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CN-122005509-A - High-efficiency absorption ergothioneine orosol film and preparation method thereof

CN122005509ACN 122005509 ACN122005509 ACN 122005509ACN-122005509-A

Abstract

The invention discloses an ergothioneine oral solution film with high-efficiency absorption and a preparation method thereof. The method comprises the steps of preparing a first layer of coating liquid from ergothioneine, substrate components, a copper ion chelating agent and a water-soluble polymer, preparing a second layer of coating liquid from a high molecular matrix, a tackifier and a temperature-sensitive adhesion polymer, and sequentially coating and drying to form a quick-release layer and an adhesion slow-release layer to prepare the double-layer oral-dissolving film. The temperature-sensitive polymer adopts LCST (LCST controlled copolymer), the lowest critical dissolution temperature is 35-39 ℃, the gel layer can be formed by phase change at the oral temperature, and the tackifier adopts sulfhydryl chitosan, quaternized chitosan or dopamine modified polymer, and can form covalent or electrostatic adhesion with mucous membrane. The present invention may also incorporate a soluble microneedle array to enhance mucosal penetration. The invention realizes the synergy of the quick release and the long-acting adhesion of the ergothioneine, effectively prolongs the retention time of the oral cavity and improves the absorption efficiency through the mucous membrane.

Inventors

  • SHANG LEI
  • WU WANGPING
  • CAI DONGLIN
  • CHEN XIANPING
  • FAN HAIFENG

Assignees

  • 上海欣峰健康科技有限公司

Dates

Publication Date
20260512
Application Date
20260330

Claims (10)

  1. 1. The preparation method of the high-efficiency absorption ergothioneine orosol film is characterized by comprising the following steps of: s1, adding ergothioneine, a substrate component, a copper ion chelating agent and a water-soluble polymer into deionized water, and stirring at 50-80 ℃ for 1-3 hours until the ergothioneine, the substrate component, the copper ion chelating agent and the water-soluble polymer are completely dissolved, so as to prepare a first layer of coating liquid; S2, adding the high molecular matrix, the tackifier and the temperature-sensitive adhesive polymer into deionized water, and stirring for 1-4 hours at 50-80 ℃ until the mixture is completely dissolved, so as to prepare a second layer of coating liquid; s3, uniformly coating the first layer coating liquid on a substrate with a coating thickness of 200-400 mu m, and drying for 6-12 hours at 40-55 ℃ to form a quick-release layer containing ergothioneine; S4, uniformly coating the second layer coating liquid on the quick release layer with the coating thickness of 150-350 mu m, drying for 6-12 hours at the temperature of 40-55 ℃ to form an adhesion slow release layer, and then cutting and subpackaging to obtain the ergothioneine orosol film.
  2. 2. The method for preparing the ergothioneine oral film according to claim 1, wherein the first layer of coating liquid in S1 is prepared by mixing 20-40 parts by mass of polyvinyl alcohol, 10-25 parts by mass of hydroxypropyl methyl cellulose, 3-15 parts by mass of ergothioneine, 0.5-5 parts by mass of substrate component, 0.1-1 part by mass of copper ion chelating agent and 8-15 parts by mass of glycerol, and preparing the coating liquid with 15-20% of solid content by deionized water.
  3. 3. The preparation method of the ergothioneine orosol film according to claim 1, wherein the second layer coating liquid in the S2 is prepared from 15-30 parts by mass of polyvinyl alcohol, 10-20 parts by mass of hydroxypropyl methyl cellulose, 2-10 parts by mass of tackifier, 0.5-5 parts by mass of temperature-sensitive adhesive polymer and 6-12 parts by mass of glycerol, and is prepared into a coating liquid with the solid content of 12-16% by deionized water, wherein the tackifier is one or more selected from thiolated trimethyl chitosan, N-trimethyl chitosan, hydroxypropyl trimethyl ammonium chloride chitosan, thiolated chitosan, dopamine-modified polyvinyl alcohol and dopamine-modified hyaluronic acid.
  4. 4. The method for preparing an ergothioneine orosol film according to claim 1, wherein the substrate component is one or more of L-carnitine, acetyl-L-carnitine, and carnitine hydrochloride.
  5. 5. The method for preparing the ergothioneine oral film according to claim 1, wherein the copper ion chelating agent is selected from one or more of disodium ethylenediamine tetraacetate, citric acid, sodium citrate and phytic acid.
  6. 6. The method for preparing the ergothioneine orosol film according to claim 1, wherein the thermosensitive adhesive polymer is one or more of thermosensitive polymers or mucoadhesive polysaccharides, and the thermosensitive polymers are one or more selected from poly (N-isopropylacrylamide-co-acrylic acid) copolymer, poly (N-isopropylacrylamide-co-acrylamide) copolymer and poly (N-vinylcaprolactam-co-vinylimidazole) copolymer, and the lowest critical dissolution temperature is 35-39 ℃.
  7. 7. The method for preparing an ergothioneine orosol film according to claim 6, wherein the mucoadhesive polysaccharide is one or more selected from hyaluronic acid, chondroitin sulfate and sodium alginate.
  8. 8. The method for preparing an ergothioneine orosol film according to claim 1, wherein the stirring speeds of the first layer coating liquid and the second layer coating liquid are each 500-1000rpm.
  9. 9. The method for preparing the ergothioneine orosol film according to claim 1, further comprising the step of S5, dissolving and mixing one or more of polyvinylpyrrolidone, hyaluronic acid and sodium carboxymethyl cellulose with ergothioneine, injecting the mixture into a microneedle mould, drying and molding the mixture at 25-40 ℃ and demolding the mixture to obtain a soluble microneedle array, attaching and fixing the microneedle array on the back surface of the ergothioneine orosol film obtained in the step S4, wherein the height of the microneedle is 100-500 mu m.
  10. 10. An efficient absorption ergothioneine orosity film prepared by the method of any one of claims 1 to 9, which is characterized in that the thickness of a quick release layer of the ergothioneine orosity film is 30 to 60 μm, the thickness of an adhesion slow release layer is 20 to 50 μm, the total thickness is 50 to 110 μm, and the moisture content is 2 to 5%.

Description

High-efficiency absorption ergothioneine orosol film and preparation method thereof Technical Field The invention belongs to the technical field of biomedicine, and particularly relates to an ergothioneine oral solution film capable of being efficiently absorbed and a preparation method thereof. Background Ergothioneine (L-Ergothioneine) is a naturally occurring sulfur-containing amino acid derivative, widely distributed in fungi such as mushrooms and certain bacteria, and has excellent antioxidant, anti-inflammatory and cytoprotective activities. Since human body cannot synthesize ergothioneine by itself and must be ingested through diet or supplements, development of a highly efficient ergothioneine delivery formulation has important application value. Ergothioneine has high hydrophilicity, good solubility in water and good chemical stability. However, cell uptake of ergothioneine is primarily dependent on the active transport process mediated by the organic cation transporter OCTN1 (SLC 22A 4), which itself is difficult to penetrate biological membranes by passive diffusion. The research shows that the OCTN1 transporter has the characteristic of saturation kinetics, the absorption efficiency is correspondingly reduced when the administration dosage is increased, and simultaneously, the SLC22A4 gene has a plurality of single nucleotide polymorphism sites, so that the absorption capacity of ergothioneine among different individuals is obviously different. The ergothioneine preparation sold in the market at present is mainly capsules and tablets, the traditional oral dosage form needs to be absorbed by the gastrointestinal tract and then enters the portal circulation, and the oral bioavailability is limited to a certain extent. The oral film as a novel oral administration type has the advantages of no need of swallowing with water, convenient administration, quick effect and the like, and is especially suitable for the old, children and special patient groups with dysphagia. The oral dissolving film can be rapidly disintegrated and dissolved after being placed in the oral cavity, and part of the medicine can be directly absorbed into the systemic circulation through the oral mucosa, so that the first pass effect of the liver is avoided, and the bioavailability of the medicine is hopefully improved. The oral mucosa has rich blood vessels, higher permeability, relatively lower activity of the mucosa surface enzyme, mild pH environment and ideal administration position. However, existing orolytic techniques still suffer from several drawbacks when applied to ergothioneine delivery. Firstly, the traditional orosol film mostly adopts a single-layer structure design, so that the rapid disintegration is the main goal, the detention time in the oral cavity is short, the contact time between the medicine and the oral mucosa is limited, and the full transmucosal absorption is difficult to realize. Secondly, although film forming materials such as polyvinyl alcohol, hydroxypropyl methyl cellulose and the like used for the conventional oral dissolving film have good film forming property and high dissolving speed, the mucous membrane has limited adhesive capability, and the film forming materials are easy to fall off and shift under the influence of oral saliva secretion and swallowing movement, so that the effective administration time is further shortened. In addition, the single-layer oral dissolving film is difficult to simultaneously meet the requirement of the synergistic function of quick release and slow release, the directional release of the medicine to the mucous membrane side cannot be realized, part of the medicine can be diluted by saliva or enter the gastrointestinal tract along with swallowing after being released to the oral cavity side, and the absorption efficiency through the mucous membrane is reduced. Aiming at the problem of insufficient adhesion of orolytic membranes, researchers try to introduce chitosan and derivatives thereof, carbomers and other mucoadhesive polymers to prolong the residence time of the preparation in the oral cavity. Temperature-sensitive polymers, which are capable of undergoing sol-gel phase transition in response to temperature changes, are also used in the study of oral drug delivery systems to facilitate in situ formation of a gel layer upon contact with oral temperature, enhancing adhesion to the mucosa. However, the minimum critical solution temperature (LCST) of the existing thermosensitive polymer such as poly-N-isopropyl acrylamide is usually about 32 ℃ and lower than the normal oral temperature, so that the expected thermosensitive response function is difficult to be exerted in practical application. In addition, the thioketone group in the ergothioneine molecule can carry out coordination reaction with metal ions such as copper ions, and oxidative degradation can be caused during storage, so that proper stabilizer needs to be added in the formulation to ensure