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CN-121987805-A - Melatonin receptor agonist complex, transdermal drug delivery system, and preparation method and application thereof

CN121987805ACN 121987805 ACN121987805 ACN 121987805ACN-121987805-A

Abstract

A melatonin receptor agonist compound, a percutaneous administration system, a preparation method and application thereof, wherein the compound comprises a high molecular pressure-sensitive adhesive, a melatonin receptor agonist, a transdermal enhancer and polyvinylpyrrolidone, wherein the melatonin receptor agonist, the transdermal enhancer and the polyvinylpyrrolidone are dispersed and mixed in the high molecular pressure-sensitive adhesive, the polyvinylpyrrolidone exists in the high molecular pressure-sensitive adhesive in a dendritic nano-skeleton structure form, and the melatonin receptor agonist and the transdermal enhancer are adsorbed around the dendritic nano-skeleton structure of the polyvinylpyrrolidone. Compared with the prior art, the invention utilizes the dendritic nano structure to absorb the permeation enhancer and the active molecules in the colloid to improve the carrying capacity, and simultaneously utilizes the good water absorbability of the nano structure to preferentially absorb water when in use, changes the local structure, opens the release passage, ensures that the permeation enhancer and the active molecules are preferentially released, and improves the conveying efficiency.

Inventors

  • YUE YANG
  • MA DANDAN
  • XU BIXIONG

Assignees

  • 鑫稳生物医药科技(嘉善)有限公司

Dates

Publication Date
20260508
Application Date
20241101

Claims (10)

  1. 1. A melatonin receptor agonist complex, characterized in that the complex comprises a dendritic nano-skeleton structure formed by polyvinylpyrrolidone, and a melatonin receptor agonist and a permeation enhancer as active components are adsorbed around the dendritic nano-skeleton structure.
  2. 2. The melatonin receptor agonist complex of claim 1, wherein the polyvinylpyrrolidone, together with its adsorbed melatonin receptor agonist and permeation enhancer, is co-dispersed in a polymeric pressure sensitive adhesive.
  3. 3. The melatonin receptor agonist complex of claim 1, wherein the diameter of the branches of the dendritic nanoshell structure is 100-1000 nm.
  4. 4. A melatonin receptor agonist complex according to claim 1, wherein the polyvinylpyrrolidone is cross-linked and/or non-cross-linked polyvinylpyrrolidone; And/or, the weight percentage of the polyvinylpyrrolidone in the compound is 5-30%, preferably 5-20%, and most preferably 7-15%.
  5. 5. The melatonin receptor agonist complex according to any one of claims 1 to 4, wherein the melatonin receptor agonist as an active ingredient comprises one or more of melatonin, agomelatine, ramelteon, tasimelteon, and corresponding derivative compounds thereof; And/or the weight percentage of the melatonin receptor agonist in the compound is 1-15%, preferably 2-12%, and most preferably 2-10%.
  6. 6. The melatonin receptor agonist complex of claim 5, wherein the permeation enhancer in the complex is a medium-long chain fatty acid composition; The medium-long chain fatty acid composition comprises fatty acid with 8-22 carbons and corresponding acyl amino acid; And/or the fatty acid comprises one or more of myristic acid, oleic acid and lauric acid; And/or the weight percentage of the fatty acid in the compound is 1-8%, preferably 2-4%; and/or the acyl amino acid comprises one or more of lauroyl sarcosine, lauroyl glutamic acid, myristoyl sarcosine and oleoyl sarcosine, and/or the weight percentage of the acyl amino acid in the compound is 1-8%, preferably 2-4%.
  7. 7. The method for preparing a melatonin receptor agonist complex according to any one of claims 1-6, comprising the steps of: (1) Using a solvent to dissolve or disperse polyvinylpyrrolidone to obtain a polyvinylpyrrolidone solution; (2) Adding a polyvinylpyrrolidone solution and a high polymer pressure-sensitive adhesive into a cosolvent capable of dissolving the high polymer pressure-sensitive adhesive, stirring and uniformly dispersing, adding the other components, and stirring uniformly to form a colloid stock solution; (3) Coating a colloid stock solution, and drying a solvent through gradient heating at 50-90 ℃ to enable polyvinylpyrrolidone to form a dendritic nano structure in a high polymer pressure sensitive adhesive; The solvent in the step (1) is an alcohol solvent comprising one or more of methanol, ethanol and isopropanol; And/or, the co-solvent of step (2) comprises one or more of ethyl acetate, heptane, hexane; And/or, in the step (3), drying is carried out for 5-10 min at 55-65 ℃, 70-80 ℃ and 80-90 ℃ respectively.
  8. 8. The use of a melatonin receptor agonist complex according to any one of claims 1 to 6, wherein the complex is used as an active pharmaceutical ingredient for the preparation of a transdermal formulation or patch.
  9. 9. The transdermal drug delivery system containing the dendritic nanometer structure sequentially comprises a back lining layer, one or more layers of drug-containing substrate layers and a release film from top to bottom, and is characterized in that the drug-containing substrate layers comprise the compound according to any one of claims 1-6.
  10. 10. Use of a transdermal delivery system comprising dendritic nanostructures according to claim 9, as a patch for transdermal delivery, wherein the transdermal delivery system is applied to the skin surface after removal of the release film.

Description

Melatonin receptor agonist complex, transdermal drug delivery system, and preparation method and application thereof Technical Field The invention relates to the field of medicines, in particular to a melatonin receptor agonist compound, a transdermal drug delivery system, a preparation method and application thereof. Background Currently oral melatonin receptor agonist drugs, mainly melatonin (melatonin), agomelatine (agomelatine), ramelteon (ramelteon), tasimelteon (tasimelteon), and the like. The general problems of oral melatonin receptor agonists include (1) the prevalence of relatively severe liver first pass effects, increasing liver burden, and causing liver damage. Such as agomelatine, presents serious liver damage problems, where the FDA is alerted to the presence of a black frame of liver damage, requiring periodic checks for liver function prior to and during administration. (2) absolute bioavailability is low. For example, agomelatine is about 3% and ramelteon is about 1.8%. Lower bioavailability results in a much larger dose to be administered than the actual effective dose. (3) short half-life, resulting in discontinuous drug effect. If the half-life of melatonin plasma is 15-20 min, agomelatine is about 90min, and tasimelteon is about 80 min. The shorter half-life results in discontinuous oral efficacy, short time to peak blood levels, and then rapid fallback. (4) the individual differences are large. Such as agomelatine, the extremely low bioavailability results in larger deviation of bioavailability among different individuals, and larger individual difference exists between the peak serum concentration (Cmax) and the area under the curve (AUC) when the drug is taken, thereby affecting the curative effect and side effect of the drug. (5) drug interaction concerns. Such as agomelatine, a strong first pass effect and co-liver enzyme metabolism, oral agomelatine is difficult to combine with other antidepressant mainstream drugs. For another example, ramelteon, AUC increases by 31% when taken in combination with high-fat foods. The transdermal administration preparation can obviously improve the defects of the traditional oral administration, firstly, the first-time effect of liver is not needed, the liver toxicity is reduced, secondly, the preparation can be stably administered for a long time, the blood concentration is very stable, the administration rate is not influenced by external factors such as diet and the like, finally, the bioavailability is high, the bioavailability can be generally improved to 50%, and the bioavailability is greatly improved compared with the oral administration. Although the transdermal drug delivery system has great advantages over oral drug delivery, the existing transdermal drug delivery system still has the problems of insufficient drug loading and low permeation efficiency, the currently marketed agomelatine tablet has the specification of 25 mg/tablet, and the conventional drug loading dosage of the transdermal drug delivery system is below 10 mg. Taking melatonin as an example, the melatonin with a conventional dosage (5-10 mg) can be added into blood for more than 0.5mg within 1 hour, and the peak value of the plasma concentration can reach 200pg/ml, if a percutaneous administration preparation is adopted, the blood adding rate is required to be maintained to be more than 100 mug/h within 8 hours. For transdermal drug delivery systems, the conventional method of increasing drug loading and permeation efficiency is to increase the patch area, but the increased patch area will first reduce the compliance of the user, and also increase the probability of side reactions, which will increase the production cost by a multiple. Therefore, further research is still needed to solve the problems of insufficient drug loading and low permeation efficiency of the transdermal drug delivery system. Disclosure of Invention The present invention has been made to solve the above problems, and an object of the present invention is to provide a transdermal drug delivery system comprising a nano-dendritic structure. The aim of the invention is achieved by the following technical scheme: in a first aspect, the present invention provides a melatonin receptor agonist complex. The complex contains a dendritic nano-skeleton structure formed by polyvinylpyrrolidone, and melatonin receptor agonist and transdermal enhancer serving as active components are adsorbed around the dendritic nano-skeleton structure. Further, the polyvinylpyrrolidone, together with the melatonin receptor agonist and the transdermal enhancer adsorbed by the polyvinylpyrrolidone, is dispersed in a high molecular pressure sensitive adhesive. The dendritic nano-skeleton structure (also called dendritic structure) in the invention can be defined as a multi-stage branch form similar to a branch from the morphological point of view, a central core starts to grow out first-stage branches, the first-stage branches f