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CN-121987579-A - Sublingual tablet of nintedanib ethanesulfonate and preparation method thereof

CN121987579ACN 121987579 ACN121987579 ACN 121987579ACN-121987579-A

Abstract

The invention relates to the technical field of medicines, in particular to a glyburide sublingual tablet of ethanesulfonic acid and a preparation method thereof, wherein the sublingual tablet contains glyburide of ethanesulfonic acid, a carrier material, a filler, a disintegrating agent, a flavoring agent and a lubricant, and compared with the glyburide sublingual tablet of ethanesulfonic acid prepared by setting the specific proportion of the raw materials and the auxiliary materials, the glyburide sublingual tablet of ethanesulfonic acid effectively solves the problem of low bioavailability caused by the liver first pass effect. At the same time, the compliance of clinical use of patients is also improved.

Inventors

  • LI SHENGCHAO
  • Ban Qiuyu
  • DONG GUANGJIN
  • LIU SHANKUI
  • LI TIEJUN

Assignees

  • 山东京卫制药有限公司

Dates

Publication Date
20260508
Application Date
20260228

Claims (10)

  1. 1. The nintedanib mesylate sublingual tablet is characterized by comprising the specific raw materials of nintedanib mesylate, a carrier material, a filler, a disintegrating agent, a flavoring agent and a lubricant, wherein the carrier material is selected from a plurality of combinations of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methyl cellulose acetate succinate, glyceryl behenate, stearoyl polyoxyethylene (32) glyceride, lauroyl polyoxyethylene (32) glyceride, caprylic-capric polyethylene glycol glyceride and glyceryl monolinoleate.
  2. 2. The nidanib sublingual tablet of claim 1, wherein the carrier material is selected from the group consisting of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, caprylic capric polyethylene glycol glyceride, lauroyl polyoxyethylene (32) glyceride.
  3. 3. The nidanib sublingual tablet according to claim 1 or 2, characterized in that the carrier material is selected from the group consisting of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and lauroyl polyoxyethylene (32) glyceride.
  4. 4. The tablet according to claim 1, wherein the disintegrating agent is selected from one or more of crospovidone, sodium carboxymethyl starch and sodium carboxymethyl cellulose, the disintegrating agent is 5-15% of the total weight of the tablet, the flavoring agent is selected from one or more of sucralose, aspartame, saccharin sodium, stevioside and acesulfame potassium, the flavoring agent is 1-5% of the total weight of the tablet, the lubricant is selected from one or more of magnesium stearate, calcium stearate, talcum powder, colloidal silicon dioxide and sodium stearyl fumarate, the lubricant is 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 is used in an amount of up to the total weight of the tablet.
  5. 5. The sub-lingual tablet of nidanib mesylate according to claim 1 or 4, wherein said filler is selected from mannitol and/or microcrystalline cellulose, said disintegrant is selected from crospovidone, said flavoring agent is selected from sucralose, and said lubricant is selected from magnesium stearate and/or colloidal silicon dioxide.
  6. 6. The tab of the nintedanib mesylate according to claim 1 is characterized in that, firstly, the nintedanib mesylate and a carrier material are prepared into a solid dispersion of the nintedanib mesylate, the solid dispersion of the nintedanib mesylate comprises, by weight, 10-30 parts of the nintedanib mesylate, 30-80 parts of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and 5-20 parts of a second carrier material, wherein the second carrier material is selected from one or more of hydroxypropyl methylcellulose acetate succinate, glyceryl behenate, stearoyl polyoxyethylene (32) glyceride, lauroyl polyoxyethylene (32) glyceride, caprylic acid capric acid polyethylene glycol glyceride and glyceryl monolinoleate, and the solid dispersion of the nintedanib mesylate in the tab of the nintedanib mesylate accounts for 20-40%.
  7. 7. The method for preparing the glyburide solid dispersion according to claim 6, which is characterized in that the glyburide solid dispersion is prepared by adding the glyburide and a carrier material into a double-screw hot-melt extruder for mixing, cooling the obtained mixture, bracing, extruding the bar into small sections, crushing, and screening by using a screen with the size not smaller than 120 meshes, wherein the particle size distribution of the finally obtained glyburide solid dispersion is 60-250 mu m.
  8. 8. The sublingual tablet of the nintedanib mesylate according to claim 7, wherein 1-3 parts by weight of colloidal silica is added as a glidant when preparing a solid dispersion of the nintedanib mesylate, each temperature interval of the twin-screw hot-melt extruder is set to 80-160 ℃, the rotating speed of the screw is 50-70rpm, the cooling temperature is 15-25 ℃, and the particle size distribution of the finally obtained solid dispersion of the nintedanib mesylate is 60-125 μm.
  9. 9. The sheet according to claim 8, wherein the temperature of each zone of the twin-screw hot-melt extruder is set to 80-100 ℃, the melt mixing zone 130-150 ℃, the metering zone 140-160 ℃ and the die temperature 130-150 ℃ in sequence.
  10. 10. The preparation method of the glyburide sublingual tablet of the ethanesulfonic acid is characterized by comprising the specific steps of sieving a filling agent, a disintegrating agent and a flavoring agent with a prescription amount through a 80-mesh sieve, uniformly mixing the glyburide solid dispersion with the filling agent, the disintegrating agent and the flavoring agent to obtain premixed powder, adding a lubricant for secondary mixing to obtain total mixed powder, and tabletting to obtain the final product, wherein the weight percentage of the glyburide solid dispersion in the glyburide sublingual tablet of the ethanesulfonic acid is 20-40%.

Description

Sublingual tablet of nintedanib ethanesulfonate and preparation method thereof Technical Field The invention relates to the technical field of new medicines, in particular to a nintedanib mesylate sublingual tablet and a preparation method thereof. Background Nidaminib ethanesulfonate (molecular formula C 31H33N5O4·C2H6O3 S, molecular weight 649.76) has the following structural formula: , The small molecule tyrosine kinase inhibitor acts on a tyrosine kinase receptor in a targeted way to block downstream signal activation of fibroblasts, thereby achieving the anti-fibrosis effect. The soft capsule of ethandibuli sulfonate (vicat ®) is the first drug worldwide to treat chronic fibrotic interstitial lung diseases with progressive phenotypes, significantly delaying the decline of lung function, and was marketed in the united states in month 9 of 2014, and was first approved in china in month 9 of 2017. However, the bioavailability of the currently marketed soft capsule of the ethandibulide (Vigat ®) is only 4.7%, the first pass effect of the liver is obvious, the effect obviously reduces the utilization efficiency of the medicine and increases the metabolism burden of the liver, the adverse reaction of the soft capsule of the ethandibulide mainly concentrates on the aspect of gastrointestinal tract, comprising vomiting (12%), abdominal pain (15%), nausea (24%), diarrhea (62.4%), abnormal liver enzymes (13.6%), the absorption of the ethandibulide after oral administration is very limited, the concentration of unabsorbed part in intestinal cavity is higher, the local high concentration has direct stimulation and cytotoxicity effect on intestinal epithelium, and the high-specification medication of 100mg and 150mg is most likely to be the root cause of serious adverse reaction of gastrointestinal tract. The nintedanib mesylate has bitter taste due to the characteristics of the medicine, so that the specification requires that the medicine should be taken together with food when the patient takes the medicine, and the whole capsule should be taken with water without chewing or crushing. For the aged over 75 years, there is often a case of liver and kidney insufficiency or dysphagia, and if the dosage has to be reduced or the aged cannot swallow because of occurrence of adverse reaction, the aged patient may accelerate progress of disease development because of incorrect dosage treatment, so that there is a great possibility that the adverse reaction needs to be managed by means of reducing the dosage. Sublingual tablet can be absorbed by sublingual mucosa to exert its effect rapidly. Avoiding the first pass effect of liver and the damage of gastrointestinal tract, being beneficial to maintaining the drug effect, improving the bioavailability of the drug and simultaneously reducing the toxic and side effects of the drug on the gastrointestinal tract and the liver. The sublingual administration is simple and easy to implement, has good compliance, avoids choking cough and aspiration risk caused by swallowing medicines, is particularly suitable for elderly patients with dysphagia, and is easier to operate. Patent WO 2022234593 A1 discloses a sublingual tablet composition comprising nildanib or salts thereof, which is prepared by reacting nildanib with cyclodextrin to form an inclusion compound, and tabletting using a wet granulation process. The disadvantage of this solution is that a large amount of acidic excipients is used for solubilization, which leads to serious taste problems and mucosal irritation, severely affecting compliance. Liu Fangfang et al (preparation and performance study of Nidamb ethanesulfonate solid dispersing agent, modern medicine and clinic, 2024,39 (01), 88-93) prepared Nidamb ethanesulfonate solid dispersing agent by solvent volatilization method, and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus ®) is used as carrier, so that the solubility of medicine is improved to a certain extent, but the prepared solid dispersing agent has stronger hygroscopicity, and the medicine crystallization phenomenon occurs after the prepared solid dispersing agent is placed for 20 days under the high-humidity condition of 25 ℃ and 92.5 percent RH. Meanwhile, the solvent method has the risk of solvent residue, and is difficult to continuously produce on a large scale. Finally, this regimen remains only in the solid dispersion intermediate stage, does not address the extremely bitter mouthfeel problem of the drug substance, nor does it relate to how to prepare it into a sublingual formulation suitable for dysphagia patients. The nintedanib ethanesulfonate itself is weakly alkaline, has strong hydrophobicity, belongs to BCS class II compounds, and increases with decreasing pH. The pH value of saliva is between 6.0 and 7.0, so that the development of the sublingual tablet of the ethandibulib mesylate which can be rapidly disintegrated under the tongue, is rapidly absorbed