Ethanesulfonic acid nintedanib sublingual tablet and preparation method thereof

Abstract

The invention relates to the technical field of medicine, in particular to an ethanesulfonic acid nintedanib sublingual tablet and a preparation method thereof.The ethanesulfonic acid nintedanib sublingual tablet contains ethanesulfonic acid nintedanib, a carrier material, a filling agent, a disintegrating agent, a flavoring agent and a lubricating agent, and the ethanesulfonic acid nintedanib sublingual tablet is prepared by setting the specific proportion of the raw materials and the auxiliary materials. Compared with an original research medicine, namely a nintedanib ethanesulfonate soft capsule, the problem that the bioavailability is low due to the liver first-pass effect is effectively solved, the medicine provided by the invention is good in taste, excellent in stability, rapid in disintegration and rapid in dissolution rate, and each detection item meets the quality standard. And meanwhile, the clinical use compliance of a patient is also improved.

Description

Technical Field

[0001] This invention relates to the field of new drug technology, specifically to a sublingual tablet of nintedanib ethanesulfonate and its preparation method. Background Technology

[0002] Nintedanib ethanesulfonate (molecular formula C) 31 H 33 N5O4·C2H6O3S (molecular weight 649.76), structural formula is shown below: , It is a small-molecule tyrosine kinase inhibitor that targets tyrosine kinase receptors, blocking downstream signal activation in fibroblasts, thereby achieving an anti-fibrotic effect. Nintedanib ethoxylate soft capsules (Vegat) ® It is the world's first drug for the treatment of chronic fibrotic interstitial lung disease with a progressive phenotype, which significantly slows the decline in lung function. It was approved for marketing in the United States in September 2014 and was first approved in China in September 2017.

[0003] However, currently available commercially available nintedanib ethoxylate soft capsules (Vegat) ® The bioavailability of nintedanib ethoxylate is only 4.7%, with a significant first-pass effect in the liver. This effect significantly reduces the drug's utilization efficiency and increases the metabolic burden on the liver. Adverse reactions to nintedanib ethoxylate soft capsules are mainly concentrated in the gastrointestinal tract, including vomiting (12%), abdominal pain (15%), nausea (24%), diarrhea (62.4%), and abnormal liver enzymes (13.6%). After oral administration, nintedanib absorption is extremely limited, and the unabsorbed portion reaches a high concentration in the intestinal lumen. This high local concentration has a direct irritant and cytotoxic effect on the intestinal epithelium. The high dosages of 100mg and 150mg are highly likely to be the culprit for severe gastrointestinal adverse reactions. Because of its bitter taste, the instructions for use also require patients to take the medication with food, swallowing the whole capsule with water, and not chewing or crushing it. For elderly people over 75 years old, there are often liver and kidney dysfunction or difficulty swallowing. If the dosage has to be reduced or swallowing is impossible due to adverse reactions, elderly patients may accelerate the progression of the disease because they do not receive the correct dosage treatment. Therefore, there is a great need to manage adverse reactions by reducing the dosage.

[0004] Sublingual tablets are absorbed through the sublingual mucosa, exerting their effects rapidly. This avoids the first-pass effect of the liver and the degradation of the gastrointestinal tract, thus preserving efficacy, improving bioavailability, and reducing toxic side effects on the gastrointestinal tract and liver. Sublingual administration is simple, easy to administer, and has good compliance, avoiding the risks of choking and aspiration caused by swallowing medication. It is particularly suitable for elderly patients with difficulty swallowing, and sublingual administration is easier to administer.

[0005] Patent WO 2022234593 A1 discloses a sublingual tablet composition containing nintedanib or its salts. The composition involves reacting nintedanib with cyclodextrin to form an inclusion complex, followed by wet granulation and compression to form sublingual tablets. A drawback of this approach is the use of a large amount of acidic excipients for solubilization, which can lead to severe taste problems and mucosal irritation, significantly impacting patient compliance.

[0006] Liu Fangfang et al. (Preparation and Performance Study of Nintedanib Isylsulfonate Solid Dispersion, Modern Drugs & Clinical, 2024, 39(01), 88-93) prepared nintedanib isylsulfonate solid dispersion by solvent evaporation method, using polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) ® While this method, acting as a carrier, improves drug solubility to some extent, the resulting solid dispersion is highly hygroscopic, exhibiting crystallization after 20 days of exposure to high humidity (25°C / 92.5% RH). Furthermore, the solvent method carries the risk of solvent residue, hindering large-scale continuous production. Finally, this approach only addresses the intermediate stage of solid dispersion, failing to resolve the extremely bitter taste of the active pharmaceutical ingredient or how to formulate it into a sublingual preparation suitable for patients with swallowing difficulties.

[0007] Nintedanib ethsulfate is weakly alkaline and highly hydrophobic, belonging to the BCS class II compounds, and its pH increases as the pH decreases. Since saliva has a pH between 6.0 and 7.0, developing a sublingual nintedanib ethsulfate tablet that can rapidly disintegrate and be quickly absorbed under the tongue, with a pleasant taste, is a pressing issue that needs to be addressed. Summary of the Invention

[0008] For the original drug nintedanib acesulfame soft capsules (Vegat) ® To address the issue of low bioavailability, this invention provides a sublingual nintedanib ethoxylate tablet with low drug loading, high absorption rate, good taste, good stability, and short disintegration time, via sublingual mucosal administration and specific solubilization techniques. The tablet contains nintedanib ethoxylate, a carrier material, a filler, a disintegrant, a flavoring agent, and a lubricant. By setting specific proportions of these raw materials, the nintedanib ethoxylate sublingual tablet effectively solves the problem of low bioavailability caused by the first-pass effect in the liver compared to the original nintedanib ethoxylate soft capsules. The drug provided by this invention has a good taste, excellent stability, rapid disintegration, and fast dissolution rate, and all test items meet quality standards. This invention reduces the accumulation of unabsorbed drug in the gastrointestinal tract by lowering the dosage, reducing the metabolic burden on the liver, achieving the therapeutic effect of the original drug at a lower dosage, and improving patient compliance in clinical use.

[0009] During the research process, the inventors unexpectedly discovered that when certain hydrophilic polymers (such as Soluplus) ® ) and specific lipid excipients (such as Gelucire) ® When 44 / 14) are combined in a specific ratio to prepare solid dispersions, the two exhibit a significant synergistic solubilizing effect, with a dissolution rate significantly better than that of using Soluplus alone. ® The prepared samples, when combined in specific proportions, produce solid dispersions with higher solubility and release rates.

[0010] Based on the above findings, the present invention first provides a sublingual tablet of nintedanib ethanesulfonate, specifically composed of nintedanib ethanesulfonate, carrier material, filler, disintegrant, flavoring agent, and lubricant.

[0011] The carrier material mentioned above is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). ® ), hydroxypropyl methylcellulose acetate succinate, glyceryl behenate, stearoyl polyoxyethylene (32) glyceryl ester (Gelucire) ® 50 / 13), lauroyl polyoxyethylene (32) glyceryl ester (Gelucire) ® 44 / 14), Caprylic / Capric ... ® ), and various combinations of monolinoleic glycerides.

[0012] In a further embodiment, the carrier material is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). ® ), caprylic / capric acid glyceride (Labrasol) ® ) and lauroyl polyoxyethylene (32) glycerol ester (Gelucire ® Multiple combinations of 44 / 14.

[0013] In a further embodiment, the carrier material is selected from polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). ® ) and lauroyl polyoxyethylene (32) glycerol ester (Gelucire ® A combination of 44 / 14.

[0014] Simply using Soluplus ® When used as a carrier, although it can form an amorphous solid dispersion, the drug's strong hydrophobicity makes it difficult for water to quickly penetrate into the matrix. However, adding Gelucire to the system... ®After 44 / 14, by utilizing its amphiphilic lipid properties, the wettability of the solid dispersion surface is significantly improved and the solid-liquid interfacial tension is reduced. This combination can increase the drug dissolution rate to over 99% at 60 minutes.

[0015] Preferably, the inventors first prepare nintedanib ethanesulfonate and carrier material into a nintedanib ethanesulfonate solid dispersion (SD-NTB), and then mix it with other excipients. The composition of the nintedanib ethanesulfonate solid dispersion is as follows: By weight: 10-30 parts of nintedanib ethanesulfonate, and Soluplus polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. ® 30-80 parts of the first type of carrier material and 5-20 parts of the second type of carrier material.

[0016] The second carrier material can preferably be one or more substances within the above-mentioned range other than polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, wherein lauroyl polyoxyethylene (32) glycerol ester is preferred. ® 44 / 14).

[0017] To ensure smooth feeding during preparation, preferably, 1-3 parts by weight of colloidal silica can be added as a flow aid.

[0018] The specific preparation method of the above-mentioned nintedanib ethanesulfonate solid dispersion is as follows: Nintedanib ethanesulfonate, carrier material and colloidal silica are added to a twin-screw hot melt extruder for mixing. After the mixture is cooled and drawn into strips, it is extruded into strips, cut into small segments and crushed. The strips are then screened using a sieve with a mesh size of not less than 120 to obtain the yellow nintedanib ethanesulfonate solid dispersion (SD-NTB).

[0019] Preferably, the temperature range of the twin-screw hot melt extruder is set to 80℃-160℃. Specifically, the temperature of each zone of the barrel is set as follows: feeding zone 80-100℃, melt mixing zone 130-150℃, metering zone 140-160℃, die temperature 130-150℃, screw speed 50-70 rpm; cooling temperature 15-25℃; output torque 4-12 N·m, screw speed 60 rpm.

[0020] The final particle size distribution of the nintedanib ethanesulfonic acid solid dispersion is 60-250 μm; more preferably 60-125 μm.

[0021] After obtaining the above-mentioned nintedanib ethanesulfonate solid dispersion, it can be mixed with other excipients to obtain nintedanib ethanesulfonate sublingual tablets. The weight percentage of the above-mentioned nintedanib ethanesulfonate solid dispersion in the final product nintedanib ethanesulfonate sublingual tablets is 20-40%, preferably 20-25%, and most preferably 20%.

[0022] In some embodiments, the nintedanib ethanesulfonate sublingual tablet contains at least one disintegrant selected from one or more of crospovidone, sodium carboxymethyl starch, and sodium carboxymethyl cellulose, and the disintegrant accounts for 5%-15% of the total weight of the tablet; in a further embodiment, the disintegrant is selected from crospovidone.

[0023] In some embodiments, the nintedanib ethanesulfonate sublingual tablet contains at least one flavoring agent selected from one or more of sucralose, aspartame, sodium saccharin, steviol glycosides, and acesulfame potassium, and the flavoring agent accounts for 1%-5% of the total weight of the tablet; in a further embodiment, the flavoring agent may be sucralose.

[0024] In some embodiments, the nintedanib ethanesulfonate sublingual tablet contains at least one lubricant selected from one or more of magnesium stearate, calcium stearate, talc, colloidal silica, and sodium stearate fumarate, and the lubricant accounts for 0.5%-5.0% of the total weight of the tablet; in further embodiments, the lubricant is selected from one or more of magnesium stearate and colloidal silica; most preferably, the lubricant is selected from magnesium stearate and colloidal silica, which accounts for 0.5%-1.0% of the total weight of the tablet.

[0025] In some embodiments, the nintedanib ethoxylate sublingual tablet contains at least one filler selected from one or more of mannitol, lactose monohydrate, sorbitol, corn starch, and microcrystalline cellulose, with the amount of filler sufficient to make up the total weight of the tablet; in a further embodiment, the filler is selected from one or more of mannitol and microcrystalline cellulose.

[0026] The inventors further disclosed the preparation method of the above-mentioned nintedanib ethanesulfonic acid sublingual tablets, the specific steps of which are as follows: The prescribed amounts of filler, disintegrant, and flavoring agent are passed through an 80-mesh sieve. The nintedanib ethanesulfonate solid dispersion is then mixed evenly with the filler, disintegrant, and flavoring agent in a three-dimensional multi-directional mixer for at least 10 minutes to obtain a premixed powder. A lubricant is then added for a second mixing, with a mixing time of at least 5 minutes, to obtain the final powder, which is then compressed into tablets. Tableting is generally performed according to the tablet size and the actual equipment conditions. For example, using an 8mm punch yields sublingual tablets with a hardness of 2-4 kg.

[0027] Compared with the prior art, the present invention has achieved the following beneficial effects: (1) Nintedanib ethanesulfonate belongs to BCS Class II drugs. Its molecular structure contains a polycyclic aromatic skeleton and there are strong π-π stacking interactions between molecules, resulting in extremely high lattice energy. This invention uses hot melt extrusion technology to forcibly break the strong intermolecular forces inside the nintedanib ethanesulfonate crystal through the synergistic effect of mechanical shear force and thermal energy, thereby destroying the drug's lattice energy and keeping the drug in a high-energy amorphous state. This can significantly improve the instantaneous solubility of the drug in saliva or weakly alkaline environments and increase the initial dissolution rate required for rapid sublingual absorption.

[0028] (2) The absorption of nintedanib in its original crystalline form is limited in vivo and its oral bioavailability is low. This technical solution uses the compound and the carrier material to form a polymer, which promotes mucosal penetration and achieves higher sublingual absorption efficiency.

[0029] (3) This invention constructs a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). ® Soluplus is a dual-carrier solid dispersion system with Soluplus as the main framework material and other auxiliary matrix materials as auxiliary functional regulators. ® Utilizing its massive polymer network structure, it serves as a fundamental carrier for dispersing drug molecules, inhibiting the formation and growth of drug crystal nuclei. Simultaneously, the introduction of other auxiliary matrix materials into the system leverages their amphiphilic structure to significantly reduce the solid-liquid interfacial tension on the dispersion surface, effectively "attracting water in" and facilitating the entry of water into Soluplus. ® The dense framework of the channel also forms a hydrophobic barrier in the microstructure, effectively solving the problem of easy hygroscopic transformation of solid dispersions in existing technologies. This significantly improves the long-term physical stability of the formulation. The combined application of these two materials enhances the smoothness of sublingual administration, significantly accelerates drug dissolution, and promotes rapid absorption under the tongue. The nintedanib ethoxylate sublingual tablets provided by this invention have a good taste, excellent stability, short disintegration time, high dissolution rate, high bioavailability, and minimal gastrointestinal irritation, greatly improving clinical compliance in special patients and demonstrating significant advantages in clinical use. Attached Figure Description

[0030] Figure 1 The figure shows the in vitro dissolution curves of the nintedanib ethanesulfonic acid solid dispersions of Comparative Example 1 and Examples 1-7 in a medium of pH 6.8. Figure 2 The in vitro dissolution curves of nintedanib ethanesulfonate sublingual tablets in Comparative Examples 2-4 and Examples 8-13 at pH 6.8 are shown. Figure 3 The sublingual tablets of nintedanib ethoxylate obtained in Example 12 and the original formulation of nintedanib ethoxylate soft capsules (Ofev) ® Mean blood drug concentration-time curve in beagle dogs. Detailed Implementation

[0031] To make the beneficial effects of the present invention more apparent and understandable, specific embodiments are provided to further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Except in special circumstances, the following embodiments are all implemented using conventional prior art.

[0032] The detection methods for evaluation indicators such as dissolution rate, disintegration time, and taste in the embodiments or specific examples of the present invention are as follows: In vitro dissolution: The dissolution and release determination method (method 3, small cup method) according to the 2025 edition of the Chinese Pharmacopoeia, 0931, was used. The dissolution medium was 250 ml of pH 6.8 phosphate buffer, and the temperature was maintained at 37 ± 0.5℃. A sample equivalent to the test specification was placed on the surface of the dissolution medium. The paddle was started, and the rotation speed was set to 50 rpm. 5 ml of solution was collected from the dissolution cup at 5, 15, 30, 45, and 60 minutes, filtered through a 0.45 μm microporous membrane, and used for measurement. The absorbance of the filtered sample was measured at 238 nm, and the dissolution amount at each time point was calculated. The average value was taken as the final dissolution curve data.

[0033] Disintegration time limit: Add approximately 2 ml of purified water to a flat-bottomed test tube with a diameter of 1.5 cm, maintain the water temperature at 37.0℃ ± 0.5℃, add one nintedanib ethanesulfonate sublingual tablet, and record the time from tablet addition to complete disintegration into powder. Perform parallel tests on 6 tablets per batch. Each tablet should completely disintegrate within the specified time limit of 2 minutes.

[0034] Hardness testing: Using a tablet hardness tester, the tablet is placed in the testing area. The drive motor, through a transmission structure, slowly and uniformly advances the indenter. Pressure is applied upon contact with the tablet until it breaks. The reading on the instrument panel is the tablet hardness. Each batch of samples should contain at least 3 tablets for testing.

[0035] Taste evaluation: The prepared nintedanib ethoxylate sublingual tablets should not have a significant bitter taste or irritation, but a suitable sweetness and gritty sensation are permissible. The homemade sample from the example was selected, and 20 volunteers (half male and half female) were allowed to taste it. After rinsing their mouths with 200ml of purified water, the volunteers placed the nintedanib ethoxylate sublingual tablets under their tongues and rated their sensations as follows: bitter (1-5 points), tingling (1-5 points), sour (1-5 points), sweet (1-5 points), and gritty (1-5 points).

[0036] Preparation of Nintedanib ethanesulfonic acid solid dispersions in Examples 1-7 and Comparative Example 1 The raw material composition of the above embodiments and Comparative Example 1, by weight, is shown in Table 1 below: Table 1. Raw material composition of nintedanib ethanesulfonate solid dispersions in Examples 1-7 and Comparative Example 1 The specific preparation method is as follows: Commercially available nintedanib ethanesulfonate (NTB) was micronized to obtain an active component of nintedanib ethanesulfonate with a particle size of less than 10 μm.

[0037] For the three prescriptions in Examples 4-6, Gelucire ® 44 / 14 requires pre-treatment and pulverization using a 40-mesh sieve, along with the active component of nintedanib ethanesulfonate and Soluplus. ® After premixing with colloidal silica, the material is added to a twin-screw hot melt extruder. The temperature range is set to 100-160℃, with the specific barrel temperatures set as follows: feeding zone 80-100℃, melt mixing zone 130-150℃, metering zone 140-160℃, die temperature 130-150℃, screw speed 60 rpm, and output torque controlled at 8 N·m. The extruded material is hardened by air cooling at 15℃, cut into 2-5mm long particles, and then pulverized through a 120-mesh sieve to obtain nintedanib ethanesulfonate solid dispersion.

[0038] For Examples 1-3, the prescribed amount of Labrasol ® After mixing with colloidal silica to form a free-flowing powder, it is then mixed with Soluplus. ® The active component, nintedanib ethanesulfonate, is mixed together and added to a twin-screw hot melt extruder. The temperature ranges are set to 100-160℃. The barrel temperatures are set sequentially as follows: feeding zone 80-100℃, melt mixing zone 130-150℃, metering zone 140-160℃, die temperature 130-150℃, screw speed 60 rpm, and output torque controlled at 10 N·m. The extruded material is hardened into strips by air cooling at 20℃, cut into 2-5 mm long particles, and then pulverized through a 120-mesh sieve to obtain a solid dispersion of nintedanib ethanesulfonate.

[0039] For Example 7, the prescribed amount of Labrasol ® After mixing with colloidal silica to form a free-flowing powder, it is then mixed with Soluplus. ® Gelucire ®The active components of 44 / 14 and nintedanib ethanesulfonate were mixed together and added to a twin-screw hot melt extruder. The temperature ranges were set to 100-160℃, with the barrel temperatures set sequentially as follows: feeding zone 80-100℃, melt mixing zone 130-150℃, metering zone 140-160℃, and die temperature 130-150℃. The screw speed was 60 rpm, and the output torque was controlled at 12 N·m. The extruded material was hardened into strips by air cooling at 15℃, cut into 2-5 mm long particles, and then pulverized through a 120-mesh sieve to obtain a solid dispersion of nintedanib ethanesulfonate.

[0040] Comparative Example 1: Nintanib ethanesulfonate active ingredient was combined with Soluplus ® The mixture is directly added to a twin-screw hot melt extruder, with each temperature range set at 100-160℃. The barrel temperatures are set sequentially as follows: feeding zone 80-100℃, melt mixing zone 130-150℃, metering zone 140-160℃, die temperature 130-150℃, screw speed 60 rpm, and output torque controlled at 10 N·m. The extruded material is hardened into strips by air cooling at 15℃, cut into 2-5mm long particles, and then pulverized through a 120-mesh sieve to obtain nintedanib ethanesulfonate solid dispersion.

[0041] The in vitro dissolution rate of nintedanib ethanesulfonate solid dispersions obtained in Examples 1-7 and Comparative Example 1 was determined. Three portions of each batch were accurately weighed and tested according to the in vitro dissolution rate testing method described above. The dissolution curves for different carrier material ratios are shown in Table 2 and [Table data would be inserted here]. Figure 1 .

[0042] Table 2. In vitro dissolution determination of nintedanib ethanesulfonate solid dispersions in Examples 1-7 and Comparative Example 1 As can be seen from the dissolution data in Table 2, the active pharmaceutical ingredient only has similar properties to Soluplus. ® When used in combination, the cumulative dissolution rate over 60 minutes was only 54.9%. (Active drug and Soluplus) ® +Labrasol ® When used in combination, the cumulative dissolution rate at each time point was significantly improved, but with the application of Labrasol... ® With the increase of [specific ingredient], dissolution rate does not increase linearly with the increase of its content, but rather enters a plateau phase. [Active drug and Soluplus] ® +Gelucire ® When used in combination with 44 / 14, the average cumulative dissolution rate over 60 minutes can reach up to 99.3%. However, the dissolution rate in this formulation does not increase linearly with increasing concentration, which may be due to the presence of Gelucire. ®When the 44 / 14 content is too high, the porosity / capillary channels of the material decrease, which can hinder drug diffusion. When Soluplus... ® Labrasol ® and Gelucire ® When 44 / 14 are used in combination, the system structure becomes more complex, and excessive lipids can lock in the drug, slowing its release and negatively impacting its release. Therefore, we selected the nintedanib ethanesulfonate solid dispersion prepared in Example 5 as the active pharmaceutical ingredient for subsequent sublingual tablet preparation.

[0043] Preparation of Nintedanib ethanesulfonate sublingual tablets in Examples 8-13 and Comparative Examples 2 and 3 The raw material composition of the above embodiments and comparative examples, expressed as a percentage by weight, is shown in Table 3 below: Table 3. Raw material composition of sublingual tablets in Examples 8-13 and Comparative Examples 2 and 3 The preparation method of the above-mentioned nintedanib sublingual tablets is as follows: (1) Pass the prescribed amount of filler, disintegrant, and flavoring agent through an 80-mesh sieve, weigh the prescribed amount of nintedanib ethanesulfonic acid solid dispersion, mix it with the filler, disintegrant, and flavoring agent, and mix for no less than 10 minutes to obtain a premixed powder; (2) Pass the lubricant through a 120-mesh sieve, add the lubricant to the above system for a second mixing, and mix for no less than 5 minutes to obtain the total powder; (3) The total powder is directly compressed into tablets to obtain tablets with a weight of 150mg, the difference not exceeding ±5%, and a hardness of 2kg-4kg for sublingual tablets.

[0044] Comparative Example 4: Sublingual tablet samples were prepared according to the preparation method disclosed in WO2022234593A1, using Example 2 from the patent. The formulation is as follows: Add an appropriate amount of 0.1N hydrochloric acid solution to ensure a clear solution is obtained after dissolution.

[0045] Preparation method: Accurately weigh all materials. Pass citric acid through a 20-mesh sieve and place it in a fluidized bed granulator as the substrate. Prepare 0.1N hydrochloric acid as a solvent, add hydroxypropyl-β-cyclodextrin and stir, then add tartaric acid and stir until dissolved. Heat the solution to 50-60 degrees Celsius, add nintedanib ethanesulfonic acid, and stir until a clear orange to yellow solution is formed. Use a spray gun to spray the hot binder solution onto the citric acid powder in the fluidized bed. Dry until the moisture content is within acceptable limits. Discharge the dried granules and pass them through a 20-mesh sieve. Pass magnesium stearate through a 60-mesh sieve and mix it with the dried granules. Use a 6.5mm round punch to compress the mixture into tablets to obtain the final product.

[0046] The samples prepared in Examples 8-13 and Comparative Examples 2-4 were tested for dissolution according to the third method of Dissolution and Release Determination, 0931, Chinese Pharmacopoeia 2025 Edition. The results are shown in Table 4. Figure 2 .

[0047] Table 4 Dissolution determination of Examples 8-13 and Comparative Examples 2-4 The results showed that the dissolution rate of the samples prepared in Comparative Examples 2 and 3 did not reach 80% within 5 minutes. This may be because excessive amounts of the hydrophobic lubricant magnesium stearate significantly hinder drug dissolution. The sample in Comparative Example 4, prepared according to patent WO2022234593A1, showed significantly inhibited dissolution in a pH 6.8 medium. This may be because the formulation of Comparative Example 4 contains a large amount of acid regulator to aid dissolution, and in a phosphate medium with strong buffering capacity, the acidic microenvironment is rapidly neutralized, making it difficult for the microcrystalline drug to dissolve further. This indicates that the existing "acidic solubilization strategy" has significant limitations in neutral environments (such as saliva). In contrast, the samples in Examples 8-13 of this application all achieved a dissolution rate of over 85% within 5 minutes, representing a significant improvement.

[0048] Samples prepared from the formulations of Examples 8-13 and Comparative Example 4 were selected. Referring to the "Technical Guidelines for Taste Design and Evaluation of Pediatric Drugs (Trial Implementation)," 20 volunteers (ten males and ten females) were selected to conduct taste evaluations. The score for each item was the average value. The evaluation scores are shown in Table 5.

[0049] Table 5. Taste evaluation of Examples 8-13 and Comparative Example 4 Conclusion: As shown in Table 5, the taste of all sublingual tablets prepared in the examples was within the acceptable range, with Example 12 showing the best taste. The sublingual tablet prepared in Comparative Example 4 had the worst taste, with subjects reporting severe sourness and tingling sensation. After evaluation, slight redness and swelling were observed on the sublingual mucosa of subjects who used the sublingual tablet in Comparative Example 4.

[0050] Based on the dissolution results in Table 4, we selected samples from Examples 8-13 and Comparative Example 4, simulated market packaging, and conducted stability studies under high temperature (60℃), accelerated (40℃ / 75%RH), and long-term (25℃ / 60%RH) conditions. The disintegration time was set at no more than 60 seconds, the content standard at 95%-105%, and the total impurities at no more than 2.0%. The results are shown in Table 6. Table 6. Stability tests of Examples 8-13 and Comparative Example 4 The results showed that all samples from the embodiments met the proposed standards after high-temperature testing, accelerated testing, and long-term testing. The formulation of Comparative Example 4, due to the use of a large amount of citric acid, was highly hygroscopic, resulting in a sticky tablet surface. This also easily led to the formation of specific acidic hydrolytic impurities in nintedanib ethanesulfonate.

[0051] Bioavailability Study of Experimental Examples The following medications were selected: Experimental group: Nintedanib ethanesulfonate sublingual tablets prepared in Example 12 Control group: Commercially available nintedanib acesulfame soft capsules (Ofev) ® ); The analytical instrument used is a SCIEX Exion LC-TQ5500; The test method is as follows: Twelve Beagles, half male and half female, weighing 8.5 ± 0.5 kg, were divided into two groups of six. The control group received oral Ofeval. ® Soft capsules; sublingual tablets were administered to experimental group 1.

[0052] Blood collection points: before drug administration, 0.5h, 1h, 3h, 5h, 7h, 12h, 18h, and 24h. 0.5ml of whole blood was collected from veins in the limbs at each time point, using sodium heparin as the anticoagulant. The collected blood samples were added to anticoagulant centrifuge tubes and shaken to thoroughly mix the blood and anticoagulant. The tubes were vortexed at 8℃ and 1500rpm for 10min, diluted, and then injected for analysis to determine the concentration of the active pharmaceutical ingredient in the plasma. Results are detailed in Table 7 and... Figure 3 .

[0053] Table 7. Blood drug concentration measurements in the experimental and control groups. The results showed that the AUC of the nintedanib ethoxylate sublingual tablets prepared in Example 12 of this application was extremely close to that of the original soft capsules (2395.2 ± 425.6 ng·h / mL), and the relative bioavailability of the two was approximately 98.6%, with no statistically significant difference from the AUC of the original nintedanib ethoxylate soft capsules. The samples prepared according to the formulation and process of this application achieved systemic drug exposure comparable to the original formulation at a lower dosage, with a faster onset of action. This successfully overcame the risk of incomplete absorption that might arise from changing the route of administration (from oral to sublingual), ensuring systemic drug exposure and therapeutic efficacy comparable to the original drug.

[0054] For those skilled in the art, the specific embodiments are merely illustrative descriptions of the present invention. Obviously, the specific implementation of the present invention is not limited to the above-described manner. Any non-substantial improvements made using the inventive concept and technical solution of the present invention, or the direct application of the inventive concept and technical solution to other situations without modification, are all within the protection scope of the present invention.

Claims

1. A sublingual tablet of nintedanib ethanesulfonate, characterized in that, The specific raw material composition is nitedanib ethanesulfonate, carrier material, filler, disintegrant, flavoring agent, and lubricant; wherein the carrier material is selected from a variety of combinations of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose acetate succinate, behenic acid glyceride, stearoyl polyoxyethylene (32) glyceride, lauroyl polyoxyethylene (32) glyceride, caprylic / capric acid polyethylene glycol glyceride, and monolinoleic acid glyceride.

2. The nintedanib ethanesulfonate sublingual tablet according to claim 1, characterized in that, The carrier material is selected from a variety of combinations of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, caprylic / capric acid glycerol ester, and lauroyl polyoxyethylene (32) glycerol ester.

3. The nintedanib ethanesulfonate sublingual tablet according to claim 1 or 2, characterized in that, The carrier material is selected from a combination of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and lauroyl polyoxyethylene (32) glycerol ester.

4. The nintedanib ethanesulfonate sublingual tablet according to claim 1, characterized in that, The disintegrant is selected from one or more of crospovidone, sodium carboxymethyl starch, and sodium carboxymethyl cellulose, and accounts for 5%-15% of the total weight of the tablet; the flavoring agent is selected from one or more of sucralose, aspartame, sodium saccharin, steviol glycosides, and acesulfame potassium, and accounts for 1%-5% of the total weight of the tablet; the lubricant is selected from one or more of magnesium stearate, calcium stearate, talc, colloidal silica, and sodium stearate fumarate, and accounts for 0.5%-5.0% of the total weight of the tablet; the filler is selected from one or more of mannitol, lactose monohydrate, sorbitol, corn starch, and microcrystalline cellulose, and the filler amount is sufficient to make up the total weight of the tablet.

5. The nintedanib ethanesulfonate sublingual tablet according to claim 1 or 4, characterized in that, The filler is selected from mannitol and / or microcrystalline cellulose; the disintegrant is selected from crospovidone; the flavoring agent is selected from sucralose; and the lubricant is selected from magnesium stearate and / or colloidal silica.

6. The nintedanib ethanesulfonate sublingual tablet according to claim 1, characterized in that, First, nintedanib ethanesulfonate and a carrier material are prepared into a nintedanib ethanesulfonate solid dispersion. The composition of the nintedanib ethanesulfonate solid dispersion by weight is as follows: 10-30 parts of nintedanib ethanesulfonate, 30-80 parts of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and 5-20 parts of a second carrier material. The second carrier material is selected from one or more of hydroxypropyl methylcellulose acetate succinate, behenicol glycerol, stearoyl polyoxyethylene (32) glycerol, lauroyl polyoxyethylene (32) glycerol, caprylic / capric polyethylene glycol glycerol, and monolinoleic acid glycerol. The weight percentage of the nintedanib ethanesulfonate solid dispersion in the nintedanib ethanesulfonate sublingual tablet is 20-40%.

7. The nintedanib ethanesulfonate sublingual tablet according to claim 6, characterized in that, The preparation method of the nitedanib ethanesulfonate solid dispersion is to add nitedanib ethanesulfonate and carrier material into a twin-screw hot melt extruder for mixing, and after cooling and drawing the resulting mixture into strips, it is cut into small segments and crushed. The segments are then screened using a sieve with a mesh size of not less than 120 to obtain the nitedanib ethanesulfonate solid dispersion. The particle size distribution of the final nitedanib ethanesulfonate solid dispersion is 60-250 μm.

8. The nintedanib ethanesulfonate sublingual tablet according to claim 7, characterized in that, When preparing the nintedanib ethanesulfonic acid solid dispersion, 1-3 parts by weight of colloidal silica are added as a flow aid; the temperature range of the twin-screw hot melt extruder is set to 80℃-160℃, the screw speed is 50-70rpm, and the cooling temperature is 15-25℃; the particle size distribution of the final obtained nintedanib ethanesulfonic acid solid dispersion is 60-125μm.

9. The nintedanib ethanesulfonate sublingual tablet according to claim 8, characterized in that, The temperatures of each zone of the twin-screw hot melt extruder are set as follows: feeding zone 80-100℃, melting and mixing zone 130-150℃, metering zone 140-160℃, and die temperature 130-150℃.

10. The method for preparing nintedanib ethanesulfonate sublingual tablets according to claim 1, characterized in that, The specific steps are as follows: Pass the prescribed amount of filler, disintegrant, and flavoring agent through an 80-mesh sieve. Mix the nintedanib ethanesulfonate solid dispersion with the filler, disintegrant, and flavoring agent evenly to obtain a premixed powder. Then add a lubricant for a second mixing to obtain a total powder. Compress the powder into tablets to obtain the final product, nintedanib ethanesulfonate sublingual tablets, which contain 20-40% nintedanib ethanesulfonate solid dispersion by weight.

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