mannitol pill cores, etc., and the mannitol pill cores are preferred.

4. The mabaloxavir direct-take granules according to claim 1, characterized in that The binder in the drug-loaded pill core is hypromellose, hydroxyethyl cellulose, or polyvinyl pyrrolidone, preferably hypromellose; the anti-adhesive agent is talc, colloidal silicon dioxide, or magnesium stearate, preferably talc; and the stabilizer is fumaric acid or ascorbic acid, preferably ascorbic acid.

5. The mabaloxavir direct-take granules according to claim 1, characterized in that: The coating material in the isolation layer is selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or polyethylene glycol 6000, preferably hydroxypropyl methylcellulose and polyethylene glycol 6000.

6. The mabaloxavir direct-take granules according to claim 1, characterized in that The anti-sticking agent in the isolation layer is talc, colloidal silicon dioxide, magnesium stearate, preferably talc.

7. The mabaloxavir direct-take granules according to claim 1, characterized in that: The taste masking agent in the taste masking layer is ethyl cellulose, Eudragit E100, Eudragit EPO, Eudragit S100, preferably Eudragit EPO; the flavoring agent in the taste masking layer is sucralose and strawberry flavor; in some embodiments, the anti-sticking agent in the taste masking layer is talc, colloidal silicon dioxide, magnesium stearate, preferably talc; the plasticizer is triethyl citrate.

8. The mabaloxavir direct-take granules according to claim 1, characterized in that: The adhesive in the smooth layer is hypromellose, and the gelling agent is xanthan gum, carbomer, or agar, preferably carbomer; the weight percentage of the gelling agent in the smooth layer is 20%-60%, preferably 35%-45%.

9. The mabaloxavir direct-take granules according to claim 1, characterized in that: Mabaloxavir direct-use granules include the following ingredients in parts by weight:

10. The method for preparing the mabaloxavir direct-take granules according to claim 1, comprising the following steps: Step 1) Preparation of drug-loaded pill cores: Dissolve hydropropyl methylcellulose in water and stir until completely dissolved, then add mabaloxavir and other excipients to prepare a suspension solution, use mannitol pill cores as blank pill cores, and apply the drug by fluidized bed spraying to prepare mabaloxavir-loaded pill cores; Step 2) Seal layer coating: Hydroxypropyl methylcellulose and polyethylene glycol 6000 are dissolved in a mixed solvent of ethanol and water, stirred until completely dissolved, and talc is added to prepare a suspension solution. The drug-loaded pellet cores of step 1) are coated using a fluidized bed, and dried after coating. Step 3) Taste-masking layer coating: Dissolve Eudragit EPO, sucralose, and strawberry essence in a mixed solvent of ethanol and water, stir until completely dissolved, add talc and triethyl citrate to prepare a suspension, and apply a taste-masking layer coating to the product obtained in step 2) using fluidized bed coating technology, and dry after coating. Step 4) Smoothing layer coating: Prepare the various smoothing layer ingredients into a suspension, and use fluidized bed coating technology to coat the product obtained in step 3) with a smoothing layer. After coating, dry the product.

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