CN114533582B - Periocular composition containing multiple osmoprotectants - Google Patents

Abstract

The present application provides a composition for the eye comprising a plurality of osmoprotectant selected from erythritol, ectoin, l-carnitine, etc., and lutein or rhamnolipid component. The composition can effectively protect the skin cells around eyes from being damaged by blue light, provides the cornea epithelial cells with the protection effect on the hypertonic environment, and is further expected to be used for treating xerophthalmia and asthenopia, even eye symptoms such as maculopathy and the like.

Description

Periocular composition containing multiple osmoprotectants

Technical Field

The present application belongs to the field of cosmetics and ophthalmic medicines, and in particular, provides a composition for caring periocular skin, which comprises various osmoprotectant selected from erythritol, ectoin, L-carnitine and the like, and lutein or rhamnolipid component.

Background

Due to factors such as illumination and pollution, the skin and tissues around the eyes can be damaged to different degrees every day. In addition, the hypertonic tears of patients suffering from ocular diseases such as dry eye, in particular, can cause damage to corneal epithelial cells and periocular skin cells.

The periocular skin naturally repairs general lesions, such as increasing the immunity of the skin to remove or reduce inflammation caused by bacterial infection. Therefore, the best method for daily maintenance of the periocular skin is to use a natural or bionic method to maintain the periocular skin, protect ocular tissues and cells under the periocular skin, improve ocular surface constancy and metabolism, alleviate ocular fatigue, delay the deepening of myopia and reduce the damage of ocular fundus macular tissues. Finding a suitable combination of active ingredient with osmoprotectant is a major approach to improving the protective effect.

Eye protection efficacy of lutein: (1) The chemical structure of lutein contains eight isoprene units, thus forming a powerful blue filter. Blue light is blocked from directly irradiating on macular tissues of retina, and the killing power of 300-500nm blue light to bottom tissues of the eye is maximum; (2) Lutein has good antioxidant capacity, can remove free radicals generated by blue light damage, so that eye front or fundus tissues are further protected, (3) lutein has anti-inflammatory effect, can reduce the expression of inflammatory cytokines and matrix metalloproteinases caused by ultraviolet rays or environmental pollution after long-term use, so that collagen is protected in one step, (4) skin color depends on the distribution content and density of melanin particles generated by melanocytes in skin around eyes, for example, lutein can effectively delay tyrosine from being oxidized and metabolized into melanin. In summary, the effect of the lutein on reducing the risks of maculopathy, leukorrhagia, diabetic retinopathy and other eye diseases is achieved by using the lutein correctly and for a long time, and more people begin to pay attention because a reasonable efficacy mechanism is gradually proved, so that the lutein also becomes an important part of great health.

Rhamnolipids are a surfactant of biological metabolic nature, and are also a biological preservative and biological emulsifier. The rhamnolipid can reduce the surface activity (from 72mN/m to about 30) of the prescription of the invention. So that the rhamnolipid can remove the environmental pollutants deposited on the skin around the eyes. Rhamnolipids are biosurfactants produced by a biological fermentation process. Almost no irritation, and is a biological antifungal agent. Besides good emulsification, the foam can be removed during mass production, the canning speed is increased, and the production time is reduced.

We generally call organic small molecule compatibilisers osmoprotectant with these properties. The osmotic pressure protective agents have the other characteristics that the osmotic pressure protective agents can freely enter and exit cells, unlike sodium chloride which enters and exits cell membranes, the osmotic pressure protective agents not only need the assistance of other factors, but also bring water molecules to damage the normal volume of the cells, so that the cells finally necrose. Even some osmoprotectant can determine whether to enter or exit cells by measuring the intracellular pressure, so 20-30% of osmoprotectant has no irritation to eyes Zhou Jifu and ocular surfaces and shows unique biocompatibility. The prescription of the invention utilizes the bionics concept of the osmotic pressure protective agent to balance and regulate the constant state of the skin and tissues of the eye epidermis, so as to furthest protect and care the skin and tissues around the eye, and even achieve a certain treatment effect.

The osmoprotectant of the invention further protects the stability and health of sebum by the synergistic effect of the osmoprotectant and the protective agent on the basis of protecting cells on the surface. The L-carnitine can effectively induce the synthesis of collagen and elastin, and the ectoin can increase the softness of healthy sebum, so that the ectoin can be uniformly distributed on the surface, and the moisturizing effect and the prevention of invasion of harmful microorganisms can be achieved only by ensuring the integrity of the sebum. The healthy epidermis is steady, which is more helpful for the percutaneous absorption of the erythritol which is the effective component of the invention, reduces the degradation of collagen and ensures the function of protecting skin elasticity by the collagen.

Erythritol is not only an osmoprotectant but also a better antioxidant. The main function is to prevent skin cell necrosis caused by skin hypertonicity, especially skin hypertonicity caused by ultraviolet irradiation. The invention mainly utilizes the moisturizing effect of erythritol to delay the damage of collagen.

Excessive fat can form orange-peel, especially under the periocular skin, causing discontinuities in the appearance of the epidermis. L-carnitine can inhibit the synthesis of fat, thereby reducing the formation of orange peel. Especially, the medicine is combined with the ectoin, so that the skin around eyes is healthy and active. The ectoin can increase the softness of fat, so that the fat is uniformly distributed under the skin, thereby not only reducing the formation of orange peel, but also preserving moisture and reducing the damage of ultraviolet irradiation to the periocular skin.

The ectoine can carry 9 water molecules, can increase the intermolecular distance, protect cells by enhancing the activity of cell membrane fat, and can increase the fluidity of skin lipid so as to reduce the loss of epidermis moisture.

The damage of ultraviolet rays to the periocular skin can be directly reduced by the L-carnitine, and the long-term deficiency of eye tissues and tears can cause eye diseases and even cataract.

Disclosure of Invention

To solve the above problems, the present invention provides a composition comprising a plurality of osmotically protective agents, which further protects sebum stability and health by synergistic effect with each other on the basis of protecting surface cells. The L-carnitine can effectively induce the synthesis of collagen and elastin; the ectoin can increase the softness of healthy sebum and thus be uniformly distributed on the surface, and only ensuring the integrity of sebum can achieve moisturizing and preventing the invasion of harmful microorganisms. The healthy epidermis is steady, which is more helpful for the percutaneous absorption of the erythritol which is the effective component of the invention, reduces the degradation of collagen and ensures the function of protecting skin elasticity by the collagen.

In one aspect, the present application provides an periocular skin or ophthalmic composition comprising an osmoprotectant selected from one or more of erythritol, ectoin, and l-carnitine.

Further, the composition is a liquid formulation.

Further, the concentration of the osmoprotectant is from 0.01% to 30%.

Further, the composition comprises 0.01% -1%, preferably 0.1% erythritol, 0.01% -1%, preferably 0.1% ectoin and 0.01% -1%, preferably 0.1% l-carnitine.

Further, the composition further comprises lutein and/or rhamnolipids.

Further, the composition comprises 0.01% -1%, preferably 0.01% lutein.

Further, the composition comprises from 0.01% to 5%, preferably 1% rhamnolipid.

Further, the composition further comprises an auxiliary material selected from a buffer, an emulsifier, an antioxidant and a preservative.

Further, the composition further comprises a component selected from the group consisting of honey locust seed extract, retinol/saccharomyces polypeptide, sodium hyaluronate, panthenol, menthol leaf extract, cyanocobalamine, magnesium PCA, manganese PCA, sodium PCA, tetrahydropyrimidine carboxylic acid, ceramide, haematococcus pluvialis extract, plantain flower, centella asiatica extract, broccoli extract, italian cabbage bud extract, sunflower bud extract, rape bud extract, cranberry fruit extract, corn kernel extract, phyllophyllum comosum extract, parsley extract, grapefruit extract, ascorbic acid, lotus flower water, water of Egyptian blue water of water lily flower, chinese ganoderma extract, gentian extract, lycium barbarum extract, p-hydroxyacetophenone, hexylene.

In another aspect, the present application provides the use of the above composition in the preparation of an ocular skin repair product.

In another aspect, the present application provides the use of the above composition in the manufacture of a medicament for treating or preventing dry eye or eye fatigue.

Drawings

FIG. 1 is a graph showing the protective effect of each group of lutein and osmoprotectant on skin keratinocytes.

FIG. 2 is a graph showing the protective effect of each group of lutein and osmoprotectant on skin fibroblasts.

Figure 3 is a graph showing the protective effect of each group of osmoprotectant on corneal epithelial cells in hypertonic environments.

Figure 4 is a graph showing the protective effect of various groups of osmoprotectant and surfactant on corneal epithelial cells in a hypertonic environment.

FIG. 5 is a graph showing the effect of osmoprotectant on corneal epithelial cell IL-6 cytokine expression.

Description of the embodiments

Principal materials and reagents

Human skin keratinocytes: ATCC CRL-2404; (according to ATCC guidelines, the medium comprises mainly eagle basal medium, 5ng/ml EGF (Epidermal Growth Factor), 2mM L-glutamine, 10000 units of penicillin, 10mg/ml streptomycin)

Human skin fibroblasts: ATCC CRL-2115 (according to the guidelines of ATCC, the medium comprises primarily eagle minimal medium, 10% FBS, 10000 units of penicillin, 10mg/ml streptomycin);

human corneal epithelial cells (HCEpC): CRL-11135, HCE-2, ACTT

Lutein: jestigmine in the united states

Erythritol). U.S. Jiaji (Cargill)

Rickettsial: germany Bitop

L-carnitine: swiss Longsha (Lonza)

Rhamnolipid: shanghai Yuan Ye Biotech Co., ltd;

tween 80: shanxi jin ocean pharmaceutical excipients Co.Ltd;

poloxamer F68: BASF;

other reagents are home-made or imported products meeting corresponding standards.

Cell survival experiments under blue light:

placing cultured human skin keratinocyte into 96-well culture dish with cell density of about 1×10 per ml ⁵ Individual cells (culture)The matrix contains lutein, osmoprotectant, etc., lutein is added after being prepared into 2.5mg/ml solution by using DSMO, other materials are directly added, and the 96-well culture dish is placed under 470nm blue light for 12 hours (1900 Lux). Viable cell numbers were observed and recorded with cells after trypan blue staining.

Cell survival experiments under hypertonic conditions:

corneal epithelial cells were seeded in 96-well plates (EpiLife medium), incubated for 72 hours with aspiration medium, replaced with fresh baseline control medium (EpiLife medium), and incubated for an additional 24 hours. The incubation was performed for 4 hours using EpiLife medium, and after one wash using EpiLife medium, the culture was incubated for 20 hours in either a baseline control EpiLife medium (310 mOsm/kg) or a hypertonic EpiLife medium (450 mOsm/kg) with osmotic pressure adjusted with sodium chloride (various osmotic pressure regulators, surfactants added to the medium). Alarm blue detects cell activity.

The applicant conducted a number of dosage and scale experiments, only a portion of the representative experimental results being shown here.

EXAMPLE 1 protective Effect of lutein and osmotically protective Agents in combination with skin keratinocytes and skin fibroblasts

The other ingredients added to the cell culture medium are shown in the following table:

the results are shown in figures 1 and 2, and show that the combination of the osmoprotectant and lutein can better protect skin keratinocytes and skin fibroblasts than the osmoprotectant or lutein alone, and reduce damage caused by blue light irradiation. The effect of the combination of the three osmotically protective agents is particularly pronounced. This may result from the different effects of different osmoprotectant on the cells.

EXAMPLE 2 protective Effect of osmoprotectant on corneal epithelial cells

Although the related products of the applicant are ophthalmic sprays, on the one hand, the sprays inevitably enter into eyes to contact cells such as corneal epithelial cells in use, and hypertonic tears also often contact periocular skin for a long time; on the other hand, the applicant also wishes to be able to further extend ophthalmic sprays to other ophthalmic formulations which are in direct contact with the eye (the osmotic pressure of tears of patients suffering from dry eye and eye strain is much higher than that of normal tears). The applicant has thus further studied the protective effect of the osmoprotectant on the corneal epithelial cells on other components added to the cell culture medium as shown in the following table:

the results are shown in fig. 3, which demonstrate that although the use of three osmoprotectants in combination largely avoids damage to the corneal epithelial cells from the hypertonic environment, the metabolic activity of the corneal epithelial cells is still greatly affected. It is necessary to further study the addition of other ingredients.

Example 3 we have subsequently tried to add various surfactants either alone or to the above formulation.

The results are shown in FIG. 4, and the results show that the addition of the surfactant alone is beneficial to the activity of the cells, but the effect is not significant, and no obvious distinction is made between various surfactants; however, the combination of surfactants, particularly rhamnolipids, with the osmoprotectant described above can advantageously enhance the protective effect of the osmoprotectant so that the corneal epithelial cells can easily survive/remain active in a hypertonic environment. Products for caring periocular skin such as ophthalmic spray prepared from osmoprotectant (L-carnitine, erythritol, etc.) or osmoprotectant and surfactant rhamnolipid can reduce irritation, damage and dryness of periocular skin due to high salt, thereby further reducing irritation and damage to superficial cells of eyes, maintaining metabolic activity and integrity of related cells, changing ocular surface steady state, reducing asthenopia, and reducing incidence of ocular surface inflammation.

Example 4

The results are shown in FIG. 5, which shows that the osmoprotectant can reduce the increase in cytokine IL-6 due to high osmotic tears. From another perspective, the reduction of the epicyto-cytokine IL-6 on the cornea again demonstrates that osmoprotectant is likely to act as ocular surface anti-inflammatory and improving ocular surface homeostasis.

EXAMPLE 5 preparation of actual pharmaceutical agent

On the basis of the above formulation containing erythritol, ectoine, l-carnitine and/or rhamnolipid, we add other examples of ingredient formulation products:

example 1

The components are as follows: water, seawater, lutein, gleditsia sinensis seed extract, retinol/saccharomyces polypeptide, sodium hyaluronate, panthenol, menthol leaf extract, cyanocobalamine, magnesium PCA, manganese PCA, sodium PCA, tetrahydropyrimidine carboxylic acid, ceramide, haematococcus pluvialis extract, plantain flower, centella asiatica extract, lotus water, water of water lily aegypti, ganoderma sinensis extract, gentian extract, lycium barbarum fruit extract, p-hydroxyacetophenone, hexylene glycol.

Efficacy: the product is added with various eye skin nutrition elements and microelements such as gleditsia sinensis, lutein, retinol/saccharomycete polypeptide, panthenol, vitamin B12 (cyanocobalamin), magnesium, manganese, sodium and the like, and is supplemented with the plant extracts such as haematococcus, centella asiatica, ganoderma lucidum, gentian, medlar and the like to achieve the effects of moistening and supplementing water, and is blended by using the sea spring water of the Fanational rose coast, carried with superfine fog beads to supplement water, sprayed and lubricated for layer-by-layer permeation repair, so that the skin around the eyes is compact and fine, and the eyes are moistened and bright.

Example 2

The components are as follows: water, seawater, lutein, gleditsia sinensis seed extract, retinol/saccharomyces polypeptide, sodium hyaluronate, panthenol, menthol leaf extract, cyanocobalamine, magnesium PCA, manganese PCA, sodium PCA, tetrahydropyrimidine carboxylic acid, ceramide, spore cabbage extract, italian cabbage bud extract, sunflower bud extract, rape bud extract, ganoderma sinensis extract, gentian extract, lycium barbarum fruit extract, p-hydroxyacetophenone, hexylene glycol.

Efficacy: the product is added with various eye skin nutrition elements and microelements such as gleditsia sinensis lam extract, lutein, retinol/saccharomycete polypeptide, panthenol, vitamin B12 (cyanocobalamine), magnesium, manganese, sodium and the like, is supplemented with plant extracts such as spore cabbage, ganoderma lucidum, gentian, medlar and the like, is blended by using the sea spring water of the coast of the Fanational rose, carries superfine fog beads, is sprayed and cleaned, is fresh and is used for repairing, and enables the skin around the eyes to be smooth and tight, and the eyes to be moist and bright.

Example 3:

the components are as follows: water, seawater, lutein, honey locust seed extract, retinol/saccharomyces polypeptide, sodium hyaluronate, panthenol, menthol leaf extract, cyanocobalamine, magnesium PCA, manganese PCA, sodium PCA, tetrahydropyrimidine carboxylic acid, ceramide, cranberry fruit extract, corn kernel extract, algae extract, parsley extract, grapefruit extract, ascorbic acid, chinese ganoderma extract, gentian extract, medlar fruit extract, p-hydroxyacetophenone, hexylene glycol.

Efficacy: the product is added with various eye skin nutrition elements and microelements such as gleditsia sinensis seed refined extract, lutein, retinol/saccharomycete polypeptide, vitamin B5 (panthenol), magnesium, manganese, sodium and the like, and is supplemented with plant refined extract such as cowberry fruit, corn kernel, phyllophyllum nodosum, parsley, ganoderma lucidum and the like, blended by the sea spring water of the seashore of the Fanational rose, carefully compounded with sodium hyaluronate, peppermint and erythritol, carried with superfine fog beads, and used for lasting care, relieving and repairing the skin around eyes, and the eyes are polished.

It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.

Claims (1)

1. Use of a periocular composition comprising a plurality of osmoprotectants for the preparation of an ocular skin repair product, characterized in that the periocular composition is a liquid formulation comprising 0.1% w/v erythritol, 0.1% w/v ectoin, 0.1% w/v l-carnitine and 0.01% w/v lutein; the periocular composition further comprises an auxiliary material selected from a buffer, an emulsifier, an antioxidant, and a preservative.

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