CN113876623A - Application of hyaluronic acid oligosaccharide composition in resisting skin aging and promoting collagen generation - Google Patents
Application of hyaluronic acid oligosaccharide composition in resisting skin aging and promoting collagen generation Download PDFInfo
- Publication number
- CN113876623A CN113876623A CN202111123265.7A CN202111123265A CN113876623A CN 113876623 A CN113876623 A CN 113876623A CN 202111123265 A CN202111123265 A CN 202111123265A CN 113876623 A CN113876623 A CN 113876623A
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- Prior art keywords
- hyaluronic acid
- acid oligosaccharide
- mass ratio
- oligosaccharide composition
- composition
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Links
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Abstract
The invention provides application of a hyaluronic acid oligosaccharide composition in resisting skin aging, wherein the hyaluronic acid oligosaccharide composition comprises hyaluronic acid oligosaccharides with a uronic acid structure at a reducing end. The hyaluronic acid oligosaccharide composition has a small molecular weight and has uronic acid at the reducing end. Can remarkably promote the generation of dermal fibroblast collagen, increase the content of the collagen in the dermis, reduce the generation of wrinkles and have certain anti-aging activity. Meanwhile, the unique triple-helix structure of the collagen can strongly lock 30 times of water, so that the skin is durably moist, glossy and tender. The hyaluronic acid oligosaccharide composition can be used for preparing anti-aging and moisturizing cosmetics, medical instruments such as facial injections, microneedle products and oral health care products.
Description
Technical Field
The invention belongs to the technical field of bioengineering, and particularly relates to an application of a hyaluronic acid oligosaccharide composition in resisting skin aging and promoting collagen generation.
Background
Hyaluronic Acid (HA) is a glycosaminoglycan ubiquitous in the extracellular matrix and consists of a disaccharide repeat sequence of N-acetylglucosamine and glucuronic acid. Hyaluronic acid is widely used in the fields of medicine, food, cosmetics and the like. The molecular weight of hyaluronic acid is one of the basic parameters for characterizing the hyaluronic acid, and the biological properties of HA are closely related to the molecular weight of the HA. Macromolecular hyaluronic acid (HMW-HA) generally functions to maintain cellular homeostasis, while small molecular hyaluronic acid (LMW-HA) and oligomeric hyaluronic acid (o-HA) function as biological activities.
The main methods for preparing small molecule hyaluronic acid are physical degradation method, chemical degradation method and enzymolysis method. The physical method mainly includes heating, irradiation and other means. The hyaluronic acid product prepared by the method has poor stability. The chemical method usually uses hydrolysis method and oxidation degradation method, which may introduce some chemical reagents, and is easy to influence the property of hyaluronic acid and the quality control of the product. The enzymolysis method is to use a specific enzyme to break the glycosidic bond in the hyaluronic acid so as to obtain the small molecule hyaluronic acid. The specificity of the cleavage of glycosidic bonds can be improved by using specific enzyme, and the micromolecule hyaluronic acid with concentrated pure molecular weight distribution and higher purity can be obtained.
Skin aging, also known as skin aging, refers to the functional aging damage of skin, which reduces the protection ability and regulation ability of skin to human body, so that the skin can not adapt to the change of internal and external environment, and the change of the overall appearance condition such as color, luster, shape, texture, etc. appears. Aging of the skin is classified into intrinsic aging and extrinsic aging. Endogenous aging refers to natural aging of the skin with aging, which is manifested by whitening of the skin, appearance of fine wrinkles, decreased elasticity, skin laxity, etc. The most prominent causes of extrinsic aging are photoaging due to sun exposure, manifested by wrinkles, loose skin, roughness, pale yellow or sallow skin discoloration, telangiectasia, formation of pigmented spots, etc.
However, the structure of the substance generally affects its biological activity, and the oligosaccharide substances also exhibit a complex and close structure-activity relationship. Non-patent document 1 (Han W, Song L, Wang Y, et al Preparation, chromatography, and inhibition of hyaluronic acid oligosaccharides in triple-negative bacterial cancers [ J ]. biomoles, 2019, 9(9): 436.) selectively produce Hyaluronic Acid Oligosaccharides (HAOs) having different degrees of polymerization and reducing ends by changing the concentration of hydrochloric acid, and data of molecular docking simulation of HAOs with CD44 and TLR4 using MOE software shows that the binding ability of HAOs to CD44 and TLR4 increases with the increase in the degree of polymerization of HAOs, while the binding ability increases significantly when the reducing end of HAOs is a GlcNAc residue, and does not change significantly when the reducing end is a GlcAAc residue. Non-patent document 2 (Yao W, Chen M, Dou X, et al, Urravel a neuroactive sHA surface pattern with neurogenesis activity by a library of defined oligosaccharides [ J ]. European journal of molecular chemistry, 2019, 163: 583. su-b.596.) discloses that sulfated hyaluronic acid (sHA) has good biological functions, and that a specific sulfation pattern plays a key role in regulating the binding pattern between glycosaminoglycan and protein, proving that sHA tetrasaccharide with 6-O-sulfation (sHA-6S) has an important role in promoting rat E18 hippocampal neuronal axonal growth in vitro. Non-patent document 3 (Solera C, Macchiane G, Maza S, et al, Chondroitin sulfate tetrasaccharides: synthesis, three-dimensional structure and interaction with midkine [ J ]. 2016.) analyzes the relative binding affinity of synthetic compounds using a fluorescence polarization competition assay and reveals the interaction between synthetic Chondroitin sulfate-like tetrasaccharides and midkine. It can be seen that differences in the degree of polymerization, spatial structure or residues of HAOs have different effects on biological activity or new functions. This is very desirable for further research. In the prior art, there has been no study on the improvement of skin aging or the promotion of collagen formation of ultra-small molecular weight hyaluronic acid having uronic acid terminal groups.
Therefore, the structure-activity relationship of HA substances is further researched to obtain more beneficial active substances and efficacies, and the structure-activity relationship HAs very important significance for expanding the application of HA.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides the application of the hyaluronic acid oligosaccharide composition in resisting skin aging and promoting collagen generation.
Specifically, the present invention relates to the following aspects:
1. use of a hyaluronic acid oligosaccharide composition for combating skin aging, wherein the hyaluronic acid oligosaccharide composition comprises a hyaluronic acid oligosaccharide of the structure of formula (I):
formula (I)
Wherein X is selected from H, K, Na, Ca or Zn, preferably Na;
n is an integer selected from 0 to 5;
in the hyaluronic acid oligosaccharide composition, the hyaluronic acid oligosaccharide,
the mass ratio of the hyaluronic acid oligosaccharide with n =1 is 35-70%, the mass ratio of the hyaluronic acid oligosaccharide with n =0 is 5-40%, the mass ratio of the hyaluronic acid oligosaccharide with n =2 is 10-50%, the mass ratio of the hyaluronic acid oligosaccharide with n =3 is 1-15%, the mass ratio of the hyaluronic acid oligosaccharide with n =4 is 0.1-10%, and the mass ratio of the hyaluronic acid oligosaccharide with n =5 is 0.01-5%.
2. The use according to item 1, characterized in that the hyaluronic acid oligosaccharide composition is resistant to skin aging by promoting collagen production and/or epidermal cell proliferation and differentiation.
3. The use according to item 1, wherein in the hyaluronic acid oligosaccharide composition, the mass ratio of hyaluronic acid oligosaccharides with n =1 is 40-60%; the mass ratio of the hyaluronic acid oligosaccharide with n =0 is 5-20%; the mass ratio of the hyaluronic acid oligosaccharide with n =2 is 20-40%; the mass ratio of the hyaluronic acid oligosaccharide with n =3 is 3-8%; the mass ratio of the hyaluronic acid oligosaccharide with n =4 is 1-5%; the mass ratio of the hyaluronic acid oligosaccharide with n =5 is 0.01-1.5%.
4. Use according to item 1, characterized in that the hyaluronic acid oligosaccharide composition has a weight-average molecular weight of less than or equal to 1 kDa.
5. Use according to item 1, characterized in that the hyaluronic acid oligosaccharide composition is applied to the skin, preferably by means of a cosmetic or medical device.
6. Use according to item 5, characterized in that the hyaluronic acid oligosaccharide composition is present in the cosmetic or medical device in a mass concentration of between 0.0001% and 5%, preferably between 0.001% and 1%.
7. Use of a hyaluronic acid oligosaccharide composition for promoting collagen production, comprising a hyaluronic acid oligosaccharide having a structure represented by formula (I):
formula (I)
Wherein X is selected from H, K, Na, Ca or Zn, preferably Na;
n is an integer selected from 0 to 5;
in the hyaluronic acid oligosaccharide composition, the hyaluronic acid oligosaccharide,
the mass ratio of the hyaluronic acid oligosaccharide with n =1 is 35-70%, the mass ratio of the hyaluronic acid oligosaccharide with n =0 is 5-40%, the mass ratio of the hyaluronic acid oligosaccharide with n =2 is 10-50%, the mass ratio of the hyaluronic acid oligosaccharide with n =3 is 1-15%, the mass ratio of the hyaluronic acid oligosaccharide with n =4 is 0.1-10%, and the mass ratio of the hyaluronic acid oligosaccharide with n =5 is 0.01-5%.
8. The use according to item 7, wherein the hyaluronic acid oligosaccharide composition is used for preparing health products for promoting collagen production, or preparing health products for protecting and strengthening viscera, or preparing health products for protecting gastric mucosa, or preparing health products for supplementing calcium, or preparing joint lubrication injection, and preferably the mass concentration of the hyaluronic acid oligosaccharide composition in the health products or the injection is 0.001% -1%.
9. The use according to item 7, wherein in the hyaluronic acid oligosaccharide composition, the mass ratio of hyaluronic acid oligosaccharides with n =1 is 40-60%; the mass ratio of the hyaluronic acid oligosaccharide with n =0 is 5-20%; the mass ratio of the hyaluronic acid oligosaccharide with n =2 is 20-40%; the mass ratio of the hyaluronic acid oligosaccharide with n =3 is 3-8%; the mass ratio of the hyaluronic acid oligosaccharide with n =4 is 1-5%; the mass ratio of the hyaluronic acid oligosaccharide with n =5 is 0.01-1.5%.
10. Use according to item 7, characterized in that the hyaluronic acid oligosaccharide composition has a weight-average molecular weight of less than or equal to 1 kDa.
The hyaluronic acid oligosaccharide composition has small molecular weight, has uronic acid at the reduction end, can remarkably promote the generation of collagen of dermal fibroblasts, increases the content of collagen in the dermis, reduces the generation of wrinkles, and has certain anti-aging activity. Meanwhile, the unique triple-helix structure of the collagen can strongly lock 30 times of water, so that the skin is durably moist, glossy and tender. The hyaluronic acid oligosaccharide composition can be used for preparing cosmetics and medical devices for resisting aging and keeping moisture. The hyaluronic acid oligosaccharide composition has the function of promoting the generation of collagen, and can be further used for preparing health-care products for promoting the generation of the collagen, or preparing health-care products for protecting and strengthening viscera, or preparing health-care products for protecting gastric mucosa, or preparing health-care products for supplementing calcium, or preparing joint lubricating injection.
Drawings
Fig. 1 is a liquid phase diagram of a hyaluronic acid oligosaccharide composition.
Fig. 2 is a graph of mass spectrum total ion current peaks of hyaluronic acid oligosaccharide compositions.
FIG. 3 is a graph of the ionic strength of hyaluronic acid disaccharide (HA 2).
Fig. 4 is a graph of the ionic strength of hyaluronic acid tetrasaccharide (HA 4).
Fig. 5 is a graph of the ionic strength of hyaluronic acid hexasaccharide (HA 6).
Fig. 6 is a graph of the ionic strength of hyaluronic acid octasaccharide (HA 8).
Fig. 7 is a graph showing the ionic strength of hyaluronic acid decasaccharide (HA 10) and hyaluronic acid decadisaccharide (HA 12).
FIG. 8 shows the collagen I secretion content of fibroblasts after using samples 1-1 and 2-1.
FIG. 9 shows the collagen I secretion levels of fibroblasts after using samples 1, 1-2, and 1-3.
Fig. 10 shows the structure of the 3D full-thickness skin model after using samples 1 and 2.
Fig. 11 shows a microscopic photograph of the skin penetration of sample 4.
Detailed Description
The present invention is further illustrated by the following examples, which are intended to be purely exemplary of the invention and are not intended to be limiting.
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in experimental or practical applications, the materials and methods are described below. In case of conflict, the present specification, including definitions, will control, and the materials, methods, and examples are illustrative only and not intended to be limiting. The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Human skin ages naturally with age or with environmental stimuli, resulting in skin aging. Natural aging is endogenous aging, which is manifested by whitening skin, fine wrinkles, decreased elasticity, skin laxity, etc., and environmental stimulation is exogenous aging, such as photoaging caused by sun exposure. If the skin is not well maintained or deteriorates with age, dead skin adheres to the surface of the skin without falling off, thereby causing a series of problems and seriously affecting beauty.
In order to solve the problem of skin aging, the present invention provides a use of a hyaluronic acid oligosaccharide composition for anti-skin aging, the hyaluronic acid oligosaccharide composition comprising a hyaluronic acid oligosaccharide having a structure represented by formula (I):
formula (I)
Wherein n is an integer selected from 0 to 5;
x is selected from H, K, Na, Ca or Zn, preferably Na.
In the hyaluronic acid oligosaccharide composition, the hyaluronic acid oligosaccharide,
the mass ratio of the hyaluronic acid oligosaccharide with n =1 is 35-70%, the mass ratio of the hyaluronic acid oligosaccharide with n =0 is 5-40%, the mass ratio of the hyaluronic acid oligosaccharide with n =2 is 10-50%, the mass ratio of the hyaluronic acid oligosaccharide with n =3 is 1-15%, the mass ratio of the hyaluronic acid oligosaccharide with n =4 is 0.1-10%, and the mass ratio of the hyaluronic acid oligosaccharide with n =5 is 0.01-5%.
The causes of skin aging are mainly reflected by the following points: 1. alteration of the extracellular matrix of the dermal layer. Collagen is a major component of the dermal extracellular matrix and accounts for approximately 90% of proteins in human dermis. The types of collagen are many, and the common types are type I, type II, type III, type V and type XI. The proteins in the dermis consist primarily of type i collagen (80%) and a small amount of type iii collagen (10%), which gives the skin its strength and elasticity. With age, collagen fibers in the skin decrease, causing the skin to lose elasticity and wrinkles to develop. Collagen in the dermis is mainly secreted by fibroblasts, and reduction of collagen secreted by the fibroblasts is also one of the major causes of aging and wrinkle generation. 2. A change in the structure of the base layer. After aging, the stratum basale structure of human skin is relaxed and the cell junction is loose, so that the dermal-epidermal material exchange efficiency is reduced. Thus, the epidermis is not nourished enough, and the epidermal cells cannot proliferate and differentiate normally. Further, the epidermis becomes thin and becomes loose.
In view of the above-mentioned major causes of skin aging, the hyaluronic acid oligosaccharide composition can be used for anti-skin aging by promoting collagen production and/or epidermal cell proliferation and differentiation.
In a specific embodiment, the hyaluronic acid oligosaccharide composition is anti-skin aging by promoting collagen production.
In a particular embodiment, the hyaluronic acid oligosaccharide composition is used for resisting skin aging by promoting epidermal cell proliferation and differentiation.
In a particular embodiment, the hyaluronic acid oligosaccharide composition can be used for resisting skin aging by promoting collagen production and epidermal cell proliferation and differentiation.
The hyaluronic acid oligosaccharide or hyaluronic acid oligosaccharide (oligosaccharide of HA, abbreviated as oligo-HA) in the invention HAs a molecular weight of 104A hyaluronic acid molecule fragment having a monosaccharide residue number of 2 to 25 (generally 4 to 16) below Da. oligo-HA belongs to a small molecule polysaccharide, and its properties are very different from those of ordinary hyaluronic acid. The research shows that Oligo-HA HAs the functions of resisting oxidation, regulating immunity, resisting inflammation, promoting wound healing and promoting angiogenesisAnd biological activity of resisting tumor, etc. More importantly, the small molecular size of the plant extract can permeate into the horny layer of the skin to play the effects of deep moisturizing and nourishing, and can be widely applied to cosmetics.
The hyaluronic acid oligosaccharide composition comprises hyaluronic acid oligosaccharide with a structure shown in a formula (I):
formula (I)
As can be seen from formula (I), the reducing end of the hyaluronic acid oligosaccharide of the present invention is an uronic acid structure.
Wherein n is selected from an integer of 0-5, for example n can be 0, 1, 2, 3, 4 or 5, X is selected from H, K, Na, Ca or Zn, preferably Na. The hyaluronic acid oligosaccharide is disaccharide when n =0, tetrasaccharide when n =1, hexasaccharide when n =2, octasaccharide when n =3, decasaccharide when n =4, and decasaccharide when n = 5. Therefore, in the hyaluronic acid oligosaccharide composition, the mass ratio of tetrasaccharide is 35-70%; the mass ratio of the disaccharide is 5-40%; the mass percentage of the hexaose is 10-50%; the mass ratio of the octaose is 1-15%; the mass ratio of the decaose is 0.1-10%; the mass ratio of the dodecasaccharide is 0.01-5%.
The mass ratio of the hyaluronic acid oligosaccharide tetrasaccharide is 35 to 70%, and may be, for example, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 31%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, preferably 40 to 60%.
The mass ratio of the hyaluronic acid oligosaccharide disaccharide is 5-40%, for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, preferably 5-20%.
The mass ratio of the hyaluronic acid oligosaccharide hexasaccharide is 10 to 50%, for example, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, preferably 20 to 40%.
The ratio of the hyaluronic acid oligosaccharide octasaccharide may be 1 to 15% by mass, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, preferably 3 to 8%.
The mass ratio of the hyaluronic acid oligosaccharide decasaccharide is 0.1-10%, and may be, for example, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, preferably 1-5%.
The mass ratio of the hyaluronic acid oligosaccharide decabiose is 0.01 to 5%, and may be, for example, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 3%, 4%, 5%, preferably 0.01 to 1.5%.
In a specific embodiment, in the hyaluronic acid oligosaccharide composition, the mass ratio of hyaluronic acid disaccharide is 5-40%, the mass ratio of hyaluronic acid tetrasaccharide is 35-70%, the mass ratio of hyaluronic acid hexasaccharide is 10-50%, the mass ratio of hyaluronic acid octasaccharide is 1-15%, the mass ratio of hyaluronic acid decasaccharide is 0.1-10%, and the mass ratio of hyaluronic acid decasaccharide is 0.01-5%.
In a specific embodiment, in the hyaluronic acid oligosaccharide composition, the mass ratio of hyaluronic acid disaccharide is 5-20%, the mass ratio of hyaluronic acid tetrasaccharide is 40-60%, the mass ratio of hyaluronic acid hexasaccharide is 20-40%, the mass ratio of hyaluronic acid octasaccharide is 3-8%, the mass ratio of hyaluronic acid decasaccharide is 1-5%, and the mass ratio of hyaluronic acid decasaccharide is 0.01-1.5%.
In a specific embodiment, in the hyaluronic acid oligosaccharide composition, the mass ratio of hyaluronic acid disaccharide is 5-10%, the mass ratio of hyaluronic acid tetrasaccharide is 45-55%, the mass ratio of hyaluronic acid hexasaccharide is 30-40%, the mass ratio of hyaluronic acid octasaccharide is 2-8%, the mass ratio of hyaluronic acid decasaccharide is 1-2%, and the mass ratio of hyaluronic acid decasaccharide is 0.01-1%.
In a specific embodiment, in the hyaluronic acid oligosaccharide composition, the mass ratio of hyaluronic acid disaccharide is 10%, the mass ratio of hyaluronic acid tetrasaccharide is 50%, the mass ratio of hyaluronic acid hexasaccharide is 33%, the mass ratio of hyaluronic acid octasaccharide is 5%, the mass ratio of hyaluronic acid decasaccharide is 1%, and the mass ratio of hyaluronic acid decasaccharide is 1%.
In a specific embodiment, in the hyaluronic acid oligosaccharide composition, the mass ratio of hyaluronic acid disaccharide is 9%, the mass ratio of hyaluronic acid tetrasaccharide is 49%, the mass ratio of hyaluronic acid hexasaccharide is 32%, the mass ratio of hyaluronic acid octasaccharide is 7%, the mass ratio of hyaluronic acid decasaccharide is 2%, and the mass ratio of hyaluronic acid decasaccharide is 1%.
Further, the hyaluronic acid oligosaccharide composition may have a weight average molecular weight of 1kDa or less, e.g. 1kDa, 990Da, 980Da, 970Da, 960Da, 950Da, 940Da, 930Da, 920Da, 910Da, 900Da, 890Da, 880Da, 870Da, 860Da, 850Da, 840Da, 830Da, 820Da, 810Da, 800Da, 790Da, 780Da, 770Da, 760Da, 750Da, 740Da, 730Da, 720Da, 710Da, 700 Da.
In the anti-skin aging use of the present invention, the hyaluronic acid oligosaccharide composition may be directly or indirectly applied to the skin, for example, by external application, injection, oral administration, or the like.
In the use for anti-skin aging according to the present invention, the hyaluronic acid oligosaccharide composition can be used for cosmetics, medical devices, and further applied to the skin. For example, the hyaluronic acid oligosaccharide composition may be formulated into cosmetics, alone or together with other active ingredients, for anti-skin aging.
Further, when the hyaluronic acid oligosaccharide composition is used for cosmetics and medical instruments, the mass concentration of the hyaluronic acid oligosaccharide composition used in cells is 0.0001-0.1%. The hyaluronic acid oligosaccharide composition may be present in the cosmetic or medical device at a mass concentration of 0.0001% to 5%, for example, 0.0001%, 0.001%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, preferably 0.001% to 1%, in terms of cell-human facial skin surface area and transdermal condition of the hyaluronic acid oligosaccharide composition.
The invention also provides application of the hyaluronic acid oligosaccharide composition in promoting collagen production.
The internal organs and tissues contain collagen, the collagen is arranged below the epidermal structures of the internal organs, and the collagen can protect and strengthen the internal organs, so the hyaluronic acid oligosaccharide composition can be used for preparing health-care products for protecting and strengthening the internal organs.
The collagen is the main component of the muscle tissue, can provide required nutrition for the muscle and protect the gastric mucosa, so the hyaluronic acid oligosaccharide composition can be used for preparing the health care product for protecting the gastric mucosa.
The collagen also forms a calcium attachment net frame to lock bone calcium and prevent calcium loss, so the hyaluronic acid oligosaccharide composition can be used for preparing health-care products for supplementing calcium.
The collagen can also effectively repair the articular cartilage, recover the lubrication of the articular cartilage surface and reduce friction. Therefore, the hyaluronic acid oligosaccharide composition can be used for preparing joint lubricating injection.
In a specific embodiment, the mass concentration of the hyaluronic acid oligosaccharide composition in the health product or injection solution is 0.0001% to 5%, for example, 0.0001%, 0.001%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, preferably 0.001% to 1%.
Examples
Example 1 preparation of hyaluronic acid oligosaccharide composition
Adding 4L of water into a 5L reactor, controlling the temperature at 30 deg.C, adding 4 × 10 of hyaluronidase (the enzyme is hirudo hyaluronidase expressed by Pichia pastoris engineering bacteria, and the preparation method refers to the method described in CN 103695448A)7U, system enzyme activity is 1 x 104U/mL, 5g hyaluronic acid (molecular weight 100 kDa) was added until it was completely dissolvedAnd then, separating the enzymolysis reactant by adopting ultrafiltration to obtain a product stock solution, and concentrating the product stock solution by adopting nanofiltration to obtain a product concentrated solution. The reaction was stirred for 12h while maintaining the system at 30 ℃. Wherein the ultrafiltration adopts ultrafiltration membrane with molecular weight cutoff of 1kDa, and the nanofiltration adopts nanofiltration membrane with molecular weight cutoff of 200 Da. After the reaction is finished, collecting nanofiltration concentrated solution, adding activated carbon for adsorption, filtering and collecting filtrate, and performing spray drying, wherein the air inlet temperature is 120 ℃, and the air outlet temperature is 60 ℃. The hyaluronic acid oligosaccharide composition is obtained, and the product yield is 84%.
Analyzing the oligosaccharide distribution of the hyaluronic acid oligosaccharide composition by using a high performance liquid chromatograph, wherein the specific chromatographic conditions are as follows:
a chromatographic column: SUPERDEX 20010/300 GL
Column temperature: 40 deg.C
A detector: ultraviolet-visible light splitting detector
Mobile phase: 1mol/L ammonium sulfate solution
Sample introduction concentration: 0.5 percent
Sample introduction amount: 20 μ L
Flow rate: 2 ml/min
Detection wavelength: 200 nm.
As shown in fig. 1, in the hyaluronic acid oligosaccharide composition, the mass ratio of hyaluronic acid disaccharide was 9.35%, the mass ratio of hyaluronic acid tetrasaccharide was 47.84%, the mass ratio of hyaluronic acid hexasaccharide was 32.92%, the mass ratio of hyaluronic acid octasaccharide was 6.04%, the mass ratio of hyaluronic acid decasaccharide was 1.48%, and the mass ratio of hyaluronic acid decasaccharide was 0.42%.
The average molecular weight of the hyaluronic acid oligosaccharide composition was measured at 920Da using a laser light scattering apparatus (model: DAWN HELEOS-II).
Comparative example 1 preparation of hyaluronic acid oligosaccharide composition
The hyaluronic acid oligosaccharide composition with higher molecular weight is prepared by the method described in CN112646055A, and the specific preparation method is as follows:
1) pretreatment: dissolving 50g of high molecular weight hyaluronic acid with the molecular weight of 1000kDa in 30 times of weight parts of water, adjusting the pH of the solution to 8.5 by using 0.1mol/L sodium methoxide solution, fully stirring and swelling at room temperature, slowly heating to 90 ℃, hydrolyzing at constant temperature for 4 hours, then leaching and filtering, repeating the leaching operation on filter residues, and combining the two filtrates for later use;
2) and (3) fractional precipitation of neutral salts: heating the solution obtained in the step 1) to 40 ℃, adding 25% of magnesium sulfate solid of the weight of the solution, stirring to completely dissolve the solution, then carrying out ultrafiltration by using a sulfonated polysulfone ultrafiltration membrane with the thickness of 0.1 mu m, then adding 43% of magnesium sulfate solid of the weight of the solution into the filtrate again, stirring to completely dissolve the solution, standing for precipitation, then carrying out filtration, ultrafiltration and drying, and then adding 6 times of purified water into the dried precipitate for redissolving;
3) and (3) filtering and purifying: performing ultrafiltration pretreatment on the solution obtained in the step 2) through a sulfonated polysulfone microfiltration membrane with the molecular weight cutoff of 4KDa under the membrane permeation pressure of 0.3 MPa; and (3) performing nanofiltration concentration on the percolate through a sulfonated polysulfone nanofiltration membrane with the intercepted molecular mass of 2KDa, and finally performing vacuum freeze drying on the obtained concentrated solution to obtain the hyaluronic acid oligosaccharide composition.
The average molecular weight of the hyaluronic acid oligosaccharide composition was measured to be 2682Da using a laser light scattering apparatus (model: DAWN HELEOS-II).
Test examples
Test example 1
(1) Mass spectrometric detection
The hyaluronic acid oligosaccharide composition of example 1 was characterized by ESI-MS, and the mass spectrometric detection conditions were: ion source parameters ESI, nebulizer pressure: 30 psi; the flow rate of the desolventizing gas is 50L/h; the temperature is 400 ℃; negative ion mode.
As shown in FIGS. 3 to 7, the mass spectrum peak [ M ] appearing at 1.380 min on the total ion current peak chart of mass spectrum (FIG. 2) was 397.1, and was identified as hyaluronic acid disaccharide (FIG. 3); the mass spectrum peak [ M ] appearing at 3.649min on the mass spectrum total ion current peak chart is 776.2, which is identified as hyaluronic acid tetrasaccharide (FIG. 4); the mass spectrum peak [ M ] appeared at 5.612min on the mass spectrum total ion current peak diagram is 1155.3, which is identified as hyaluronic acid hexasaccharide (FIG. 5); the mass spectrum peak [ M ] appeared at 6.724 min on the mass spectrum total ion current peak diagram and is 1535.5, which is identified as hyaluronic acid octasaccharide (FIG. 6); the mass spectrum peak [ M ] appearing at 7.257 min on the mass spectrum total ion current peak chart was 1913.5, which was identified as hyaluronic acid decasaccharide (FIG. 7), and the mass spectrum peak [ M ] appearing thereafter was 2292.6, which was identified as hyaluronic acid decadisaccharide.
(2) Reduction end identification of hyaluronic acid oligosaccharide composition
The hyaluronic acid oligosaccharide compositions obtained in example 1 and comparative example 1 were subjected to reducing end identification.
The reducing end of the hyaluronic acid oligosaccharide composition was determined colorimetrically using the Morgan-Elson reaction. If reddened, the reducing end is N-acetylglucosamine, and if not reddened, the reducing end is uronic acid.
Reaction buffer: an alkaline boric acid solution (1.73 g H3BO3 and 0.78 g KOH in 10ml water, 0.8 g ml-1K 2CO3, one-tenth of its volume added before use) p-dimethylaminobenzaldehyde solution (2 g p-dimethylaminobenzaldehyde solution dissolved in 2.5 ml concentrated hydrochloric acid and 7.5 ml glacial acetic acid diluted with 4 times the volume of glacial acetic acid before use).
Mu.l of 10g/L hyaluronic acid oligosaccharide composition solution was taken, 110. mu.l alkaline boric acid solution was added thereto, boiled for 4min, added with 1.5ml p-dimethylaminobenzaldehyde, and incubated at 37 ℃ for 20 min.
Hyaluronic acid (molecular weight 1500 kDa), hyaluronic acid tetrasaccharide (HA 4, purchased from Sigma, reduced end N-acetylglucosamine) solution was used as a control.
As shown in Table 1, the hyaluronic acid oligosaccharide compositions prepared in example 1 and comparative example 1 did not show red color through Moran-Elson reaction, confirming that the reducing end is uronic acid.
TABLE 1
| Morgan-Elson reaction results | |
| Example 1 | Does not change into red |
| Comparative example 1 | Does not change into red |
Test example 2
10mg of each of the hyaluronic acid oligosaccharide compositions of example 1 and comparative example 1 was weighed, dispersed in 10mL of DMEM medium, and sterile-filtered through a 0.22 μm filter to obtain sample 1 and sample 2, respectively, at a mass concentration of 0.1%.
Test example 2-1 measurement of collagen content
Collagen determines the physical properties of human tissues, including the skin. Collagen in the dermis is secreted mainly by fibroblasts. The effect of the hyaluronic acid composition on the promotion of collagen production is evaluated by evaluating the effect of the hyaluronic acid composition on the ability of fibroblasts to secrete collagen.
1. Sample preparation
20 μ L of sample 1 and sample 2 were added to 1.98mL of 10% FBS-DMEM medium, respectively, to prepare solutions with a final mass concentration of 0.001% to obtain samples 1-1 and 2-1.
2. Human fibroblast collagen I secretion experiment
Human fibroblasts were plated in 96-well plates at a density of 1 ten thousand per well and cultured in an incubator for 24 hours. The supernatant was discarded and samples 1, 1-2, 1-3, 2-1 were added to the well plate at 200. mu.L per well. Placing in an incubator to incubate for 48 h. The supernatant was collected, diluted ten-fold with DMEM medium, and the collagen i in the supernatant was quantified using Human Col i Elisa Kit. The results are shown in FIGS. 8 and 9, in which the control group is a test group without any sample added.
3. Results display
As shown in FIG. 8, although both samples 1-1 and 2-1 had a certain collagen production-promoting effect, the collagen production-promoting effect of sample 1-1 having a small molecular weight was more remarkable. Wherein the sample 1-1 increased the amount of collagen I secretion by 33%, while the sample 2-1 showed no significant difference in the amount of collagen I secretion compared to the control group.
As shown in fig. 9, each of samples 1, 1 to 2, and 1 to 3 has a significant collagen production promoting effect, which indicates that the hyaluronic acid oligosaccharide composition of example 1 has a collagen secretion promoting effect on fibroblasts at a mass concentration of 0.0001% to 0.1%. Particularly, the effect is best when the mass concentration is 0.001%.
Test examples 2-23D skin models
The effect of the hyaluronic acid composition on the proliferation and differentiation of epidermal cells is evaluated by evaluating the influence of the hyaluronic acid composition on the tissue structure of a 3D full-thickness skin model.
The 3D full-thickness skin model is an active tissue which is similar to a human skin structure and is formed by reconstructing normal human skin cells in vitro by using a proper culture medium by utilizing a tissue engineering technology. The role of the sample in anti-aging can be judged by assessing the tissue structure of the 3D skin model. The stratum basale is the material exchange barrier between dermis and epidermis, and the more stable the structure of the stratum basale, the more nutrients the epidermis layer can absorb, the better the proliferation and differentiation of the epidermal cells, thereby achieving the anti-aging effect.
1. Construction of 3D full-thickness skin model
The collagen and human dermal fibroblasts are combined to construct a dermis layer of a 3D full-layer skin model, and then the human keratinocytes are inoculated on the dermis layer to form an epidermis layer, so that the complete skin model with a dermis-epidermis structure is obtained. Then, the samples 1 and 2 were added and processed.
2. 3D full-thickness skin model paraffin tissue section
Placing the tissue into an embedding box, and respectively placing the tissue into 4% paraformaldehyde, 70% ethanol-water solution, 80% ethanol-water solution, 90% ethanol-water solution, 95% ethanol-water solution, absolute ethanol I, absolute ethanol II, methylcyclohexane I and methylcyclohexane II for gradient dehydration, wherein the solution is placed in each cylinder for 1 h. After dehydration, the tissue was embedded in paraffin, trimmed and cut into paraffin sections of 5 μm thickness.
3. 3D full-thickness skin model hematoxylin-eosin staining
And (3) respectively putting the paraffin sections into methylcyclohexane I, methylcyclohexane II, absolute ethyl alcohol, 95% ethanol-water solution, 80% ethanol-water solution, 70% ethanol-water solution and distilled water, soaking for 10 min, dewaxing and rehydrating. Placing into hematoxylin staining solution for staining for 8 min, sequentially placing into hydrochloric acid-ethanol solution for differentiation for 2s, and rewetting in ammonia water solution for 1 min. Dyeing with eosin solution for 1min, dewatering in 70% ethanol-water solution, 95% ethanol-water solution, anhydrous ethanol, and methylcyclohexane solution, and sealing with neutral gum. Take pictures under microscope. The results are shown in FIG. 10. Wherein the control group is a test group without any sample added.
4. Results display
As shown in fig. 10, compared to the control group and sample 2, after sample 1 was added, the basal layer cells of the 3D full-thickness skin model were tightly connected, the epidermal layer was well differentiated, the structure was intact, and the spinous layer and granular layer were clearly structured. Indicating that sample 1 had good anti-aging effect.
Test example 3 transdermal verification of hyaluronic acid oligosaccharide composition
1. Fluorescent labeling of samples
2g of the hyaluronic acid oligosaccharide composition of example 1 was dispersed in 40mL of water to prepare a solution with a concentration of 50mg/mL, and 20mL of the MSO solution was added and mixed. To the above 60mL solution were added 500. mu.L of a 50mg/mL 5-hydroxyfluorescein solution, 25. mu.L of cyclohexylisonitrile, and 100. mu.L of a 25% acetaldehyde solution, and the mixture was stirred at room temperature for 5 hours. 40mL of the fluorescently labeled solution was transferred, and 560mL of supernatant of a saturated sodium chloride solution in glacial ethanol was added to precipitate fluorescently labeled hyaluronic acid. The solution was transferred to a centrifuge tube and placed in a centrifuge for 10 minutes at 4000 × g of centrifugal force, the supernatant liquid was discarded, and the fluorescein-labeled example 1 was removed.
2. Fluorescent marker transdermal delivery
15mg of example 1 labeled with a fluorescent label was dissolved in 1mL of water to prepare sample 4 having a final mass concentration of 1.5%. 15mL of 1 XPBS were used as receiving solution and 25mm diameter pigskin was loaded on a manual transdermal device. The receiving solution was heated in a water bath at (32.0. + -. 0.1) ℃ and equilibrated for 1 hour under constant-speed magnetic stirring (300. + -. 5) r/min. Add 500. mu.L of sample 4 to the upper layer of the skin and cover. After 20h, taking down the pigskin and drying in the air.
3. Frozen section of pigskin
The dried pigskin is taken and placed in OCT in liquid nitrogen for rapid cooling. The sections were cut into sections of 10. mu.M in thickness in a cryomicrotome and observed under a fluorescence microscope.
4. Results display
As shown in fig. 11, sample 4 had fluorescence intensity in both the epidermis and dermis layers, indicating that sample 4 penetrated both the epidermis and dermis layers well. The above results demonstrate that example 1 can penetrate and stay in the dermis and epidermis to function.
Claims (13)
1. Use of a hyaluronic acid oligosaccharide composition for combating skin aging, wherein the hyaluronic acid oligosaccharide composition comprises a hyaluronic acid oligosaccharide of the structure of formula (I):
formula (I)
Wherein X is selected from H, K, Na, Ca or Zn;
n is an integer selected from 0 to 5;
in the hyaluronic acid oligosaccharide composition, the hyaluronic acid oligosaccharide,
the mass ratio of the hyaluronic acid oligosaccharide with n =1 is 35-70%, the mass ratio of the hyaluronic acid oligosaccharide with n =0 is 5-40%, the mass ratio of the hyaluronic acid oligosaccharide with n =2 is 10-50%, the mass ratio of the hyaluronic acid oligosaccharide with n =3 is 1-15%, the mass ratio of the hyaluronic acid oligosaccharide with n =4 is 0.1-10%, and the mass ratio of the hyaluronic acid oligosaccharide with n =5 is 0.01-5%.
2. Use according to claim 1, characterized in that the hyaluronic acid oligosaccharide composition is resistant to skin ageing by promoting collagen production and/or epidermal cell proliferation and differentiation.
3. The use according to claim 1, characterized in that in the hyaluronic acid oligosaccharide composition, the mass proportion of hyaluronic acid oligosaccharides with n =1 is 40-60%; the mass ratio of the hyaluronic acid oligosaccharide with n =0 is 5-20%; the mass ratio of the hyaluronic acid oligosaccharide with n =2 is 20-40%; the mass ratio of the hyaluronic acid oligosaccharide with n =3 is 3-8%; the mass ratio of the hyaluronic acid oligosaccharide with n =4 is 1-5%; the mass ratio of the hyaluronic acid oligosaccharide with n =5 is 0.01-1.5%.
4. Use according to claim 1, characterized in that the hyaluronic acid oligosaccharide composition has a weight-average molecular weight of less than or equal to 1 kDa.
5. Use according to claim 1, characterized in that the hyaluronic acid oligosaccharide composition is applied to the skin.
6. Use according to claim 5, characterized in that the mode of application to the skin is by means of a cosmetic or medical device, the hyaluronic acid oligosaccharide composition being present in the cosmetic or medical device in a concentration by mass ranging from 0.0001% to 5%.
7. Use according to claim 6, characterized in that the hyaluronic acid oligosaccharide composition is present in the cosmetic or medical device in a mass concentration of 0.001% to 1%.
8. Use of a hyaluronic acid oligosaccharide composition for promoting collagen production, comprising a hyaluronic acid oligosaccharide having a structure represented by formula (I):
formula (I)
Wherein X is selected from H, K, Na, Ca or Zn;
n is an integer selected from 0 to 5;
in the hyaluronic acid oligosaccharide composition, the hyaluronic acid oligosaccharide,
the mass ratio of the hyaluronic acid oligosaccharide with n =1 is 35-70%, the mass ratio of the hyaluronic acid oligosaccharide with n =0 is 5-40%, the mass ratio of the hyaluronic acid oligosaccharide with n =2 is 10-50%, the mass ratio of the hyaluronic acid oligosaccharide with n =3 is 1-15%, the mass ratio of the hyaluronic acid oligosaccharide with n =4 is 0.1-10%, and the mass ratio of the hyaluronic acid oligosaccharide with n =5 is 0.01-5%.
9. The use according to claim 8, wherein the hyaluronic acid oligosaccharide composition is used for preparing health products for promoting collagen production, or for preparing health products for protecting and strengthening viscera, or for preparing health products for protecting gastric mucosa, or for preparing health products for supplementing calcium, or for preparing joint lubrication injection.
10. The use according to claim 9, wherein the mass concentration of the hyaluronic acid oligosaccharide composition in the health product or injection is 0.0001-5%.
11. The use according to claim 10, wherein the mass concentration of the hyaluronic acid oligosaccharide composition in the health product or injection is 0.001% -1%.
12. The use according to claim 8, wherein in the hyaluronic acid oligosaccharide composition, the mass proportion of hyaluronic acid oligosaccharides with n =1 is 40-60%; the mass ratio of the hyaluronic acid oligosaccharide with n =0 is 5-20%; the mass ratio of the hyaluronic acid oligosaccharide with n =2 is 20-40%; the mass ratio of the hyaluronic acid oligosaccharide with n =3 is 3-8%; the mass ratio of the hyaluronic acid oligosaccharide with n =4 is 1-5%; the mass ratio of the hyaluronic acid oligosaccharide with n =5 is 0.01-1.5%.
13. Use according to claim 8, characterized in that the hyaluronic acid oligosaccharide composition has a weight-average molecular weight of less than or equal to 1 kDa.
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