Use of triethanolamine complex for improving transdermal penetration and efficacy of macromolecular substances

Abstract

Provided in the present invention is the use of a triethanolamine complex for improving the transdermal penetration and / or efficacy of macromolecular substances. The triethanolamine complex can improve the transdermal absorption of macromolecular substances, improve the bioavailability thereof, and enhance the efficacy thereof.

Description

Application of triethanolamine complex in improving transdermal penetration and efficacy of macromolecular substances

[0001] This application claims priority to:

[0002] The priority of the prior application entitled "Application of triethanolamine complex in improving transdermal penetration and efficacy of macromolecular substances", filed with the China National Intellectual Property Office on July 29, 2024, and having the patent application number 202411023879.1, is hereby claimed.

[0003] The entire contents of the prior application are incorporated herein by reference. TECHNICAL FIELD

[0004] The present application belongs to the field of medicine, and specifically relates to an application of a triethanolamine complex in improving transdermal penetration and efficacy of macromolecular substances. BACKGROUND

[0005] Transdermal drug delivery systems are widely considered to be a safe, non-invasive and effective drug delivery method due to their advantages of avoiding liver first-pass effect, reducing gastrointestinal enzymatic hydrolysis, providing sustained therapeutic effect, and improving patient compliance. In the field of cosmetics, various external skin care products are the most basic skin care and beauty means.

[0006] Collagen and hyaluronic acid exist in the tissues of animal skin, bone, tendon, ligament and blood vessels, and have various effects such as moisturizing, anti-wrinkle, and promoting skin self-repair, and thus are widely used in the fields of skin care and medicine. siRNA drugs can regulate gene expression and have significant therapeutic effect in various diseases. However, these macromolecular substances are limited in size and physical and chemical properties, and their transdermal absorption is challenging. Therefore, a delivery system compatible with the microenvironment of the skin is needed to promote the effective transdermal absorption of collagen, hyaluronic acid and siRNA. SUMMARY

[0007] The present application provides an application of a triethanolamine complex in improving transdermal penetration and / or efficacy of macromolecular substances.

[0008] According to an embodiment of the present application, the triethanolamine complex is composed of triethanolamine and a fatty acid, or an organic acid. According to an embodiment of the present application, the fatty acid is selected from oleic acid, linoleic acid. According to an embodiment of the present application, the organic acid is selected from citric acid.

[0009] According to an embodiment of the present application, the triethanolamine complex is selected from a complex composed of triethanolamine and linoleic acid, a complex composed of triethanolamine and oleic acid, and a complex composed of triethanolamine and citric acid.

[0010] According to an embodiment of the present application, the molar ratio of triethanolamine to fatty acid, or organic acid in the triethanolamine complex is 1:10-10:1, preferably 1:5-5:1, for example 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1.

[0011] According to an embodiment of the present application, the triethanolamine complex is selected from any one of the following: triethanolamine linoleic acid [TEA][LOA] (molar ratio 1:1), triethanolamine oleic acid [TEA][OLA] (molar ratio 1:1), triethanolamine citric acid [TEA][CA] (molar ratio 1:1, 2:1, 3:1).

[0012] According to an embodiment of the present application, the macromolecular substance is selected from a proteinaceous substance, a nucleic acid substance, a polysaccharide substance. According to an embodiment of the present application, the proteinaceous substance is, for example, collagen. According to an embodiment of the present application, the nucleic acid substance is selected from nucleic acid drugs, preferably including DNA drugs, RNA drugs, for example siRNA. According to an embodiment of the present application, the polysaccharide substance is, for example, hyaluronic acid (sodium).

[0013] According to an embodiment of the present application, the improvement of the transdermal penetration of the macromolecular substance and / or the improvement of the efficacy of the macromolecular substance includes at least one of the following: improvement of the transdermal absorption (transdermal penetration) of the macromolecular substance, improvement of the bioavailability of the macromolecular substance, improvement of the biological activity (for example, nutritional repair activity, etc.) of the macromolecular substance.

[0014] According to an embodiment of the present application, the application is the application of the triethanolamine complex in improving the transdermal penetration of the proteinaceous substance and / or improving the efficacy of the proteinaceous substance; preferably, the proteinaceous substance is collagen; preferably, the application is the application of the triethanolamine complex in improving the transdermal penetration of the collagen and / or improving the efficacy of the collagen; preferably, the improvement of the efficacy of the collagen is specifically: improvement of the bioavailability of the collagen, and / or improvement of the nutritional repair efficacy of the collagen. According to an embodiment of the present application, the triethanolamine complex is selected from the complex composed of triethanolamine and linoleic acid, the complex composed of triethanolamine and oleic acid; preferably, the molar ratio of triethanolamine to linoleic acid, oleic acid is 1:10-10:1, preferably 1:5-5:1, for example 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1.

[0015] According to an embodiment of the present application, the use is the use of a triethanolamine complex in improving the transdermal penetration of nucleic acid substances; preferably, the nucleic acid substances are selected from nucleic acid drugs, preferably including DNA drugs, RNA drugs, such as siRNA; preferably, the triethanolamine complex is selected from a complex consisting of triethanolamine and linoleic acid, a complex consisting of triethanolamine and oleic acid; preferably, the molar ratio of triethanolamine to linoleic acid, oleic acid is 1:10-10:1, preferably 1:5-5:1, for example 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1.

[0016] According to an embodiment of the present application, the use is the use of a triethanolamine complex in improving the transdermal penetration of polysaccharide substances; preferably, the polysaccharide substances are, for example, hyaluronic acid (sodium); preferably, the triethanolamine complex is selected from a complex consisting of triethanolamine and citric acid; the molar ratio of triethanolamine to citric acid is 1:10-10:1, preferably 1:5-5:1, for example 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1.

[0017] The present application also provides a composition comprising the above-mentioned triethanolamine complex and macromolecular substances.

[0018] According to an embodiment of the present application, the dosage form of the composition is selected from emulsions, gels, ointments, creams, emulsions, foams, solutions, suspensions, etc.

[0019] According to an embodiment of the present application, the composition comprises the above-mentioned triethanolamine complex and protein substances (such as collagen); preferably, the triethanolamine complex is selected from a complex consisting of triethanolamine and linoleic acid, a complex consisting of triethanolamine and oleic acid; preferably, the molar ratio of triethanolamine to linoleic acid, oleic acid is 1:10-10:1, preferably 1:5-5:1, for example 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1.

[0020] According to an embodiment of the present application, the composition comprises a proteinaceous substance (e.g. collagen) and a matrix comprising the triethanolamine complex described above. According to an embodiment of the present application, the collagen comprises low molecular weight collagen, medium molecular weight collagen, high molecular weight collagen. According to an embodiment of the present application, the content of the proteinaceous substance (e.g. collagen) in the composition is 0.001-1.0%, preferably 0.01%-0.50%, for example 0.02%, 0.03%, 0.04%, 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%. Low molecular weight collagen, whose molecular weight is less than 10 kd. Medium molecular weight collagen, whose molecular weight is between 10 kd and 100 kd. High molecular weight collagen, whose molecular weight is greater than 100 kd.

[0021] According to an embodiment of the present application, the matrix comprising the triethanolamine complex described above comprises the triethanolamine complex described above and a pharmaceutically or cosmetically acceptable adjuvant; preferably, the pharmaceutically or cosmetically acceptable adjuvant is selected from one, two or more of emulsifiers, oil solvents, thickening agents, skin feel modifiers, humectants, rheology modifiers, gel bases, preservatives, fillers, diluents, binders, lubricants, surfactants, wetting agents, solvents, pH adjustors, etc.; preferably, the pharmaceutically or cosmetically acceptable adjuvant is selected from one, two or more of Emulium Delta MB, Emulium Dolcea MB, Emulfree CBG MB, glyceryl stearate, caprylic / capric triglyceride, jojoba oil, medium chain triglyceride, cyclomethicone, glyceryl behenate, cetyl stearyl alcohol, octyldodecyl myristate, propylene glycol, 1,3-butylene glycol, water, glycerin, xanthan gum, microcrystalline cellulose, carbomer 980, carbomer U-20, phenoxyethanol, NaOH, citric acid, etc.

[0022] According to an embodiment of the present application, the emulsifier is selected from one, two or more of Emulium Delta MB, Emulium Dolcea MB, Emulfree CBG MB, Emulium Dermolea MB, Emulium Mellifera MB, Emulium Kappa MB, Emulium 22 MB, Emulium Stearique MB, PEG-8 beeswax, glyceryl stearate, polyethylene glycol-7 stearate, glyceryl mono-diplastylate / polyoxyethylene-75 stearate, polyglyceryl-3 diisostearate, polyethylene glycol-6 stearate / polyethylene glycol-32 stearate, etc. According to an embodiment of the present application, the oil solvent is selected from one, two or more of caprylic / capric triglyceride, jojoba oil, medium chain triglyceride, soybean oil, propylene glycol dicaprylate caprate, glyceryl monooleate, mixed fatty acid glycerides, etc. According to an embodiment of the present application, the thickening agent is selected from one, two or more of glyceryl behenate, cetyl stearyl alcohol, glyceryl mono-diplastylate, glyceryl distearate, etc. According to an embodiment of the present application, the feel modifier is selected from one, two or more of cyclopentasiloxane, octyldodecanol myristate, etc. According to an embodiment of the present application, the moisturizer is selected from glycerin. According to an embodiment of the present application, the rheology modifier is selected from one, two or more of xanthan gum, tragacanth gum, acrylates / C10-30 alkyl acrylate crosspolymer, starch acetate / adipate (and) citric acid, microcrystalline cellulose, sodium hyaluronate, etc. According to an embodiment of the present application, the gel base is selected from one, two or more of carbomer 980, carbomer U-20, carbomer ETD-2020, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc. According to an embodiment of the present application, the preservative is selected from phenoxyethanol. According to an embodiment of the present application, the solvent is selected from water, alcoholic solvents (e.g., propylene glycol, 1,3-butanediol). According to an embodiment of the present application, the acid / base regulator is selected from organic acids, inorganic acids, organic bases, inorganic bases, e.g., NaOH, citric acid, etc.

[0023] According to an embodiment of the present application, the content of the above-mentioned triethanolamine-based complex in the above-mentioned base containing the same is 1.0% to 10.0%, preferably 2.0% to 8.0%, e.g., 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%.

[0024] According to an embodiment of the present application, the above-mentioned base containing the above-mentioned triethanolamine-based complex includes the following components:

[0025] The above triethanolamine complex 1.0% to 10.0% (e.g., 3.0%, 4.0%, 5.0%, 6.0%, 7.0%), emulsifier 0.5% to 5.0% (e.g., 1.0%, 2.0%, 3.0%, 4.0%), oil solvent 1.0% to 8.0% (e.g., 2.0%, 3.0%, 4.0%, 5.0%, 6.0%), skin feel modifier 1.0% to 8.0% (e.g., 2.0%, 3.0%, 4.0%, 5.0%, 6.0%), humectant 0.5% to 5.0% (e.g., 1.0%, 2.0%, 3.0%, 4.0%), rheology modifier 0.01% to 0.50% (e.g., 0.10%, 0.15%, 0.20%), gel base 0.01% to 0.50% (e.g., 0.10%, 0.15%, 0.20%), preservative 0.1% to 3.0% (e.g., 0.3%, 0.5%, 1.0%), alcohol solvent 1.0% to 10.0% (e.g., 3.0%, 4.0%, 5.0%, 6.0%, 7.0%), adjust pH to 5.0 to 7.0 (e.g., 5.5 to 6.0), and the balance is water.

[0026] According to an embodiment of the present application, the above triethanolamine complex containing base includes the following components:

[0027] The above triethanolamine complex 5.0%, emulsifier 2.0%, oil solvent 4.0%, skin feel modifier 4.0%, humectant 2.0%, rheology modifier 0.15%, gel base 0.15%, preservative 0.5%, alcohol solvent 5.0%, adjust pH to 5.5 to 6.0, and the balance is water.

[0028] According to an embodiment of the present application, the above triethanolamine complex containing base includes the following components:

[0029] The above triethanolamine complex 5.0%, Emulium Delta MB 2.0%, caprylic / capric triglyceride 3.0%, jojoba oil 1.0%, cyclomethicone 4.0%, propylene glycol 5.0%, glycerin 2.0%, xanthan gum 0.15%, carbomer 980 0.15%, phenoxyethanol 0.5%, adjust pH to 5.5 to 6.0, and the balance is water. p H to 5.5 to 6.0, and the balance is water.

[0030] According to an embodiment of the present application, the above triethanolamine complex containing base includes the following components:

[0031] The above triethanolamine complex 1.0% - 10.0% (e.g., 3.0%, 4.0%, 5.0%, 6.0%, 7.0%), emulsifier 0.5% - 5.0% (e.g., 1.0%, 2.0%, 3.0%, 4.0%), oil solvent 1.0% - 8.0% (e.g., 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%), thickening agent 0.5% - 5.0% (e.g., 1.0%, 2.0%, 3.0%, 4.0%), skin feel modifier 3% - 15% (e.g., 5%, 6%, 7%, 8.0%, 9.0%, 10.0%), rheology modifier 0.5% - 5.0% (e.g., 1.0%, 2.0%, 2.2%, 2.5%, 3.0%, 4.0%), humectant 1.0% - 8.0% (e.g., 3.0%, 4.0%, 5.0%, 6.0%, 7.0%), 1,3-butanediol 1.0% - 8.0% (e.g., 2.0%, 3.0%, 4.0%, 5.0%, 6.0%), preservative 0.1% - 3.0% (e.g., 0.5%, 0.8%, 1.0%, 1.5%, 2.0%), alcohol solvent 1.0% - 10.0% (e.g., 3.0%, 4.0%, 5.0%, 6.0%, 7.0%), adjust pH to 5.0 - 8.0 (e.g., 6.0 - 7.0), and the balance is water.

[0032] According to embodiments of the present application, the above triethanolamine complex containing base includes the following components:

[0033] The above triethanolamine complex 5.0%, emulsifier 3.0%, oil solvent 5.0%, thickening agent 2.0%, skin feel modifier 8.0%, rheology modifier 2.2%, humectant 6.0%, alcohol solvent 4.0%, preservative 1.0%, adjust pH to 6.0 - 7.0, and the balance is water.

[0034] According to embodiments of the present application, the above triethanolamine complex containing base includes the following components:

[0035] The above triethanolamine complex 5.0%, Emulium Dolcea MB 3.0%, caprylic / capric triglyceride 5.0%, glyceryl behenate 2.0%, octyldodecyl myristate 8.0%, xanthan gum 0.2%, microcrystalline cellulose 2.0%, glycerin 6.0%, 1,3-butanediol 4.0%, phenoxyethanol 1.0%, adjust pH to 6.0 - 7.0, and the balance is water.

[0036] According to embodiments of the present application, the above triethanolamine complex containing base includes the following components:

[0037] The above triethanolamine complex 1.0% - 10.0% (e.g., 3.0%, 4.0%, 5.0%, 6.0%, 7.0%), emulsifier 0.5% - 5.0% (e.g., 1.0%, 2.0%, 3.0%, 4.0%), thickening agent 0.5% - 5.0% (e.g., 1.0%, 2.0%, 3.0%, 4.0%), oil solvent 5.0% - 15.0% (e.g., 6.0%, 8.0%, 10.0%, 12.0%, 15.0%), skin feel modifier 0.5% - 5.0% (e.g., 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 4.0%), humectant 5.0% - 30.0% (e.g., 10.0%, 15.0%, 18.0%, 20.0%, 23.0%, 25.0%), gel base 0.05% - 0.50% (e.g., 0.10%, 0.15%, 0.20%, 0.25%, 0.30%), rheology modifier 0.01% - 0.50% (e.g., 0.10%, 0.15%, 0.20%, 0.3%, 0.4%), preservative 0.1% - 3.0% (e.g., 0.5%, 0.8%, 1.0%, 1.5%, 2.0%), adjust pH to 5.0 - 5.5, and the balance water.

[0038] According to embodiments of the present application, the above triethanolamine complex containing base includes the following components:

[0039] The above triethanolamine complex 5.0%, emulsifier 3.0%, thickening agent 2.0%, oil solvent 10.0%, skin feel modifier 2.0%, humectant 20.0%, gel base 0.2%, rheology modifier 0.2%, preservative 1.0%, adjust pH to 5.0 - 5.5, and the balance water. According to embodiments of the present application, the above triethanolamine complex containing base includes the following components:

[0040] The above triethanolamine complex 5.0%, Emulfree CBG MB 2.0%, cetylstearyl alcohol 2.0%, glyceryl stearate 1.0%, medium chain triglyceride 5.0%, octyldodecyl myristate 2.0%, caprylic / capric triglyceride 5.0%, glycerin 20.0%, carbomer U-20 2.0%, xanthan gum 0.2%, phenoxyethanol 1.0%, adjust pH to 5.0 - 5.5, and the balance water.

[0041] According to an embodiment of the present application, the composition comprises the above-mentioned triethanolamine complex and a nucleic acid substance. According to an embodiment of the present application, the nucleic acid substance is selected from the group consisting of nucleic acid drugs, preferably comprising DNA drugs, RNA drugs, such as siRNA. Preferably, the triethanolamine complex is selected from the group consisting of a complex of triethanolamine and linoleic acid, a complex of triethanolamine and oleic acid; preferably, the molar ratio of triethanolamine to linoleic acid, oleic acid is 1 : 10-10: 1, preferably 1 : 5-5: 1, such as 1 : 4.5, 1 : 4, 1 : 3.5, 1 : 3, 1 : 2.5, 1 : 2, 1 : 1.5, 1 : 1, 1.5: 1, 2: 1, 2.5: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1.

[0042] According to an embodiment of the present application, the molar ratio of the above-mentioned triethanolamine complex to the nucleic acid substance in the composition is 5*10 3 : 1-100*10 3 : 1, preferably 15*10 3 : 1-30*10 3 : 1, such as 20*10 3 : 1, 21*10 3 : 1, 22*10 3 : 1, 23*10 3 : 1, 23.3*10 3 : 1, 24*10 3 : 1, 25*10 3 : 1.

[0043] According to an embodiment of the present application, the content of the above-mentioned triethanolamine complex in the composition is 1%-80%, preferably 5%-70%, such as 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%.

[0044] According to an embodiment of the present application, the composition comprises the above-mentioned triethanolamine complex and a polysaccharide substance. Preferably, the polysaccharide substance is, for example, hyaluronic acid (sodium); preferably, the triethanolamine complex is selected from the group consisting of a complex of triethanolamine and citric acid; the molar ratio of triethanolamine to citric acid is 1 : 10-10: 1, preferably 1 : 5-5: 1, such as 1 : 4.5, 1 : 4, 1 : 3.5, 1 : 3, 1 : 2.5, 1 : 2, 1 : 1.5, 1 : 1, 1.5: 1, 2: 1, 2.5: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1.

[0045] According to an embodiment of the present application, the mass ratio of the above-mentioned triethanolamine complex and the polysaccharide substance in the composition is 50:1 to 1000:1, preferably 100:1 to 800:1, for example, 150:1, 200:1, 250:1, 300:1, 350:1, 400:1, 450:1, 500:1, 550:1, 600:1, 650:1, 700:1.

[0046] According to an embodiment of the present application, the content of the above-mentioned triethanolamine complex in the composition is 1% to 80%, preferably 5% to 70%, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%.

[0047] According to an embodiment of the present application, the ratio is a weight percentage.

[0048] The present application also provides a base material comprising the above-mentioned triethanolamine complex and a pharmaceutically or cosmetically acceptable excipient. According to an embodiment of the present application, the base material has the definition of the aforementioned base material comprising the above-mentioned triethanolamine complex.

[0049] The present application also provides a mask comprising the above-mentioned composition and a mask base material.

[0050] According to an embodiment of the present application, the composition comprises the above-mentioned triethanolamine complex and a protein substance (for example, collagen). According to an embodiment of the present application, the mask base material comprises a silk mask base material, a non-woven fabric mask base material, a bio-fiber mask base material, a Tencel mask base material, a pure cotton fiber mask base material. Advantages

[0051] The present application provides the use of a triethanolamine complex in improving the transdermal penetration of a macromolecular substance and / or improving the efficacy of a macromolecular substance. The triethanolamine complex can improve the transdermal absorption of a macromolecular substance, improve the bioavailability, and also enhance the efficacy. BRIEF DESCRIPTION OF DRAWINGS

[0052] Figure 1: Intra-dermal retention per unit area of each sample in Example 2 (Mean ± SD, n = 3; *: p < 0.05; NS: p > 0.05).

[0053] Figure 2: Intra-dermal distribution of low molecular weight collagen ordinary emulsion in Example 2.

[0054] Figure 3: Intra-dermal distribution of medium molecular weight collagen ordinary emulsion in Example 2.

[0055] Figure 4: Intra-dermal distribution of high molecular weight collagen ordinary emulsion in Example 2.

[0056] Figure 5: Intracutaneous distribution of low molecular weight collagen DES emulsion in Example 2.

[0057] Figure 6: Intracutaneous distribution of medium molecular weight collagen DES emulsion in Example 2.

[0058] Figure 7: Intracutaneous distribution of high molecular weight collagen DES emulsion in Example 2.

[0059] Figure 8: Intracutaneous distribution of low molecular weight collagen linoleic acid emulsion in Example 2.

[0060] Figure 9: Schematic diagram of the last administration position and administration time of the single administration and multiple administration groups of the Example 3 Bama minipig skin coating.

[0061] Figure 10: Collagen cream Bama minipig skin distribution drug time curve of Example 3.

[0062] Figure 11: Efficacy test of different masks in Example 4 (when the TEWL value is reduced to 12 g / h·m 2 The following is considered to be the recovery of skin barrier function).

[0063] Figure 12: Example 5: Intracutaneous retention per unit area of each sample (**: p < 0.01).

[0064] Figure 13: Intracutaneous distribution of Naked siRNA solution in Example 5.

[0065] Figure 14: Intracutaneous distribution of siRNA-DES solution in Example 5.

[0066] Figure 15: Intracutaneous distribution of siRNA-TEA solution in Example 5.

[0067] Figure 16: Intracutaneous distribution of RhB-HA ordinary solution in Example 6.

[0068] Figure 17: Intracutaneous distribution of RhB-HA 20% DES solution in Example 6.

[0069] Figure 18: Intracutaneous distribution of RhB-HA 40% DES solution in Example 6.

[0070] Figure 19: Intradermal distribution of Example 6 RhB-HA 60% DES solution. DETAILED DESCRIPTION

[0071] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively and explain the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology achieved based on the above description of the present application is covered within the scope intended to be protected by the present application.

[0072] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0073] Example 1 Preparation of triethanolamine DES

[0074] (1) Preparation of [TEA][LOA] (triethanolamine linoleic acid, molar ratio 1:1)

[0075] Linoleic acid 5.61 g and triethanolamine 2.98 g were weighed, and the two were mixed and stirred for 4 h under heating in a water bath at 40°C to obtain a viscous paste, and the product was stored in a sealed container.

[0076] (2) Preparation of [TEA][OLA] (triethanolamine oleic acid, molar ratio 1:1)

[0077] Oleic acid 5.65 g and triethanolamine 2.98 g were weighed, and the two were mixed and stirred for 4 h under heating in a water bath at 40°C to obtain a viscous paste, and the product was stored in a sealed container.

[0078] (3) Preparation of [TEA][CA] (triethanolamine citric acid, molar ratio 1:1)

[0079] Citric acid 3.84 g and triethanolamine 2.98 g were weighed, and the citric acid was dissolved in 30 mL of ethanol; triethanolamine was added, and the mixture was stirred for 4 h to obtain a white emulsion; ethanol was removed using a rotary evaporator to obtain a colorless to light yellow clear viscous liquid; after being sucked out while hot, it was dried under reduced pressure for 48 h; the sample was stored in a sealed container at low temperature.

[0080] (4) Preparation of 2[TEA][CA] (triethanolamine citric acid, molar ratio 2:1)

[0081] Citric acid 3.84 g and triethanolamine 5.97 g were weighed, and the citric acid was dissolved in 30 mL of ethanol; triethanolamine was added, and the mixture was stirred for 4 h to obtain a white emulsion; ethanol was removed using a rotary evaporator to obtain a colorless to light yellow clear viscous liquid; after being sucked out while hot, it was dried under reduced pressure for 48 h; the sample was stored in a sealed container at low temperature.

[0082] (5) Preparation of 3[TEA][CA] (triethanolamine citric acid, molar ratio 3:1)

[0083] Weigh citric acid 3.84g, and triethanolamine 8.95g; add 30mL ethanol to dissolve citric acid; add triethanolamine, stir and mix for 4h to obtain a white emulsion; use a rotary evaporator to remove ethanol to obtain a colorless to light yellow clear viscous liquid; after hot suction, dry under reduced pressure for 48h; the obtained sample is stored at low temperature after sealing.

[0084] Example 2 [TEA][LOA] (triethanolamine linoleic acid, molar ratio 1:1) for improving the transdermal of protein collagen

[0085] 1. Preparation of test samples

[0086] 1.1 Preparation of [TEA][LOA] (triethanolamine linoleic acid, molar ratio 1:1)

[0087] See Example 1.

[0088] 1.2 Preparation of blank emulsion base and blank DES emulsion base

[0089] Prescription:

[0090] Process: weigh each excipient, disperse xanthan gum and carbomer 980 in propylene glycol and glycerol, after adding water, stir and mix uniformly in water bath at 80℃; for blank DES emulsion base, add [TEA][LOA] again, continue to stir and mix uniformly. Mix the ingredients in phase A, and keep warm to 80℃; add phase A to phase B, homogenize at 8000rpm for 3min; cool to 40-50℃, add phenoxyethanol; then adjust the pH to 5.5-6.0 with NaOH (10%); stir uniformly.

[0091] 1.3 Preparation of emulsions of FITC collagen with different molecular weights

[0092] FITC-labeled collagen was purchased from Ankejin Biological, and according to the molecular weight, there are low molecular weight FITC collagen, medium molecular weight FITC collagen and high molecular weight FITC collagen.

[0093] Weigh 3mg of low molecular weight FITC collagen and 7mg of unlabelled low molecular weight collagen, add 1mL of purified water, vortex for 2min to completely dissolve, to obtain a low molecular weight FITC collagen stock solution (1%); prepare medium molecular weight FITC collagen stock solution (1%) and high molecular weight FITC collagen stock solution (1%) in the same way.

[0094] FITC low molecular weight collagen mother liquor mixed with blank emulsion matrix in a ratio of 1:9, using high shear homogenization emulsifier to mix evenly, to get T1 low molecular weight collagen ordinary emulsion (0.1%); FITC medium and high molecular weight collagen mother liquor mixed with blank emulsion matrix in a ratio of 1:19, using high shear homogenization emulsifier to mix evenly, to get T2 medium molecular weight collagen ordinary emulsion (0.05%), T3 high molecular weight collagen ordinary emulsion (0.05%). The same method to get T4 low molecular weight collagen DES emulsion (0.1%), T5 medium molecular weight collagen DES emulsion (0.05%), T6 high molecular weight collagen DES emulsion (0.05%). The same method to get T7 low molecular weight collagen sublinoleic acid emulsion (0.1%).

[0095] 2.1 VPT examination

[0096] Franz diffusion cell was used to carry out IVPT test with Bama miniature pig (age ≤3 months) ex vivo skin; 24h later, the receiving liquid (Trans-Skin Penetration) was taken; after the end of the test, the skin was washed and divided into two parts for weighing; one part was subjected to tissue disruption to obtain the intradermal retention extraction liquid (Skin Deposition); the other part was subjected to frozen section, and after DAPI staining, laser confocal microscope was used to observe the intradermal distribution of collagen. The obtained receiving liquid and skin extraction liquid were detected for fluorescence intensity using an enzyme label instrument, and the content of FITC labeled collagen in the sample was calculated.

[0097] 3. Results and conclusions

[0098] The intradermal retention amount per unit area of each sample is shown in Figure 1. Low molecular collagen (T1) has a certain intradermal retention amount, which is significantly higher than that of medium molecular collagen (T2) (p=0.023<0.05), and high molecular collagen (T3) is difficult to penetrate into the skin to form retention. The intradermal retention of low molecular collagen (T4) using DES penetration is higher, which has a significant difference compared with T1 (p=0.029<0.05).

[0099] The intradermal distribution of low molecular weight collagen ordinary emulsion is shown in Figure 2. The epidermis layer and hair follicle part of the skin show a certain intensity of green fluorescence, and part of the skin folds can see the fluorescence of the residual sample (T1-4); it is shown that low molecular collagen can penetrate into the epidermis layer and hair follicle.

[0100] The intradermal distribution of medium molecular weight collagen ordinary emulsion is shown in Figure 3. The epidermis layer of the skin shows weak green fluorescence, and part of the green fluorescence can be seen in the hair follicle; it is shown that medium molecular collagen also penetrates into the epidermis layer in a small amount, but the penetration amount is smaller than that of low molecular collagen.

[0101] The intradermal distribution of high molecular weight collagen ordinary emulsion is shown in Figure 4. The green fluorescence is dim. The epidermis and hair follicles of some samples show very weak green fluorescence, but there is no significant difference compared with the control skin. This shows that high molecular weight collagen is difficult to penetrate the skin.

[0102] The intradermal distribution of low molecular weight collagen DES emulsion is shown in Figure 5. The green fluorescence in the epidermis and hair follicles is the strongest. This shows that the use of DES penetration technology can improve the penetration of low molecular collagen.

[0103] The intradermal distribution of medium molecular weight collagen DES emulsion is shown in Figure 6. Green fluorescence of a certain intensity can be seen in the epidermis and hair follicles, which is slightly higher than T2. This shows that the use of DES penetration can improve the penetration of medium molecular collagen.

[0104] The intradermal distribution of high molecular weight collagen DES emulsion is shown in Figure 7. There is weak green fluorescence in some shallow pores and epidermis. This shows that DES can make large molecular weight collagen penetrate to a certain extent. Combined with Figure 1, it can be seen that the amount of large molecular weight collagen penetrating is still very small and difficult to detect.

[0105] The intradermal distribution of low molecular weight collagen linoleic acid emulsion is shown in Figure 8. There is almost no green fluorescence in the epidermis of the skin, and the fluorescence in the hair follicles is also very weak. The overall intensity of fluorescence distribution is even weaker than that of the low molecular weight collagen ordinary emulsion group. This shows that the addition of linoleic acid not only fails to promote the penetration of collagen, but also hinders the release of collagen and deteriorates its transdermal penetration.

[0106] Example 3 [TEA][LOA] (triethanolamine linoleic acid, molar ratio 1:1) for improving the penetration of collagen in the skin of Bama miniature pigs

[0107] 1. Preparation of test samples

[0108] 1.1 Preparation of [TEA][LOA] (triethanolamine linoleic acid, molar ratio 1:1)

[0109] See Example 1.

[0110] 1.2 Preparation of blank cream base and blank DES cream base

[0111] Prescription:

[0112] Process: each auxiliary material is weighed, xanthan gum and microcrystalline cellulose are dispersed in glycerol and 1,3-butanediol, after adding water, stirring and mixing uniformly in water bath at 75℃; for the blank DES cream base, add [TEA][LOA] again, continue to stir and mix uniformly. Mix the ingredients in phase A, and keep warm to 75℃; add phase A to phase B, homogenize at 6000 rpm for 5 min; cool to 50-55℃, add phenoxyethanol; then adjust the pH to 6.0-7.0 with citric acid (10% solution); stir until completely cooled.

[0113] 1.3 Preparation of FITC collagen cream

[0114] Low molecular weight FITC labeled collagen was purchased from Ankegen Biotech. 3 mg of low molecular weight FITC collagen and 7 mg of unlabeled low molecular weight collagen were mixed, 1 mL of purified water was added, and vortexed for 2 min to completely dissolve, to obtain a low molecular weight FITC collagen stock solution (1%).

[0115] The low molecular weight FITC collagen stock solution was mixed with the blank cream base at a ratio of 1:9, and a high shear homogenizer was used to mix uniformly to obtain a low molecular weight collagen ordinary cream (0.1%); the same method was used to obtain a low molecular weight collagen DES cream (0.1%).

[0116] 2. Study on the distribution kinetics of collagen cream in the skin of Bama miniature pigs

[0117] Eight Bama miniature pigs were divided into groups A and B, each group with 2 males + 2 females. The animals in group A were given low molecular weight collagen ordinary cream (0.1%), and the animals in group B were given low molecular weight collagen DES cream (0.1%).

[0118] The back of the animal was shaved before administration (using an electric shaver to avoid skin damage), and 4 areas were selected on both sides of the center line, a total of 8 areas, namely left 1-4 and right 1-4. Each area was 3 cm*3 cm, the left and right areas were spaced 10 cm apart, and the same side areas were spaced 5 cm apart. The control sampling area in the middle 1 was on the neck of the pig on the center line of the back, and the longitudinal distance from left 1 and right 1 was also 5 cm. The specific diagram is shown in Figure 9, and about 90 mg of the test product was evenly applied to the specified administration site of the pig (the administration area is shown in Figure 9).

[0119] After the animals were euthanized, the administration site was cleaned and then taped with medical adhesive tape for 20 times to remove the surface residual test product. A skin sampling drill with a diameter of 15 mm was used to take 2 pieces of skin with a diameter of 15 mm and a depth of about 8 mm from each administration site (one piece was subjected to stratification and then subjected to biological sample detection, and the other piece was reserved), and the subcutaneous fat was removed. The removed skin was placed flat on dry ice with the epidermis facing down for storage.

[0120] Homogenate of skin tissue: each skin tissue was weighed, and 2-8 °C pre-cooled 50% methanol water was added at a weight volume ratio of 1:2. The tissue homogenate was prepared using a multi-tube homogenizer. The tissue homogenate was centrifuged at 12000 rpm for 5 min, and 900 μL of supernatant was taken into a 1.5 mL centrifuge tube. After blowing off the solvent with a nitrogen blowing instrument, 120 μL of 50% methanol water was used to re-dissolve the test solution. 100 μL of the test solution was taken to a 96-well plate, and the fluorescence intensity was detected using an enzyme-labeled instrument to calculate the content of FITC-labeled collagen in the sample.

[0121] 3. Results and discussion

[0122] The summary of skin distribution kinetic parameters is shown in Table 1, and the intradermal distribution time curve is shown in Figure 10. The test results show that the AUC last and C max of the collagen DES cream are 2.8 times and 3.5 times that of the ordinary collagen cream, respectively. This indicates that DES can significantly improve the bioavailability of collagen.

[0123] Table 1 Summary of skin distribution kinetic parameters of collagen cream in Bama minipigs

[0124] Example 4 [TEA][OLA] (triethanolamine oleic acid, molar ratio 1:1) for improving the efficacy of collagen nutritional repair

[0125] 1. Preparation of test samples

[0126] 1.1 Preparation of [TEA][OLA] (triethanolamine oleic acid, molar ratio 1:1)

[0127] See Example 1.

[0128] 1.2 Preparation of blank mask liquid matrix and blank DES mask liquid matrix

[0129] Prescription:

[0130] Process: weigh each auxiliary material, disperse and wet carbomer U-20 in water; disperse xanthan gum in glycerol and add to the carbomer U-20 dispersion, and heat to 80 °C; for the blank DES mask liquid matrix, add [TEA][OLA] and continue to stir until uniform. Mix the ingredients in phase A and keep warm to 80 °C; add phase A to phase B and homogenize at 7500 rpm for 3 min; cool to 35-40 °C, add phenoxyethanol; then adjust the pH to 5.0-5.5 with sodium hydroxide (10% solution); stir until completely cooled.

[0131] 1.3 Preparation of compound collagen mask

[0132] Weigh 10 mg of low molecular weight collagen, 10 mg of medium molecular weight collagen and 5 mg of high molecular weight collagen, add 2.5 mL of purified water, vortex for 2 min to completely dissolve, and obtain a composite collagen stock solution (1%).

[0133] Mix the composite collagen stock solution with the blank ordinary mask liquid matrix at a ratio of 1:9, mix uniformly using a high shear homogenizer, and obtain a composite collagen ordinary mask liquid (0.1%); mix the composite collagen stock solution and the blank DES mask liquid matrix by the same method to obtain a composite collagen DES mask liquid (0.1%).

[0134] Mask preparation: Cut the silk mask substrate into a rectangle of 2 cm * 3 cm. Take another 100 mL beaker, add 50 mL of the prepared mask liquid, then immerse the mask substrate completely in the mask liquid, stir and disperse, and soak for more than 3 h.

[0135] 2. Nutritional repair efficacy study of collagen DES mask

[0136] Divide 16 female SD rats into A, B, C, and D groups, 4 rats in each group, and mark each animal with an ear tag. The animals in group A are given a composite collagen ordinary mask (0.1%), the animals in group B are given a composite collagen DES mask (0.1%), the animals in group C are given a composite collagen oleic acid mask (0.1%), and the animals in group D are given a saline mask.

[0137] Animal treatment: One day before administration, remove the back hair of the animals using depilatory cream. The next day, use VeporMeter to measure the trans-epidermal water loss (TEWL) value of the back skin, measure 3 areas on the back of each rat, and take the average value as the baseline value. Then use a roller to treat the back skin of the rats, and measure the TEWL value of 3 areas on the back skin at this time, and take the average value as the D0 value.

[0138] Administration: The back skin is outward, and the rats are fixed on the rat plate. Then clamp the mask to no liquid dripping, and apply it to the back skin of the rats. After 20 min of application, tear off the mask, and release the rats back to the rat cage for normal feeding.

[0139] Observation and testing: 8 h after the end of mask application, observe the condition of the back of the rats, and measure the TEWL value of 3 areas on the back skin, and take the average value as the TEWL value of each animal on the same day.

[0140] Administration frequency and cycle: Mask application is performed every morning, and observation and TEWL value testing are performed in the afternoon, for 10 consecutive days.

[0141] 3. Results and discussion

[0142] The change of TEWL value of each mouse was counted, and the results were shown in Figure 11. The results showed that the TEWL value of the back skin of the rats in group D (normal saline group) recovered the slowest; the TEWL value of the back skin of the rats in group A (ordinary collagen mask group) recovered slightly faster than that in group D; the TEWL value of the back skin of the rats in group C (collagen oleic acid mask group) recovered slightly faster than that in group D; and the recovery speed of group B (collagen DES mask group) was the fastest. This shows that the addition of DES can enhance the nutritional repair effect of collagen and help the rapid recovery of damaged skin; at the same time, it shows that the use of oleic acid alone has no significant effect on the nutritional repair effect of collagen, and after forming a triethanolamine complex, its enhancing effect is significantly improved.

[0143] Example 5 [TEA][LOA] (triethanolamine linoleic acid, molar ratio 1:1) for improving the transdermal delivery of nucleic acid drug siRNA

[0144] 1. Preparation of test samples

[0145] 1.1 Preparation of [TEA][LOA] (triethanolamine linoleic acid, molar ratio 1:1)

[0146] The preparation of [TEA][LOA] is described in Example 1.

[0147] 1.2 Preparation of siRNA-Cy5 stock solution

[0148] The siRNA-Cy5 used was purchased from Genki Gene. According to the instructions, 815 μL of DEPC water was added to a single tube of siRNA-Cy5 sample to obtain a siRNA-Cy5 stock solution with a concentration of 200 μM.

[0149] 1.3 Preparation of samples to be tested

[0150] T1 (naked siRNA solution): 100 μL of siRNA-Cy5 stock solution was taken, 300 μL of DEPC water was added, and vortexed to mix. Store at 4°C in the dark for future use.

[0151] T2 (siRNA-DES solution): 0.2 g of [TEA][LOA] was taken, 100 μL of DEPC water was added, and vortexed to mix; 100 μL of siRNA-Cy5 stock solution was added, and vortexed to mix. Store at 4°C in the dark for future use.

[0152] T3 (siRNA-TEA solution): 0.2 g of triethanolamine was taken, 100 μL of DEPC water was added, and vortexed to mix; 100 μL of siRNA-Cy5 stock solution was added, and vortexed to mix. Store at 4°C in the dark for future use.

[0153] 2. IVPT investigation

[0154] Franz diffusion cell was used to carry out IVPT test with Bama miniature pigs (age ≤ 3 months) in vitro skin; the receiving liquid was taken after 24 h (Trans-Skin Penetration); after the end of the test, the skin was washed, and the skin was divided into two parts and weighed; one part was subjected to tissue disruption to obtain the skin deposition extraction liquid (Skin Deposition); the other part was subjected to frozen section, and after DAPI staining, the intracutaneous distribution of collagen was observed using a laser confocal microscope. The receiving liquid and the skin extraction liquid were detected for fluorescence intensity using HPLC-FLD, and the content of siRNA-Cy5 in the sample was calculated.

[0155] 3. Results and discussion

[0156] As shown in FIG. 12, there is little difference in the residual of each sample in the stratum corneum (SC); since the stratum corneum is thin and has low storage capacity, it is difficult to detect the difference in each group; the penetration of each sample in the epidermis (Epidermis) is significantly different, and compared with the Naked siRNA solution group, the penetration of the siRNA-DES solution group is significantly improved (P < 0.01); the siRNA-TEA group does not show a penetration-promoting effect; in the dermis (Dermis), the penetration of each group is very low, indicating that it is difficult to deliver siRNA to the dermis.

[0157] As shown in FIG. 13, in the T1 (Naked siRNA solution) group, only part of the samples in the stratum corneum has partial residual fluorescence, and the epidermis and dermis under the stratum corneum have no obvious red fluorescence; it is believed that siRNA in the form of simple aqueous solution cannot penetrate into the skin.

[0158] As shown in FIG. 14, in the T2 (siRNA-DES solution) group, the stratum corneum and epidermis have significant fluorescence; in some samples, the dermis also has more red fluorescence distribution; it is shown that the penetration-promoting effect of [TEA][LOA] is obvious, and siRNA can penetrate into the epidermis and part of the dermis.

[0159] As shown in FIG. 15, in the T3 (siRNA-TEA solution) group, only part of the samples in the stratum corneum has partial residual fluorescence, and the epidermis and dermis under the stratum corneum have no obvious red fluorescence; it is shown that triethanolamine alone cannot promote the transdermal penetration of siRNA.

[0160] Example 6 3[TEA][CA] (triethanolamine citric acid, molar ratio 3:1) for improving the transdermal penetration of polysaccharide sodium hyaluronate

[0161] 1. Preparation of test samples

[0162] 1.1 Preparation of 3[TEA][CA] (triethanolamine citric acid, molar ratio 3:1)

[0163] See Example 1.

[0164] 1.2 Preparation of Rhodamine-labeled sodium hyaluronate (RhB-HA) stock solution (1%)

[0165] Weigh 0.1 g of RhB-labeled sodium hyaluronate and 9.9 g of purified water; while stirring, slowly add the sodium hyaluronate to the water; continue stirring until the sodium hyaluronate is completely dispersed to form a homogeneous solution.

[0166] 1.3 Preparation of samples with different DES concentrations

[0167] Weigh 0.5g of RhB-HA stock solution, add 0g, 1g, 2g and 3g of [TEA][CA], and then add water to make up to 5g. Mix well to obtain RhB-HA ordinary solution, 20% DES solution, 40% DES solution and 60% DES solution.

[0168] 2. IVPT Investigation

[0169] Using excised skin from Bama miniature pigs (≤3 months old), in Fran z IVPT assay was performed in the diffusion cell; the receiving solution (trans-skin penetration) was collected after 24 hours; after the experiment, the skin was washed, and the skin was divided into frozen sections. After DAPI staining, the intradermal distribution of sodium hyaluronate was observed using a fluorescence microscope.

[0170] 3. Results and Discussion

[0171] The intradermal distribution of RhB-HA in ordinary solution is shown in Figure 16. Comparing it with the DAPI map, it can be observed that only the residual stratum corneum emits fluorescence, while the epidermis and dermis under the stratum corneum do not show obvious red fluorescence. Furthermore, in the area where the stratum corneum has been completely removed, no red fluorescence can be observed in the epidermis and dermis.

[0172] The intradermal distribution of RhB-HA 20% DES solution is shown in Figure 17. The thickness of the red fluorescence in the epidermis is uniform, and the residual stratum corneum has no effect on the penetration thickness of the dermis. Red fluorescence can also be observed in the dermis. Fluorescence is also present in the hair follicle area, which is in line with expectations.

[0173] The intradermal distribution of RhB-HA 40% DES solution is shown in Figure 18. In the dark areas, some red fluorescence is visible, but the low exposure time selected results in a darker image, and only some red fluorescence can be observed in the epidermal layer.

[0174] The intradermal distribution of RhB-HA 60% DES solution is shown in Figure 19. In the dark area, a continuous and uniform red fluorescence was observed in the epidermis layer. However, the intensity of the red fluorescence was weaker than that of the RhB-HA 20% DES group.

[0175] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, and the like made within the spirit and principle of the present application should be included in the scope of protection of the present application.

Claims

1. Use of a triethanolamine complex in improving transdermal penetration of a macromolecular substance and / or improving efficacy of a macromolecular substance; the triethanolamine complex is composed of triethanolamine and a fatty acid, or an organic acid; the fatty acid is selected from oleic acid, linoleic acid; the organic acid is selected from citric acid. The triethanolamine complex is selected from a complex composed of triethanolamine and linoleic acid, a complex composed of triethanolamine and oleic acid, a complex composed of triethanolamine and citric acid.

2. Use according to claim 1, characterized in that, Preferably, the molar ratio of triethanolamine to fatty acid, or organic acid in the triethanolamine complex is 1:10-10:1, preferably 1:5-5:1; preferably, the triethanolamine complex is selected from any one of the following: triethanolamine linoleic acid [TEA][LOA], triethanolamine oleic acid [TEA][OLA], triethanolamine citric acid [TEA][CA]; Preferably, the macromolecular substance is selected from a protein substance, a nucleic acid substance, a polysaccharide substance; Preferably, improving transdermal penetration of a macromolecular substance and / or improving efficacy of a macromolecular substance comprises at least one of the following: improving transdermal absorption of a macromolecular substance, improving bioavailability of a macromolecular substance, improving efficacy of a macromolecular substance. The use is specifically: use of a triethanolamine complex in improving transdermal penetration of a protein substance and / or improving efficacy of a protein substance; preferably, the protein substance is collagen.

3. Use according to claim 1 or 2, characterized in that, The use is specifically: use of a triethanolamine complex in improving transdermal penetration of a nucleic acid substance; preferably, the nucleic acid substance is selected from a nucleic acid drug, preferably including a DNA drug, an RNA drug, such as siRNA.

4. Use according to claim 1 or 2, characterized in that, The use is specifically: use of a triethanolamine complex in improving transdermal penetration of a polysaccharide substance; preferably, the polysaccharide substance is, for example, hyaluronic acid (sodium).

5. Use according to claim 1 or 2, characterized in that, 6. A composition comprising a triethanolamine complex and a macromolecular substance; the triethanolamine complex has the definition of any one of claims 1-2. The composition comprises the triethanolamine complex and a protein substance (such as collagen); preferably, the composition comprises a protein substance (such as collagen), a matrix comprising a triethanolamine complex; preferably, the collagen comprises low molecular weight collagen, medium molecular weight collagen, high molecular weight collagen; preferably, the content of the protein substance (such as collagen) is 0.001-1.0%, preferably 0.01%-0.50%.

7. The composition of claim 6, wherein, The composition comprises the triethanolamine complex and a nucleic acid substance; preferably, the nucleic acid substance is selected from a nucleic acid drug, preferably including a DNA drug, an RNA drug, such as siRNA; 8. The composition of claim 6, wherein, Preferably, the content of the triethanolamine complex is 1%-80%, preferably 5%-70%; Preferably, the molar ratio of the triethanolamine complex and the nucleic acid substance is 5*10 3 : 1 to 100*10 3 : 1, preferably 15*10 3 : 1 to 30*10 3 :

1. Alternatively, the composition comprises the triethanolamine complex and a polysaccharide substance; preferably, the polysaccharide substance is, for example, hyaluronic acid (sodium). Preferably, the mass ratio of the above-mentioned triethanolamine complex and polysaccharide substance is 50:1-1000:1, preferably 100:1-800:1; ​ Preferably, the triethanolamine complex is present in an amount of 1% to 80%, preferably 5% to 70%.

9. A substrate comprising the triethanolamine complex of any one of claims 1-2, and a pharmaceutically or cosmetically acceptable excipient.

10. A facial mask comprising the composition of claim 7 and a facial mask substrate.

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