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CN-122005522-A - Eutectic mixture of colchicine and lidocaine, and preparation method and application thereof

CN122005522ACN 122005522 ACN122005522 ACN 122005522ACN-122005522-A

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly discloses a colchicine and lidocaine eutectic mixture, a preparation method and application thereof, and in order to solve the problems that the colchicine has poor transdermal effect, has large oral gastrointestinal side effect and is insufficient for timely meeting the requirements of acute gout on anti-inflammatory and analgesic, and the like, the colchicine and the lidocaine are prepared into the eutectic mixture by solvent auxiliary grinding according to the molar ratio of 0.1:0.9-0.9:0.1, and the melting point of the eutectic mixture is 46.1-64.7 ℃, and the eutectic mixture is also prepared into an external pharmaceutical composition. The compound has obviously improved solubility and transdermal effect, can realize the high-efficiency delivery of colchicine and lidocaine to the part of the diseased joint, fully exerts the complementary synergistic effect of the two medicines on anti-inflammatory and analgesic mechanisms, simultaneously avoids the toxic and side effects of the oral administration of the gastrointestinal tract, has good safety and good skin tolerance, and is suitable for treating acute gout arthritis.

Inventors

  • ZHANG JIAN
  • XU XIAQIAN
  • ZHU ANQI
  • Lin Yanna
  • Fan Linpan
  • WANG YIJING
  • HAO CHAO

Assignees

  • 江苏海洋大学

Dates

Publication Date
20260512
Application Date
20260325

Claims (10)

  1. 1. The eutectic mixture of colchicine and lidocaine is characterized in that the molar ratio of colchicine to lidocaine is 0.1:0.9-0.9:0.1.
  2. 2. The eutectic mixture of colchicine and lidocaine according to claim 1, wherein the molar ratio of colchicine to lidocaine is 0.4:0.6 to 0.5:0.5.
  3. 3. The eutectic mixture of colchicine and lidocaine according to claim 2, characterized in that the molar ratio of colchicine and lidocaine is 0.4:0.6.
  4. 4. The eutectic mixture of colchicine and lidocaine according to claim 1, wherein the eutectic mixture melts at 46.1-64.7 ℃.
  5. 5. A method for preparing a eutectic mixture of colchicine and lidocaine according to any one of claims 1 to 4, wherein a solvent-assisted grinding method is used, comprising the specific steps of grinding colchicine and lidocaine with the aid of a solvent, and then drying to obtain the eutectic mixture.
  6. 6. The preparation method according to claim 5, wherein the solvent is one or more of methanol, ethanol, propylene glycol, isopropanol, diethylene glycol monoethyl ether, acetonitrile and ethyl acetate.
  7. 7. The method according to claim 6, wherein the solid-to-liquid ratio of the sum of the mass of colchicine and lidocaine to the solvent in the solvent-assisted milling method is (1-3) g/1 mL.
  8. 8. A pharmaceutical composition, which is characterized by comprising the eutectic mixture of colchicine and lidocaine according to any one of claims 1-4 and pharmaceutically acceptable excipients, wherein the dosage form of the pharmaceutical composition is cream, patch, emulsion or gel.
  9. 9. Use of a eutectic mixture of colchicine and lidocaine according to any one of claims 1-4 for the preparation of a medicament for the treatment or alleviation of pain in acute gout arthritis.
  10. 10. Use of a pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment or alleviation of pain in acute gout arthritis.

Description

Eutectic mixture of colchicine and lidocaine, and preparation method and application thereof Technical Field The invention relates to the technical field of pharmaceutical preparations, in particular to a colchicine and lidocaine eutectic mixture, and a preparation method and application thereof. Background Gout is an inflammatory arthritis caused by deposition of sodium urate crystals on joints, and the global prevalence rate of the arthritis is remarkably increased in recent years, and the arthritis has become one of common metabolic diseases. During acute onset of gout, the joints of patients have severe pain, redness and swelling and dysfunction, which seriously affect the quality of life. Colchicine is used as a first-line medicine for treating acute gout, and can effectively control inflammatory response by inhibiting NLRP3 inflammatory body activation and neutrophil chemotaxis, however, the oral administration of colchicine has serious gastrointestinal toxicity and systemic side effects such as diarrhea, nausea and vomiting, the therapeutic index is narrow, the clinical application is greatly limited, and long-term oral administration of colchicine can also cause liver and kidney function injury. Furthermore, oral administration is affected by first pass effects, systemic drug exposure is unavoidable, further increasing the risk of systemic toxic side effects. Therefore, it is of great clinical importance to explore alternative routes of administration that can bypass the systemic circulation, delivering colchicine directly to the local part of the inflammatory joint. Transdermal administration is particularly interesting for drugs with narrow therapeutic indices and low recommended doses, because it bypasses first pass metabolism, reduces systemic exposure, avoids gastrointestinal irritation, and allows sustained and stable delivery of the drug at the site of action. However, the strong barrier function of the skin, particularly the stratum corneum, constitutes a primary barrier to transdermal delivery. The stratum corneum is composed of highly crosslinked keratin cells and ordered lipid bilayers, allowing only a few drug molecules with desirable physicochemical properties (usually required to have a molecular weight <500 Da, proper water and lipid solubility, lower melting point, etc.) to penetrate in a passive diffusion manner. Colchicine has high solubility and insufficient fat solubility, is difficult to effectively distribute into the lipid environment of the stratum corneum, has poor skin permeability, and is a core physicochemical obstacle which restricts the transdermal development of colchicine. In addition, the melting point is relatively high, the lattice stability is high, and the dissolution and diffusion of the medicine in the skin are further limited. In order to overcome the obstacle, researchers have explored various technical means such as chemical permeation promoters, nano drug carrying systems, microneedle arrays and the like, but the methods have limitations such as skin irritation risks of the chemical permeation promoters, complex nano carrier preparation processes and the like. Therefore, developing a strategy that can fundamentally change the solid physicochemical properties of the drug to break through the skin barrier becomes a research hotspot in the field. Eutectic mixtures (Eutectic Mixtures, EM) refer to multicomponent systems formed by intermolecular non-covalent interactions such as hydrogen bonding, van der waals forces, etc. after mixing two or more solid components in a specific molar ratio, which have a lower melting point than either of the pure components. The core driving force of the eutectic mixture for promoting transdermal penetration is the improvement of thermodynamic activity, and according to the ideal solution theory, the ideal solubility of the drug in skin lipid is exponentially and inversely related to the melting point, and the ideal solubility of the drug is obviously increased due to the reduction of the melting point, so that the transdermal flux is improved. In addition, the formation of the eutectic mixture can saturate the hydrogen bond donor and acceptor sites among the components, reduce the active sites for competitive combination of drug molecules and the endogenous lipid of the stratum corneum, and simultaneously enhance the compatibility of the system and the lipid of the stratum corneum, so as to further promote the percutaneous permeation of the drug. The permeation promoting mechanism has solubility driving of a thermodynamic level and barrier intervention of a physical level, can be realized without introducing an exogenous chemical permeation promoting agent, and has higher safety and controllability. The clinical characteristics of acute gouty arthritis are that inflammation and pain coexist, and the pain often reaches a peak value before an inflammatory drug takes effect, and the immediate pain relieving urgent requirement of a