CN118121502A - Ergothioneine composition embedding delivery preparation, preparation method and application thereof - Google Patents

Ergothioneine composition embedding delivery preparation, preparation method and application thereof Download PDF

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Publication number
CN118121502A
CN118121502A CN202410110161.XA CN202410110161A CN118121502A CN 118121502 A CN118121502 A CN 118121502A CN 202410110161 A CN202410110161 A CN 202410110161A CN 118121502 A CN118121502 A CN 118121502A
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ergothioneine
entrapping
active ingredient
composition
preparation
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Inventor
王大力
朱新远
冯标
李群凤
杨姗
鲍杰
周林珠
童刚生
周伟正
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Hefei Hechen Biotechnology Co ltd
Shanghai Jiaotong University
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Hefei Hechen Biotechnology Co ltd
Shanghai Jiaotong University
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Abstract

The invention discloses an ergothioneine composition embedding and delivering preparation, a preparation method and application thereof, wherein the ergothioneine composition embedding and delivering preparation comprises embedding carrier particles and active components loaded on the embedding carrier particles; wherein the particle size of the embedding carrier particles ranges from 10nm to 1mm; the embedded carrier particles are liposomes; the active component comprises a hydrophilic active ingredient and a hydrophobic active ingredient; the hydrophilic active ingredient is ergothioneine. The ergothioneine composition embedding and delivering preparation has the advantages of low transdermal absorption rate, low bioavailability, poor light stability and other pain points of ergothioneine, simultaneously, synchronous steady embedding and delivering of hydrophilic ergothioneine and hydrophobic functional active ingredients, and improving the formula compatibility and stability of the hydrophobic functional active ingredients.

Description

Ergothioneine composition embedding delivery preparation, preparation method and application thereof
Technical Field
The invention relates to the technical field of biochemistry, in particular to an ergothioneine composition embedding delivery preparation, a preparation method and application thereof.
Background
The functional active raw materials are widely applied to industries such as cosmetics, health foods, biological medicines and the like, but many active raw materials have the problems of instability, peculiar smell, poor compatibility, low bioavailability and the like, so that the application of the functional active raw materials in cosmetics and foods is severely restricted.
Functional active materials can be broadly divided into hydrophilic and hydrophobic active materials, which generally require different entrapment techniques to achieve steady state delivery. Therefore, the cost is increased in the development of the front-end embedding technology, and the complexity of the design and development of the product formula is increased in the application process.
Ergothioneine is a natural antioxidant, is safe and nontoxic, can protect cells in human body, and is an important active substance in the body. It has the functions of scavenging free radical, detoxication, maintaining DNA biosynthesis, normal cell growth, cell immunity, etc. and may be used widely in cosmetics and skin care products. However, ergothioneine is used as a water-soluble small molecule, has strong water solubility, is difficult to directly penetrate through the stratum corneum into the skin, and has very limited percutaneous efficiency; meanwhile, the ergothioneine is easily influenced by the external environment to oxidize, so that the anti-aging effect of the ergothioneine is reduced; in addition, ergothioneine can emit unpleasant peculiar smell, and the application of the ergothioneine is restricted. Therefore, how to improve the transdermal absorption, stability and peculiar smell of ergothioneine is one of the problems of application pain to be solved urgently.
Therefore, it is necessary to develop an advanced ergothioneine composition embedding delivery preparation, solve the above pain point problem in the application process of ergothioneine, and develop an integrated ergothioneine and hydrophobic active compound efficacy combination embedding delivery preparation, enhance efficacy synergy, reduce the pain point of product formulation compatibility, and promote the product innovation and upgrading of the ergothioneine in cosmetics and health foods.
Disclosure of Invention
The invention aims to solve the problems of poor light stability, low transdermal absorption rate, peculiar smell, low bioavailability and the like of ergothioneine, thereby providing an ergothioneine composition embedding and delivering preparation, a preparation method and application thereof.
In order to achieve the above object, the present invention provides an ergothioneine composition entrapping delivery preparation containing a hydrophobic active ingredient having entrapping carrier particles supported on the entrapping carrier particles and a hydrophilic active ingredient entrapped in vesicles of the entrapping carrier particles; wherein,
The embedded carrier particles are liposomes;
the hydrophilic active ingredient is ergothioneine.
The invention also provides a preparation method of the ergothioneine composition embedding delivery preparation, which comprises the following steps:
Providing an organic phase solution containing entrapping vector particles and a hydrophobic active ingredient, wherein the entrapping vector particles are liposomes;
providing an aqueous solution containing a hydrophilic active ingredient, wherein the hydrophilic active ingredient is ergothioneine;
and (3) dripping the organic phase solution containing the embedded carrier particles and the hydrophobic active ingredient into the aqueous phase solution containing the hydrophilic active ingredient under the condition of 25-65 ℃ while stirring, and reacting for 10-120min.
The invention further provides an ergothioneine composition embedding delivery preparation prepared by the preparation method.
The invention further provides application of the ergothioneine composition embedding delivery preparation in cosmetics, health foods, health products, medical instruments and medical products.
In the technical scheme, the ergothioneine composition embedding and delivering preparation provided by the invention has the advantages that hydrophilic ergothioneine is embedded in the inner part and the inner water phase of vesicles of phospholipid bilayer of the liposome by constructing an embedding structure, the hydrophobic active ingredient is loaded between the phospholipid bilayer of the liposome, and the embedding carrier particles are utilized for synchronously and stably embedding and delivering the ergothioneine and the hydrophobic active ingredient.
The invention not only effectively solves the problems of bad smell, poor light stability and other pain points of the ergothioneine, improves the transdermal absorptivity and bioavailability of the ergothioneine, but also overcomes the defects of poor formula compatibility and poor stability of hydrophobic active ingredients.
Meanwhile, the preparation method of the ergothioneine composition embedding and delivering preparation is simple and easy to operate, can be used for mass production, and provides more possibility for design development and innovation and upgrading of functional cosmetics and functional health foods.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
The accompanying drawings are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate the invention and together with the description serve to explain, without limitation, the invention. In the drawings:
FIG. 1 is a schematic representation of an entrapment delivery technique for an entrapment delivery formulation of an ergothioneine composition of the present invention;
Fig. 2 is a scanning electron micrograph of the ergothioneine composition entrapping delivery formulation prepared in examples 1, 4 and 7.
Detailed Description
The following describes specific embodiments of the present invention in detail. It should be understood that the detailed description and specific examples, while indicating and illustrating the invention, are not intended to limit the invention.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
The invention provides an ergothioneine composition embedding and delivering preparation, which comprises embedding carrier particles, hydrophobic active ingredients loaded on the embedding carrier particles and hydrophilic active ingredients embedded in embedding carrier particle vesicles; wherein,
The embedded carrier particles are liposomes;
the hydrophilic active ingredient is ergothioneine.
According to the ergothioneine composition embedding and delivering preparation, hydrophilic ergothioneine is embedded in vesicles of a liposome and in an internal water phase, hydrophobic active ingredients are loaded between phospholipid bilayer of the liposome, and the ergothioneine and the hydrophobic active ingredients are synchronously and stably embedded and delivered by using embedding carrier particles, so that the pain point problems of peculiar smell, poor light stability and the like of the ergothioneine are effectively solved, the transdermal absorption rate and bioavailability of the ergothioneine are improved, and the defects of poor formula compatibility and poor stability of the hydrophobic active ingredients are overcome.
According to a preferred embodiment of the present invention, in order to facilitate the use of the entrapping particles in cosmetics, foods and biological medicine, the entrapping delivery formulation of the ergothioneine composition has a better dispersity, and the entrapping carrier particles have a particle size in the range of 10nm to 1mm, preferably 50nm to 500. Mu.m, more preferably 100nm to 100. Mu.m, still more preferably 200nm to 10. Mu.m.
According to a preferred embodiment of the present invention, the liposome is selected from one or more of hydrogenated soybean lecithin, soybean phospholipid PC90, soybean phospholipid PC70, soybean phospholipid PC50, soybean lecithin, egg yolk lecithin, cholesterol and PEGylated phospholipid in order to allow simultaneous entrapping delivery of hydrophilic ergothioneine and hydrophobic active ingredient.
According to the preferred embodiment of the invention, the hydrophobic active ingredient mainly refers to oil-soluble or lipophilic functional active raw materials applied to products such as cosmetics, foods and health care products, and the hydrophobic active ingredient is one or more selected from phloretin, ceramide, vitamin E, vitamin A alcohol, astaxanthin, curcumin, docosahexaenoic acid, lutein, carotene and glabridin.
According to a preferred embodiment of the present invention, the stability of the ergothioneine composition entrapping delivery formulation may also be improved by adding an enhancer, and thus, in order to improve the stability of the ergothioneine composition entrapping delivery formulation, the ergothioneine composition entrapping delivery formulation further contains an enhancer.
According to a preferred embodiment of the present invention, the strengthening agent is a polymeric strengthening agent and/or an inorganic particle strengthening agent. The polymer reinforcer is added into the ergothioneine aqueous phase solution, the polymer and the ergothioneine have weak interaction, the viscosity of the aqueous phase is improved, the stability of the embedded particles is improved, the inorganic particle reinforcer is generally added into the ergothioneine aqueous phase solution, the inorganic particle reinforcer and the ergothioneine have weak interaction, and the embedding efficiency and the stability of the active substances are improved.
According to a preferred embodiment of the present invention, the polymer enhancer is one or more selected from the group consisting of chitosan, chitin, cellulose, protein, nucleic acid and starch.
According to a preferred embodiment of the present invention, the inorganic particle reinforcer is one or two or more selected from the group consisting of silica, titania, calcium carbonate, calcium silicate and calcium phosphate.
According to a preferred embodiment of the present invention, the particle size of the inorganic particle reinforcer is 5nm to 100. Mu.m, preferably 10nm to 50. Mu.m, more preferably 10nm to 10. Mu.m.
According to the preferred embodiment of the invention, in order to better improve the transdermal absorption rate and bioavailability of the ergothioneine and ensure that the hydrophobic active ingredient has better compatibility, the mass ratio of the liposome to the ergothioneine to the hydrophobic active ingredient is 1:0.001-2:0.001-1, preferably 1:0.01-1:0.01-0.2, more preferably 1:0.02-0.2:0.02-0.1.
The invention also provides a preparation method of the ergothioneine composition embedding delivery preparation, which comprises the following steps:
Providing an organic phase solution containing entrapping vector particles and a hydrophobic active ingredient, wherein the entrapping vector particles are liposomes;
providing an aqueous solution containing a hydrophilic active ingredient, wherein the hydrophilic active ingredient is ergothioneine;
and (3) dripping the organic phase solution containing the embedded carrier particles and the hydrophobic active ingredient into the aqueous phase solution containing the hydrophilic active ingredient under the condition of 25-65 ℃ while stirring, and reacting for 10-120min.
The preparation method provided by the invention is simple and easy to operate, and can be used for mass production.
According to a preferred embodiment of the present invention, the method of providing an organic phase solution comprising entrapped carrier particles and hydrophobic active ingredient is to dissolve liposomes and hydrophobic active in an organic solvent to obtain an organic phase solution.
According to a preferred embodiment of the present invention, the method of providing an aqueous solution comprising a hydrophilic active ingredient is to dissolve ergothioneine in water to obtain an aqueous solution of ergothioneine.
According to a preferred embodiment of the present invention, in order to facilitate the product application of cosmetics and health foods, and at the same time, to provide better dispersibility and compatibility of the prepared ergothioneine composition entrapping delivery preparation, the entrapping support particles have a particle size in the range of 10nm to 1mm, preferably 50nm to 500. Mu.m, more preferably 100nm to 100. Mu.m, still more preferably 200nm to 10. Mu.m.
According to a preferred embodiment of the present invention, the liposome is selected from one or more of hydrogenated soybean lecithin, soybean phospholipid PC90, soybean phospholipid PC70, soybean phospholipid PC50, soybean lecithin, egg yolk lecithin, cholesterol and PEGylated phospholipid in order to provide better entrapment conditions for ergothioneine and hydrophobic active ingredient.
According to the preferred embodiment of the invention, the hydrophobic active ingredient mainly refers to oil-soluble or lipophilic functional active raw materials applied to products such as cosmetics, foods and health care products, and the hydrophobic active ingredient is one or more selected from phloretin, ceramide, vitamin E, vitamin A alcohol, astaxanthin, curcumin, docosahexaenoic acid, lutein, carotene and glabridin.
According to a preferred embodiment of the present invention, the organic solvent is selected from one or more of ethanol, acetone and tetrahydrofuran in order that the hydrophobic active ingredient may be better supported between phospholipid bilayer embedding carrier particles.
According to a preferred embodiment of the present invention, in order to provide better entrapment and compatibility of the hydrophobic active ingredient, the mass ratio of the liposome to the hydrophobic active is 1:0.001-1, preferably 1:0.01 to 0.2, more preferably 1:0.02-0.1.
According to a preferred embodiment of the present invention, the preparation method of the organic phase solution is selected from one or more of an organic solvent injection method, a thin film dispersion method, a T-channel method, a cross-flow injection method and a microfluidic method in order that the hydrophobic active ingredient may be supported between phospholipid bilayer embedding carrier particles; the organic solvent injection method is preferred.
According to a preferred embodiment of the present invention, in order to obtain better transdermal absorption and bioavailability of ergothioneine, the amount of ergothioneine is 0.001-2 times, preferably 0.01-1 times, more preferably 0.02-0.2 times the mass of the liposome.
According to a preferred embodiment of the present invention, the reaction temperature is provided by conventional heating means in the art such as oil bath, water bath, electric heating, steam heating, etc., in order to make the prepared ergothioneine composition entrapping delivery formulation more stable.
According to a preferred embodiment of the present invention, the conditions of the oil bath include: the temperature is 25-65deg.C, preferably 60deg.C, and the time is 15min.
According to a preferred embodiment of the present invention, in order to make the prepared ergothioneine composition entrapping delivery preparation more stable, the method for preparing the ergothioneine composition entrapping delivery preparation further comprises: and adding a reinforcing agent into the aqueous phase solution containing the hydrophilic active ingredient.
The strengthening agent is preferably a polymer strengthening agent and/or an inorganic particle strengthening agent, wherein the polymer strengthening agent is one or more than two of chitosan, chitin, cellulose, protein, nucleic acid and starch; the inorganic particle reinforcer is one or more than two selected from silicon dioxide, titanium dioxide, calcium carbonate, calcium silicate and calcium phosphate.
According to a preferred embodiment of the invention, the mass ratio of ergothioneine to enhancer is 1:0.01-10, more preferably 1:0.1-5, more preferably 1:0.2-1.
The inorganic particle reinforcer is generally porous particles or nano particles, and the particle size is generally 5nm-1mm, more preferably 10nm-100 μm, and still more preferably 10nm-10 μm; in general, the specific surface area of the inorganic particulate reinforcing agent is >10m 2/g, more preferably >20m 2/g.
According to a preferred embodiment of the present invention, in order to remove the organic solvent during the preparation process and to improve the dispersibility of the prepared ergothioneine composition-embedded delivery preparation, so as to make its properties more stable, the preparation method of the ergothioneine composition-embedded delivery preparation further comprises: and (3) dripping the organic phase solution containing the embedded carrier particles and the hydrophobic active ingredient into the aqueous phase solution containing the hydrophilic active ingredient, and then performing drying and/or particle size reduction process.
According to a preferred embodiment of the present invention, the drying method is a method and conditions conventional in the art, and may be selected from one or more of freeze-drying, spray-drying, vacuum-drying, bipyramid-drying, heat-drying and normal-temperature air-drying.
According to a preferred embodiment of the present invention, in order to increase the water solubility, dispersibility and compatibility of the ergothioneine composition entrapping delivery formulation, it is desirable to add a drying protecting agent at the time of drying, the protecting agent type including, but not limited to, one or more of sucrose, fructose, trehalose, mannitol, lactose, glucose, maltose or various oligosaccharides, etc.
According to a preferred embodiment of the present invention, the dry protectant is present in a proportion of 5% to 95% by mass of the solid content in order to increase the water solubility, dispersibility and compatibility of the ergothioneine composition entrapping delivery formulation.
According to a preferred embodiment of the present invention, the solution is concentrated to remove the organic solvent before drying, and the concentration method includes heating evaporation, room temperature evaporation, membrane filtration, and the like.
In order to remove the organic solvent during the preparation process, the present invention preferably uses rotary evaporation for concentration, and the conditions of the rotary evaporation method include: the temperature is 35-80deg.C, the time is 15-60min, the rotation speed is 50-200r/min, preferably the temperature is 60 ℃, the time is 45min, and the rotation speed is 100r/min.
According to the preferred embodiment of the invention, the final form of the product is powder, solid particles, semi-solid paste or dispersion liquid and the like according to the actual application requirements.
According to a preferred embodiment of the present invention, the particle size reduction process is selected from one or two or more of a mechanical stirring method, a shear homogenizing method, a high pressure homogenizing method, a micro-jet homogenizing method and an extrusion method.
The invention further provides an ergothioneine composition embedding delivery preparation prepared by the preparation method.
The invention further provides application of the ergothioneine composition embedding delivery preparation in cosmetics, health foods, health products, medical instruments and medical products.
The invention will be described in detail below by way of examples. In the following examples, the medicines and the medicaments are conventional commercial products.
Example 1
Preparation of ergothioneine-phloretin composition entrapping delivery formulation:
(1) Organic phase solution preparation: respectively weighing soybean phospholipid PC90 mg, cholesterol 16.65mg and phloretin 4mg, and sequentially dissolving in 2mL of absolute ethyl alcohol to prepare phloretin-lipid ethanol solution;
(2) Preparing an aqueous phase solution: weighing 80mg of ergothioneine in a 50mL round-bottom flask, and adding 10mL of deionized water for dissolution to prepare an aqueous solution of ergothioneine;
(3) Preparation of composition entrapping delivery formulation: slowly dripping 2mL phloretin-lipid ethanol solution prepared in the step (1) into the ergothioneine aqueous phase solution under the condition of 60 ℃ oil bath stirring, and continuously stirring for 15min to obtain a mixed solution;
(4) And (3) subsequent treatment: steaming the mixed solution at 60deg.C for 30min, removing ethanol and part of water, adding 0.5g trehalose, ultrasonic dispersing for 10min, dissolving and dispersing uniformly, freezing, and lyophilizing for 24 hr to obtain ergothioneine-phloretin composition embedding delivery preparation, denoted as B1.
Example 2
Preparation of ergothioneine-vitamin E composition entrapping delivery formulation:
(1) Organic phase solution preparation: respectively weighing soybean phospholipid PC90 mg, cholesterol 6.24mg and vitamin E2.25 mg, dissolving in 1.25mL of absolute ethyl alcohol, and preparing vitamin E-lipid ethanol solution;
(2) Preparing an aqueous phase solution: weighing 46.875mg of ergothioneine in a 10mL glass bottle, and adding 10mL of deionized water for dissolution to prepare an aqueous solution of ergothioneine;
(3) Preparation of composition entrapping delivery formulation: slowly dripping 1.25mL of vitamin E-lipid ethanol solution prepared in the step (1) into the ergothioneine aqueous phase solution under the condition of stirring in an oil bath at 60 ℃, and continuously stirring for 15min to obtain a mixed solution;
(4) And (3) subsequent treatment: rotary evaporating the mixed solution at 60deg.C for 30min, removing ethanol, adding 0.5g mannitol, ultrasonic dispersing for 10min, dissolving and dispersing uniformly, and freeze drying for 24 hr to obtain ergothioneine-vitamin E composition embedding delivery preparation, denoted as B2.
Example 3
Preparation of ergothioneine-ceramide composition entrapping delivery formulation:
(1) Organic phase solution preparation: 200mg of egg yolk lecithin EPC, 16.65mg of cholesterol and 2mg of ceramide are weighed and dissolved in 2mL of tetrahydrofuran to prepare a ceramide-lipid tetrahydrofuran solution;
(2) Preparing an aqueous phase solution: weighing 80mg of ergothioneine in a 50mL round-bottom flask, and adding 10mL of deionized water for dissolution to prepare an aqueous solution of ergothioneine;
(3) Preparation of composition entrapping delivery formulation: slowly dripping 2mL of the ceramide-lipid tetrahydrofuran solution prepared in the step (1) into the ergothioneine aqueous phase solution under the condition of 50 ℃ oil bath stirring, and continuously stirring for 15min to obtain a mixed solution;
(4) And (3) subsequent treatment: the mixed solution is steamed for 30min, tetrahydrofuran and partial water are removed, the liquid is concentrated to 5mL, then 0.2g butanediol and 0.1g hexanediol are added, and the solution is dissolved and dispersed uniformly, thus obtaining the liquid-form ergothioneine-ceramide composition embedding delivery preparation, which is marked as B3.
Example 4
Preparation of ergothioneine-vitamin E-phloretin composition embedding delivery formulation:
(1) Organic phase solution preparation: weighing 75mg of hydrogenated soybean lecithin, 6.24mg of cholesterol, 3.75mg of vitamin E and 0.75mg of phloretin, and dissolving in 1.25mL of absolute ethyl alcohol to prepare a vitamin E-phloretin-lipid ethanol solution;
(2) Preparing an aqueous phase solution: weighing 46.875mg of ergothioneine in a 10mL glass bottle, and adding 5mL of deionized water for dissolution to prepare an aqueous solution of ergothioneine;
(3) Preparation of composition entrapping delivery formulation: slowly dripping 1.25mL of the vitamin E-phloretin-lipid ethanol solution prepared in the step (1) into the ergothioneine aqueous phase solution under the condition of 60 ℃ oil bath stirring, and continuously stirring for 15min to obtain a mixed solution;
(4) And (3) subsequent treatment: steaming the mixed solution for 30min, removing ethanol and part of water, adding 0.50g maltodextrin, dispersing with ultrasound for 10min, dissolving and dispersing uniformly, and freeze drying for 24 hr to obtain ergothioneine-vitamin E-root Pi Subao buried delivery preparation, denoted as B4.
Example 5
Preparation of ergothioneine-vitamin E-silica composition entrapping delivery formulation:
(1) Organic phase solution preparation: respectively weighing soybean phospholipid PC90 mg, cholesterol 12.48mg and vitamin E3.75 mg, dissolving in 1.25mL of absolute ethyl alcohol, and preparing vitamin E-lipid ethanol solution;
(2) Preparing an aqueous phase solution: weighing 50mg of ergothioneine in a 20mL glass bottle, adding 10mL of deionized water for dissolution, and then adding 10mg of nano silicon dioxide to prepare an ergothioneine-silicon dioxide aqueous phase solution;
(3) Preparation of composition entrapping delivery formulation: slowly dripping 1.25mL of vitamin E-lipid ethanol solution prepared in the step (1) into the ergothioneine-silicon dioxide aqueous phase solution under the condition of 60 ℃ oil bath stirring, and continuously stirring for 15min to obtain a mixed solution;
(4) And (3) subsequent treatment: the mixed solution is subjected to rotary evaporation for 30min, ethanol and part of water are removed to obtain concentrated solution, then 0.5g of mannitol is added, ultrasonic dispersion is carried out for 10min, the solution and the dispersion are uniform, vacuum drying is carried out at 35 ℃ to prepare the ergothioneine-vitamin E-silicon dioxide composition embedding delivery preparation, which is marked as B5.
Example 6
Preparation of ergothioneine-vitamin E-methylcellulose composition entrapping delivery formulation:
(1) Organic phase solution preparation: weighing soybean phospholipid PC 90.75 mg, cholesterol 12.48mg and vitamin E3.75 mg, dissolving in 1.25mL absolute ethyl alcohol, and preparing vitamin E-lipid ethanol solution;
(2) Preparing an aqueous phase solution: weighing 50mg of ergothioneine in a 10mL glass bottle, adding 5mL of deionized water for dissolution, and then adding 2.5mg of methylcellulose for uniform dissolution to prepare an ergothioneine-methylcellulose water phase solution;
(3) Preparation of composition entrapping delivery formulation: slowly dripping 1.25mL of vitamin E-lipid ethanol solution prepared in the step (1) into the ergothioneine-methyl cellulose organic phase solution under the condition of 60 ℃ oil bath stirring, and continuously stirring for 15min to obtain a mixed solution;
(4) And (3) subsequent treatment: steaming the mixed solution for 30min, removing ethanol and part of water, adding 0.5g of mannitol, dispersing with ultrasound for 10min, dissolving and dispersing uniformly, and freeze drying for 24h to obtain the ergothioneine-vitamin E-methylcellulose composition embedding delivery preparation, which is marked as B6.
Example 7
Preparation of ergothioneine-vitamin a alcohol-silk fibroin composition entrapping delivery formulation:
(1) Organic phase solution preparation: weighing soybean lecithin PC90 1200mg, vitamin A alcohol 12mg, dissolving in 5mL petroleum ether, and preparing vitamin A alcohol-lipid petroleum ether solution;
(2) Preparing an aqueous phase solution: weighing 250mg of ergothioneine, and adding 20mL of deionized water for dissolution to prepare an aqueous solution of ergothioneine;
(3) Film dispersion: spin drying 5mL of the vitamin A alcohol-lipid petroleum ether solution prepared in the step (1) by adopting a rotary evaporation method under the condition of 60 ℃ oil bath stirring, and forming a layer of liposome film on the bottle wall of a round-bottom flask;
(4) Liposome preparation: hydrating the liposome film with the ergothioneine aqueous phase solution, and shearing and homogenizing for 15min by a shearing homogenizer to obtain ergothioneine-vitamin A alcohol composition dispersion;
(5) And (3) subsequent treatment: adding 0.5g of silk fibroin into the dispersion liquid, carrying out ultrasonic treatment for 10min, uniformly dispersing, and freeze-drying for 24h to prepare the ergothioneine-vitamin A alcohol-silk fibroin composition embedding delivery preparation, which is marked as B7.
Example 8
Preparation of ergothioneine-vitamin a alcohol-multiple complex phospholipid entrapping delivery formulation:
(1) Organic phase solution preparation: respectively weighing 70 mg of soybean lecithin PC, 100mg of egg yolk lecithin EPC, 16.65mg of cholesterol and 2mg of vitamin A alcohol, and dissolving in 2mL of absolute ethyl alcohol to prepare phloretin-lipid ethanol solution;
(2) Preparing an aqueous phase solution: weighing 80mg of ergothioneine in a 50mL round-bottom flask, and adding 100mL of deionized water for dissolution to prepare an aqueous solution of ergothioneine;
(3) Preparation of composition entrapping delivery formulation: slowly dripping 2mL of the vitamin A alcohol-lipid ethanol solution prepared in the step (1) into the ergothioneine aqueous phase solution under the condition of 60 ℃ oil bath stirring, and continuously stirring for 15min to obtain a mixed solution;
(4) And (3) subsequent treatment: and (3) steaming the mixed solution for 30min, removing ethanol and part of water to obtain a concentrated solution, adding 0.5g of mannitol, performing ultrasonic dispersion for 10min, dissolving and dispersing uniformly, and performing freeze drying to obtain the ergothioneine-vitamin A alcohol-multiple phospholipid composite embedding delivery preparation, which is marked as B8.
Detection example 1
The ergothioneine inclusion rate determination was performed on ergothioneine combination encapsulation delivery formulations B1-B8 prepared in examples 1-8, as follows:
(1) Weighing 1g of the ergothioneine combined embedding delivery preparation B1-B8 powder prepared in examples 1-8 respectively, dissolving in deionized water, uniformly dispersing by ultrasonic, and measuring the total content of the ergothioneine by using an HPLC method;
(2) Weighing 1g of the ergothioneine combined embedding delivery preparation B1-B8 powder prepared in examples 1-8 respectively, dissolving in deionized water, separating free ergothioneine and liposome-embedded ergothioneine (supernatant component) by ultra-high speed centrifugation (50 ten thousand g), and measuring the content of free ergothioneine (in the water at the lower layer) by an HPLC method;
(3) The embedding rate of ergothioneine is calculated, and the calculation formula is as follows.
The ergothioneine inclusion rate for ergothioneine combination encapsulation delivery formulations B1-B8 prepared in examples 1-8 is shown in table 1.
TABLE 1
As can be seen from the data in Table 1, the ergothioneine composition of the present invention without the inclusion of the inclusion enhancer had an ergothioneine inclusion rate of about 50% in the ergothioneine composition of the present invention, which was as high as about 50% in the ergothioneine composition of the present invention, and the ergothioneine composition of the present invention, which had the inclusion enhancer added, had the ergothioneine inclusion rate of about 5 to B7 in the ergothioneine composition and the ergothioneine composition of the present invention, which had the ergothioneine composition of the present invention, which had the complex liposome as the inclusion carrier particle, had a significant improvement in the ergothioneine inclusion rate of about 80% from about 50%.
Detection example 2
The hydrophobic active ingredient entrapment rate was determined for ergothioneine combination entrapment delivery formulations B1-B8 prepared in examples 1-8, as follows:
(1) Weighing 1g of ergothioneine combined embedding delivery preparation B1-B8 powder prepared in examples 1-8 respectively, dissolving in deionized water, uniformly dispersing by ultrasonic, and measuring the total content of phloretin by HPLC;
(2) Weighing 1g of ergothioneine combined embedding delivery preparation B1-B8 powder prepared in examples 1-8 respectively, dissolving in deionized water, separating free hydrophobic active ingredient and hydrophobic active ingredient embedded by liposome (existing in liposome of supernatant) by low-speed centrifugation (3000 rpm), and measuring the content of the encapsulated hydrophobic active ingredient in the supernatant by HPLC;
(3) The entrapment rate of the hydrophobic active was calculated.
The hydrophobic active ingredient entrapment rates of ergothioneine combination entrapment delivery formulations B1-B8 prepared in examples 1-8 are shown in table 2.
TABLE 2
As can be seen from the data in Table 2, the hydrophobic active ingredient is well entrapped with an entrapment rate of substantially above 90%, wherein the entrapment rate is slightly lower, but exceeds 85%, due to poor solubility of the ceramide.
Detection example 3
The ergothioneine combination encapsulation delivery formulations B1-B8 prepared in examples 1-8 were tested for dispersibility index (PDI) and the results are shown in Table 3.
TABLE 3 Table 3
As can be seen from Table 3, the particle size of the entrapping vector particles of the entrapping delivery formulations B1 to B4 of the ergothioneine composition without the entrapping enhancer of the present invention is substantially less than 200nm, and the monodispersity is better, while the particle size of the entrapping vector particles of the entrapping delivery formulations B5 to B7 of the ergothioneine composition with the entrapping enhancer and the entrapping vector particles of the entrapping delivery formulation B8 of the ergothioneine composition using the composite liposome as the entrapping vector particles is about 250nm, and the dispersibility index is slightly high, but good dispersibility is maintained.
Detection example 4
Scanning electron microscopy analysis was performed on the ergothioneine composition-embedded delivery formulations B1, B4, and B7 prepared in examples 1, 4, and 7, and the results are shown in fig. 2.
As can be seen from the scanning electron microscope image of the ergothioneine composition-entrapped delivery preparation of fig. 2, the liposomes in the ergothioneine composition-entrapped delivery preparation of the present invention are spherical, the particle size of the liposomes of the ergothioneine composition-entrapped delivery preparation B1 and B4 without the entrapped enhancer is substantially less than 200nm, and the particle size of the liposomes of the ergothioneine composition-entrapped delivery preparation B7 with the silk fibroin enhancer is larger, and the result is substantially consistent with the PDI test result of test example 3.
Detection example 5
Since ergothioneine is relatively sensitive to light and has poor light stability, the ergothioneine or the ergothioneine composition embedding delivery formulations B1-B8 of examples 1-8 of the invention are prepared into aqueous solutions by referring to a drug light stability test method, the concentration of the ergothioneine is about 1mg/mL, the light stability test evaluation is carried out at 37 ℃, and the test results are shown in Table 4.
TABLE 4 Table 4
As can be seen from table 4, the stability of the ergothioneine composition-embedded delivery formulations B1-B8 of examples 1-8 of the present invention is significantly better than that of the aqueous solution of ergothioneine alone, and from the data on day 30 of the accelerated experiments, the retention rate of ergothioneine in the ergothioneine composition-embedded delivery formulations B1-B8 of examples 1-8 of the present invention is 1.5 times or more than that of the solution of ergothioneine alone, and the retention rate of ergothioneine in the ergothioneine composition-embedded delivery formulations B5-B7 with the embedding enhancer added and the ergothioneine composition-embedded delivery formulation B8 using the composite liposome as the embedding carrier particles are higher, further demonstrating the enhancing effect of the addition of the embedding enhancer on the stability of ergothioneine.
Application example 1
Application of ergothioneine-phloretin composition embedding delivery formulation B1 prepared in example 1 and ergothioneine-vitamin A alcohol-silk fibroin composition embedding delivery formulation B7 in "soothing and repairing essence", control sample formulation was formulation with direct addition of ergothioneine, concentration of ergothioneine remained consistent, and brief process for preparation of 3 formulation systems were as follows:
(1) Sequentially weighing the phase A raw materials, and heating and stirring uniformly at 40 ℃;
(2) After stirring and cooling, adding the phase B, stirring uniformly, and discharging to obtain the relief repair essence;
wherein, specific formulations of the A phase and the B phase are shown in tables 5-7 for the above 3 formulation systems.
Table 5 ergothioneine-essence model formulation
Table 6 ergothioneine-phloretin composition entrapping delivery formulation B1-essence model formulation
Table 7 ergothioneine-vitamin a alcohol-silk fibroin composition entrapping delivery formulation B7-essence model formulation
The above 3 essence model formulations were subjected to ergothioneine transdermal test efficacy evaluation and comparison, the evaluation methods are referred to "chemical skin absorption in vitro test methods", and the evaluation results are shown in Table 8.
TABLE 8
From the results of the transdermal efficacy evaluation of table 8, the transdermal absorption amount of ergothioneine of the essence prepared by using the ergothioneine composition-embedding delivery preparation prepared in example 1 and example 7 of the present invention is about 2 times that of ergothioneine alone, which is significantly superior to that of ergothioneine alone, thereby proving that the ergothioneine composition-embedding delivery preparation of the present invention can improve the transdermal efficiency of ergothioneine.
In conclusion, the ergothioneine composition embedding and delivering preparation effectively solves the problems of poor light stability, poor transdermal absorption, peculiar smell and other application pain points of the ergothioneine, and improves the light stability of the ergothioneine by more than 50% in a simulated illumination experiment; in the transdermal absorption efficacy evaluation experiment, the transdermal quantity of ergothioneine is improved by 100 percent; in addition, in the formula application of the cosmetic product, the peculiar smell of the embedded ergothioneine is obviously reduced, almost no peculiar smell exists, and powerful guarantee is provided for the high-concentration application of the ergothioneine.
Meanwhile, the embedding delivery preparation of the ergothioneine composition further improves the embedding rate and stability of the ergothioneine by adding an embedding enhancer. The ergothioneine and the hydrophobic active ingredient are compositely embedded, and the development of an integrated efficacy combined embedding delivery preparation is also an important innovation of the invention. The integrated embedding delivery preparation not only improves the stability and bioavailability of the hydrophobic active ingredient, but also improves the efficacy synergy, simultaneously reduces pain points of compatibility of product formulation design, and provides powerful technical support and guarantee for product innovation and upgrading of efficacy cosmetics and functional foods.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Moreover, any combination of the various embodiments of the invention can be made without departing from the spirit of the invention, which should also be considered as disclosed herein.

Claims (10)

1. An ergothioneine composition entrapping delivery formulation, characterized in that the ergothioneine composition entrapping delivery formulation contains entrapping carrier particles, a hydrophobic active ingredient supported on the entrapping carrier particles, and a hydrophilic active ingredient entrapped in vesicles of the entrapping carrier particles; wherein,
The embedded carrier particles are liposomes;
the hydrophilic active ingredient is ergothioneine.
2. The ergothioneine composition entrapping delivery formulation according to claim 1, wherein the entrapping carrier particles have a particle size in the range of 10nm-1mm, preferably 50nm-500 μm, more preferably 100nm-100 μm, even more preferably 200nm-10 μm;
preferably, the liposome is selected from one or more of hydrogenated soybean lecithin, soybean phospholipid PC90, soybean phospholipid PC70, soybean phospholipid PC50, soybean lecithin, egg yolk lecithin, cholesterol and PEGylated phospholipid;
More preferably, the hydrophobic active ingredient is selected from one or more of phloretin, ceramide, vitamin E, vitamin a alcohol, astaxanthin, curcumin, docosahexaenoic acid, lutein, carotene, and glabridin.
3. The ergothioneine composition entrapping delivery formulation of claim 1 or 2, further comprising an enhancer;
preferably, the strengthening agent is a high molecular strengthening agent and/or an inorganic particle strengthening agent;
more preferably, the polymer enhancer is one or more selected from the group consisting of chitosan, chitin, cellulose, protein, nucleic acid and starch;
further preferably, the inorganic particle reinforcer is selected from one or more of silica, titanium dioxide, calcium carbonate, calcium silicate and calcium phosphate;
Still more preferably, the particle size of the inorganic particle reinforcer is 5nm to 100. Mu.m, preferably 10nm to 50. Mu.m, still more preferably 10nm to 10. Mu.m.
4. A delivery formulation for embedding a ergothioneine composition according to any of claims 1-3, characterized in that the mass ratio of the liposomes, ergothioneine and hydrophobic active ingredient is 1:0.001-2:0.001-1, preferably 1:0.01-1:0.01-0.2, more preferably 1:0.02-0.2:0.02-0.1.
5. A method of preparing an ergothioneine composition-entrapped delivery formulation, the method comprising:
Providing an organic phase solution containing entrapping vector particles and a hydrophobic active ingredient, wherein the entrapping vector particles are liposomes;
providing an aqueous solution containing a hydrophilic active ingredient, wherein the hydrophilic active ingredient is ergothioneine;
and (3) dripping the organic phase solution containing the embedded carrier particles and the hydrophobic active ingredient into the aqueous phase solution containing the hydrophilic active ingredient under the condition of 25-65 ℃ while stirring, and reacting for 10-120min.
6. The method of claim 5, wherein the particle size of the entrapping support particles is in the range of from 10nm to 1mm, preferably from 50nm to 500 μm, more preferably from 100nm to 100 μm, still more preferably from 200nm to 10 μm;
preferably, the liposome is selected from one or more of hydrogenated soybean lecithin, soybean phospholipid PC90, soybean phospholipid PC70, soybean phospholipid PC50, soybean lecithin, egg yolk lecithin, cholesterol and PEGylated phospholipid;
More preferably, the hydrophobic active ingredient is selected from one or more of phloretin, ceramide, vitamin E, vitamin a alcohol, astaxanthin, curcumin, docosahexaenoic acid, lutein, carotene, and glabridin;
Further preferably, the solvent of the organic phase solution is one or more selected from ethanol, acetone, petroleum ether, dichloromethane and tetrahydrofuran;
Still more preferably, the mass ratio of the liposome to the hydrophobic active is 1:0.001-1, more preferably 1:0.01 to 0.2, more preferably 1:0.02-0.1;
Still more preferably, the preparation method of the organic phase solution is selected from one or more of an organic solvent injection method, a thin film dispersion method, a T-channel method, a cross-flow injection method, and a microfluidic method, and more preferably, the organic solvent injection method.
7. The process according to claim 5 or 6, wherein the ergothioneine is used in an amount of 0.001-2 times, preferably 0.01-1 times, more preferably 0.02-0.2 times the mass of the entrapping support particles.
8. The method of any one of claims 3-6, wherein the method of preparing the ergothioneine composition entrapping delivery formulation further comprises: adding a reinforcing agent into the aqueous phase solution containing the hydrophilic active ingredient;
preferably, the strengthening agent is a high molecular strengthening agent and/or an inorganic particle strengthening agent;
more preferably, the polymer enhancer is one or more selected from the group consisting of chitosan, chitin, cellulose, protein, nucleic acid and starch;
more preferably, the inorganic particle reinforcer is selected from one or more of silica, titanium dioxide, calcium carbonate, calcium silicate and calcium phosphate;
Further preferably, the particle size of the inorganic particle reinforcer is 5nm to 100 μm, preferably 10nm to 50 μm, more preferably 10nm to 10 μm;
Still further preferably, the method of preparing the ergothioneine composition entrapping delivery formulation further comprises: and (3) dripping the organic phase solution containing the embedded carrier particles and the hydrophobic active ingredient into the aqueous phase solution containing the hydrophilic active ingredient, and then performing drying and/or particle size reduction process.
9. An ergothioneine composition-entrapping delivery formulation prepared by the method of any of claims 5-8.
10. Use of the ergothioneine composition according to any of claims 1-4 or the ergothioneine composition according to claim 9 in cosmetics, health foods, health products, medical devices and pharmaceutical products.
CN202410110161.XA 2024-01-25 2024-01-25 Ergothioneine composition embedding delivery preparation, preparation method and application thereof Pending CN118121502A (en)

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