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CN-122005430-A - Indomethacin long-acting suppository for resisting inflammation and easing pain and preparation method thereof

CN122005430ACN 122005430 ACN122005430 ACN 122005430ACN-122005430-A

Abstract

The invention relates to the technical field of pharmaceutical preparations, and in particular discloses an anti-inflammatory analgesic indomethacin long-acting suppository and a preparation method thereof, wherein the suppository consists of indomethacin slow-release microspheres and a modified fatty matrix, the slow-release microspheres are prepared by taking Eudragit RS100/RL100 as a compound skeleton through a spherulitic granulation process, and the modified fatty matrix is prepared by a mixed fatty glyceride compound matrix slow-release auxiliary agent, a three-dimensional suspension-assisting dispersing agent and the like through a melting, pre-crystallization and high-speed homogenization process, and the three-dimensional suspension-assisting dispersing agent contains modified nano silicon dioxide, glyceryl monostearate and beeswax. The preparation method constructs a microsphere-matrix dual controlled release system, eliminates abrupt release of the drug, realizes long-acting stable release, prevents sedimentation and agglomeration of the microsphere through a physical locking mechanism, is matched with a dual antioxidant system, improves the storage stability of the preparation, reduces irritation of rectal mucosa, has simple preparation process and controllable quality, is suitable for anti-inflammatory and analgesic of various diseases, and has wide clinical application prospect.

Inventors

  • ZHANG DI
  • HE JINGLIANG
  • FU HUI

Assignees

  • 江苏远恒药业有限公司

Dates

Publication Date
20260512
Application Date
20260327

Claims (10)

  1. 1. The indomethacin long-acting suppository is characterized by comprising, by weight, 60-70 parts of indomethacin sustained-release microspheres and 900-1000 parts of modified fatty matrix.
  2. 2. The anti-inflammatory analgesic indomethacin long-acting suppository according to claim 1, wherein the preparation method of the indomethacin sustained-release microsphere is as follows: adding the indomethacin, the acrylic resin compound and the first antioxidant into an acetone-absolute ethyl alcohol mixed solvent, stirring and dissolving to obtain a mixed solution A, dropwise adding the mixed solution A into a dilute hydrochloric acid solution under the stirring condition, continuously stirring until spherical crystals are completely formed after the dropwise adding is finished, filtering, washing, vacuum drying and sieving to obtain the indomethacin slow-release microspheres.
  3. 3. The indomethacin long-acting suppository for resisting inflammation and easing pain according to claim 2, wherein the acrylic resin compound consists of Eudragit RS100 and Eudragit RL100 in a mass ratio of 3-5:1, and the first antioxidant is butyl hydroxy anisole.
  4. 4. The indomethacin long-acting suppository for resisting inflammation and easing pain according to claim 2, wherein the dosage ratio of indomethacin, an acrylic resin compound, a first antioxidant and an acetone-absolute ethyl alcohol mixed solvent is 5g (43-50 g) (0.01-0.02 g:100 mL), and the volume ratio of acetone to absolute ethyl alcohol in the acetone-absolute ethyl alcohol mixed solvent is 3-5:1.
  5. 5. The anti-inflammatory analgesic indomethacin long-acting suppository according to claim 1, wherein the preparation method of the modified fatty matrix is as follows: Mixing the mixed fatty glyceride, the matrix slow-release auxiliary agent and the second antioxidant, heating to 70-75 ℃, stirring and melting to obtain an oil phase, cooling the oil phase to 55-60 ℃, preserving heat for 15-25min for pre-crystallization treatment, heating to 65-70 ℃, adding polyoxyethylene stearate and a three-dimensional suspension-aid dispersing agent, and stirring to obtain the modified fatty matrix.
  6. 6. The indomethacin long-acting suppository for resisting inflammation and easing pain according to claim 5, wherein the matrix slow-release auxiliary agent consists of glyceryl behenate and stearic acid in a mass ratio of 1-1.4:1, and the second antioxidant is ascorbyl palmitate.
  7. 7. The indomethacin long-acting suppository for resisting inflammation and easing pain according to claim 5, wherein the three-dimensional suspension-assisting dispersing agent is composed of modified nano silicon dioxide, glyceryl monostearate and beeswax in a mass ratio of 1:9-11:7-9.
  8. 8. A method for preparing an anti-inflammatory analgesic indomethacin long-acting suppository according to any one of claims 1 to 7, comprising the steps of: s1, heating the modified fat matrix, and then, preserving heat and stirring to obtain a pretreated modified fat matrix; s2, adding indomethacin slow-release microspheres into the pretreated modified fatty matrix, stirring, and performing ultrasonic dispersion to obtain a microsphere-matrix mixed system; s3, cooling the microsphere-matrix mixed system, then injecting the cooled microsphere-matrix mixed system into a preheated suppository mold, standing the mold after mold filling at room temperature for solidification, and demolding to obtain the anti-inflammatory analgesic indomethacin long-acting suppository.
  9. 9. The method for preparing the indomethacin long-acting suppository with anti-inflammatory and analgesic effects according to claim 8, wherein in the step S1, the modified fat substrate is heated to 60-70 ℃, the stirring speed is 200-300rpm, and the stirring time is 8-12min.
  10. 10. Use of an anti-inflammatory analgesic indomethacin long-acting suppository according to any one of claims 1 to 7 in the preparation of a medicament for the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and acute gout flares.

Description

Indomethacin long-acting suppository for resisting inflammation and easing pain and preparation method thereof Technical Field The invention relates to the technical field of pharmaceutical preparations, in particular to an anti-inflammatory analgesic indomethacin long-acting suppository and a preparation method thereof. Background Indomethacin is a non-steroidal anti-inflammatory drug commonly used in clinic, plays a remarkable role in anti-inflammatory, analgesic and antipyretic by inhibiting prostaglandin synthesis, and is widely applied to symptomatic treatment of inflammatory diseases such as rheumatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, acute gout attack and the like. The suppository formulation for rectal administration can effectively avoid the gastrointestinal tract irritation problem caused by oral preparations, improves the bioavailability of the medicament and the medication compliance of patients, and becomes a preferred administration form of the medicament clinically. The indomethacin suppository in the existing clinical application is mostly prepared by adopting a conventional fatty matrix, has the defect of over-high drug release speed, is easy to cause large fluctuation of blood concentration in a human body and obvious peak-valley effect, is difficult to maintain long-acting blood concentration even if being administered every day, has a night curative effect blind area, and cannot meet the long-term and stable pain relieving treatment requirement of chronic inflammatory patients. Meanwhile, the conventional indomethacin Xin Shuanji also has the problems of main medicine sedimentation and matrix layering easily occurring under high-temperature storage, the content uniformity and the preparation stability are poor, and part of the preparation also has rectal mucosa irritation caused by drug burst, so that the drug administration experience and compliance of patients are further reduced. Therefore, there is a need for an indomethacin Xin Zhichang suppository with stable release, durable efficacy, excellent stability and high safety, which is suitable for the practical requirements of long-term clinical treatment. Based on the above statement, the invention provides an anti-inflammatory analgesic indomethacin long-acting suppository and a preparation method thereof. Disclosure of Invention The invention provides an anti-inflammatory analgesic indomethacin long-acting suppository and a preparation method thereof, and aims to solve the problems that in the prior art, indomethacin Xin Shuanji is excessively fast in drug release, large in blood concentration fluctuation and short in drug effect maintenance time, main drug sedimentation and matrix delamination are easy to occur during high-temperature storage, content uniformity and preparation stability are poor, and rectal mucosa irritation is easy to be caused by drug burst. In a first aspect, the invention provides an anti-inflammatory analgesic indomethacin long-acting suppository, which adopts the following technical scheme: an anti-inflammatory analgesic indomethacin long-acting suppository is prepared from the following raw materials (by weight ratio) indomethacin slow-release microspheres 60-70 parts and modified fat matrix 900-1000 parts. Preferably, the preparation method of the indomethacin sustained-release microsphere comprises the following steps: adding the indomethacin, the acrylic resin compound and the first antioxidant into an acetone-absolute ethyl alcohol mixed solvent, stirring and dissolving to obtain a mixed solution A, dropwise adding the mixed solution A into a dilute hydrochloric acid solution under the stirring condition, continuously stirring until spherical crystals are completely formed after the dropwise adding is finished, filtering, washing, vacuum drying and sieving to obtain the indomethacin slow-release microspheres. Preferably, the specific preparation method of the indomethacin sustained-release microsphere comprises the following steps: Adding indomethacin, an acrylic resin compound and a first antioxidant into an acetone-absolute ethyl alcohol solvent according to the mass volume ratio, stirring and dissolving for 30-40min at 500-700rpm to obtain a mixed solution A, dripping the mixed solution A into a dilute hydrochloric acid solution with the concentration of 0.1-0.2mol/L under the stirring condition of 500-700rpm, controlling the dripping time period to be 4-6h, continuously stirring for 50-70min at 500-700rpm until spherical crystals are formed after dripping is completed, filtering and collecting the spherical crystals, washing the spherical crystals with deionized water for 2-4 times, drying the washed spherical crystals in a 35-45 ℃ vacuum drying oven for 12-16h, and sieving the dried spherical crystals with a 60-100 mesh sieve to obtain the indomethacin slow-release microspheres. Preferably, the acrylic resin compound consists of Eudragit RS100 and Eudragit RL1