Scar formation inhibitor

Abstract

The present invention provides a scar formation inhibitor useful for suppressing scar formation and healing skin ulcers that extend to the mid-dermis, as well as erosions and shallow skin ulcers, and an ointment characterized by containing the said scar formation inhibitor. [Solution] A scar formation inhibitor characterized by containing sacran as an active ingredient for inhibiting scar formation, and an ointment characterized by containing the scar formation inhibitor and petrolatum.

Description

Technical Field

[0005]

[0001] The present invention relates to a scar formation inhibitor. More specifically, the present invention relates to a scar formation inhibitor useful for healing skin ulcers without leaving scars on skin ulcers with a depth up to the middle dermis, as well as skin ulcers with erosions and shallow skin ulcers, and an ointment containing the scar formation inhibitor.

Background Art

[0002] When an epidermal defect occurs due to burns, trauma, etc., and a skin ulcer develops, in order to protect the wound where the skin ulcer has occurred, promote granulation formation, and rapidly treat the skin ulcer, a covering material obtained by sterilizing and drying porcine dermis and processing it into a sheet, a covering material obtained by processing chitin into a cotton-like form, a covering material obtained by processing a hydrocolloid into a sheet, etc. are used. However, since these covering materials have a weak scar formation inhibitory effect, when applied to deep skin ulcers, a part of the skin ulcer may scar.

[0003] Conventionally, as a scar formation inhibitor for suppressing the formation of scars on skin ulcers, a glial scar formation inhibitor containing 2-O-desulfated heparin as an active ingredient and a glial scar formation inhibitor containing 6-O-desulfated heparin of 18 sugars as an active ingredient have been proposed (for example, see Patent Document 1). According to the glial scar formation inhibitor, by suppressing the same action of a substance having a morphological change action of astrocytes secreted from astrocytes or suppressing the activation of astrocytes, it is said that glial scar formation due to morphological changes causing thin glial cells adhering to each other by intercellular bridges and forming aggregates can be effectively suppressed (for example, see paragraph

[0003] of Cited Document 1). <00000​​​​ Furthermore, other abnormal scar formation inhibitors containing sulfated glucosaminoglycans have been proposed (see, for example, Patent Document 3). These abnormal scar formation inhibitors are said to be able to effectively suppress the formation of hypertrophic scars.

[0006] Furthermore, other antiscarring agents have been proposed, including hypertrophic scar formation inhibitors containing the culture supernatant of mesenchymal stem cells (see, for example, Patent Document 4). These hypertrophic scar formation inhibitors are said to be able to suppress the formation of hypertrophic scars while promoting wound healing.

[0007] However, in recent years, there has been a growing demand for the development of scar formation inhibitors that are useful in suppressing scar formation and healing skin ulcers not only in erosions and shallow skin ulcers, but also in skin ulcers that extend to the mid-dermis, thereby preventing scarring. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Patent No. 4463510 [Patent Document 2] Patent No. 4488902 [Patent Document 3] Japanese Patent Publication No. 2017-088541 [Patent Document 4] Japanese Patent Publication No. 2018-052897 [Overview of the project] [Problems that the invention aims to solve]

[0009] The present invention has been made in view of the prior art described above, and aims to provide a scar formation inhibitor useful for suppressing scar formation not only for erosions and shallow skin ulcers, but also for skin ulcers that extend to the middle layer of the dermis, thereby preventing scarring and promoting healing of such skin ulcers, and an ointment containing the scar formation inhibitor. [Means for solving the problem]

[0010] The present invention (1) Scar formation inhibitors containing sacran as an active ingredient, (2) an ointment containing the scar formation inhibitor described in (1) above and petrolatum, and (3) Furthermore, the ointment described in (2) contains silver ions. Regarding. [Effects of the Invention]

[0011] The present invention provides a scar formation inhibitor useful for suppressing scar formation and healing skin ulcers that extend to the mid-dermis, as well as erosions and shallow skin ulcers, without leaving scars, and an ointment containing the scar formation inhibitor. [Brief explanation of the drawing]

[0012] [Figure 1] These are illustrative photographs showing the before and after application of Sacran ointment to a traumatic skin ulcer on a girl's face that reached the mid-dermis. [Figure 2] These are illustrative photographs showing the before and after application of Sacran ointment to a shallow, broad traumatic skin ulcer on a boy's face caused by scratching with his fingernails. [Figure 3] These are photographic representations of the before and after application of sacran silver ointment to an erosion on a boy's neck. [Figure 4] These are illustrative photographs showing the before and after application of silver sacran ointment to a woman's facial acne-like rash. [Modes for carrying out the invention]

[0013] [Scar formation inhibitor] The suppression of skin scarring is primarily achieved by inhibiting the abnormal proliferation of skin fibroblasts and activating skin keratinocytes.

[0014] In contrast, as a result of intensive research by the present inventors, it has been found that sakuran forms a wound environment suitable for suppressing abnormal proliferation of skin fibroblasts and activating skin keratinocytes. Since the scar formation inhibitor of the present invention contains sakuran as an active ingredient for suppressing scar formation, it forms a wound environment suitable for suppressing abnormal proliferation of skin fibroblasts and activating skin keratinocytes. Therefore, according to the scar formation inhibitor of the present invention, not only erosion and shallow skin ulcers but also skin ulcers with a depth reaching the middle layer of the dermis can be healed by suppressing the formation of scars and leaving no scars.

[0015] Therefore, since the scar formation inhibitor of the present invention exhibits an extremely excellent effect of being able to suppress the formation of scars and heal the skin ulcers without leaving scars not only for erosion and shallow skin ulcers but also for skin ulcers with a depth reaching the middle layer of the dermis, it is expected to be used as a scar formation inhibitor that substitutes for conventional scar formation inhibitors applied to the skin.

[0016] Incidentally, when the above-mentioned wound environment is not good, scars and marks remain on the skin without completely disappearing.

[0017] The sakuran used in the present invention is a high molecular polysaccharide extracted from Euglena gracilis. Since sakuran is extracted from Euglena gracilis in this way, it is considered to have high safety for the human body. In addition, sakuran has a solubility of about 2 to 30% in water at 25°C.

[0018] Euglena gracilis is a unique edible alga in Japan and is cultivated using groundwater in some parts of Fukuoka Prefecture and Kumamoto Prefecture. Euglena gracilis may be of natural origin or cultivated. Euglena gracilis may be used as it is or in a dried state. Sakuran, which is the main component of Euglena gracilis, has a high molecular weight among natural macromolecular compounds and has a high water retention capacity (5 to 10 times that of hyaluronic acid).

[0019] Sakuran has repeating units of sugar chains in which a sugar structure having a hexose structure and a sugar structure having a pentose structure are linked linearly or branched by an α-glycoside bond or a β-glycoside bond, and the sugar chain contains sulfated muramic acid.

[0020] Examples of methods for preparing sakuran include, for example, the method described in International Publication No. 2008 / 062574 pamphlet. More specifically, examples of methods for preparing sakuran include, for example, adding Sargassum horneri to an aqueous alkali solution and extracting the sakuran contained in Sargassum horneri with the aqueous alkali solution, but the present invention is not limited only to such examples.

[0021] Note that the water-soluble pigment in Sargassum horneri may be removed in advance, for example, by washing with water, and the fat-soluble pigment may be removed in advance by washing Sargassum horneri with an alcohol such as methanol, ethanol, or isopropanol.

[0022] Examples of the alkali used in the aqueous alkali solution include sodium hydroxide, potassium hydroxide, aqueous ammonia, etc., but the present invention is not limited only to such examples. Among these alkalis, sodium hydroxide is preferred. The concentration of the alkali in the aqueous alkali solution is usually preferably about 0.01 to 1N.

[0023] The temperature of the aqueous alkali solution when adding Sargassum horneri to the aqueous alkali solution is preferably 20 to 90°C, more preferably 60 to 85°C. After adding Sargassum horneri to the aqueous alkali solution, it is preferable to stir the resulting mixture for about 1 to 5 hours.

[0024] As described above, sacran can be extracted from Suizenji-nori into the alkaline aqueous solution. The extracted sacran may be separated from the alkaline aqueous solution by centrifugation or other means, recovered by filtration, and purified by washing with a solvent such as alcohol.

[0025] The molecular weight of sacran can be adjusted, for example, by adding an acid to an alkaline aqueous solution containing sacran extracted from Suizenji-nori, and heating the resulting mixed solution to a temperature of approximately 20 to 80°C. The heating time of the mixed solution varies depending on the heating temperature and other factors, and therefore cannot be determined definitively, but it is usually around 0.5 to 2 hours. Examples of acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, formic acid, acetic acid, and butyric acid, but the present invention is not limited to these examples.

[0026] Furthermore, to reduce the molecular weight of sacran, for example, sacrans with a low molecular weight can be obtained by cleaving the sugar chain using enzymes such as β-galactosidase, hexosaminidase A, hexosaminidase B, α-galactosidase A, β-glucosidase, α-L-idulonidase, N-acetyl-α-glucosaminidase, β-glucuronidase, hyaluronidase, N-acetyl-β-glucosaminidase, α-fucosidase, α-mannosidase, β-mannosidase, α-N-acetylgalactosaminidase, α-neuraminidase, and α-1,4-glucosidase. The ends of the cleaved sugar chains may be modified with, for example, carboxyl groups, amino groups, sulfate groups, etc. Sacrans with modified sugar chain ends are included in the concept of sacran as used in this invention. Furthermore, at least one of the hydroxyl, hydrogen, carboxyl, and amino groups of sacran may be substituted with another group. Sacran substituted with such other substituents is also included in the concept of sacran as used in this invention.

[0027] The lower limit of the weight-average molecular weight of sacran is not particularly limited, but is preferably 2000 or more, more preferably 5000 or more, and even more preferably 10,000 or more. Furthermore, the lower limit of the weight-average molecular weight of sacran is not particularly limited, but is preferably 40 million or less, more preferably 20 million or less, even more preferably 10 million or less, even more preferably 5 million or less, even more preferably 3 million or less, and particularly preferably 1 million or less. Note that the weight-average molecular weight of sacran is the value measured by gel filtration chromatography.

[0028] Furthermore, sacran can be used in the form of a pharmacologically acceptable salt, provided that the objectives of the present invention are not hindered. Examples of pharmacologically acceptable salts of sacran include inorganic salts such as hydrochloride and sulfate, and organic salts such as citric acid, but the present invention is not limited to these examples. Among these pharmacologically acceptable salts of sacran, hydrochloride or sulfate is preferred, and sulfate is more preferred. In the present invention, pharmacologically acceptable salts of sacran are encompassed within the concept of sacran used in the scar formation inhibitor of the present invention. Thus, sacran as used in the present invention includes sacran itself and pharmacologically acceptable salts of sacran.

[0029] Sacran can be readily obtained from Green Science Material Co., Ltd. A suitable sacran for the present invention is formula (I):

[0030] [ka]

[0031] (In the formula, R independently represents a hydrogen atom, a -OSO3H group, or a uronic acid residue.) Examples include sacrans having a structural unit represented by formula (I). Sacrans represented by formula (I) can be suitably used as a scar formation inhibitor of the present invention from the viewpoint of suppressing scar formation not only for erosions and shallow skin ulcers but also for skin ulcers that extend to the middle layer of the dermis, thereby healing the skin ulcers without leaving scars.

[0032] In formula (I), R is independently a hydrogen atom, an -OSO3H group, or a uronic acid residue. In formula (I), there are an average of 2.5 sites where R can be substituted with sugar residues. For example, when R is an -OSO3H group, the maximum amount of -OSO3H groups relative to the total amount of sugar residues is theoretically 250%. However, from the viewpoint of suppressing scar formation and healing skin ulcers that extend to the mid-dermis, as well as erosions and shallow skin ulcers, it is preferable that the amount of -OSO3H groups relative to the total amount of sugar residues be 3-150%, and the amount of uronic acid residues relative to the total amount of sugar residues be 10-40%. In this case, the remainder of the -OSO3H groups and uronic acid residues is a hydrogen atom.

[0033] Sacran, represented by formula (I), has two structural units (enclosed in parentheses) linked by an ether bond via oxygen. These two structural units linked by the ether bond may be polymerized. Furthermore, sacran, represented by formula (I), may contain structural units other than these, as long as the objectives of the present invention are not hindered.

[0034] Sacran can be used in various forms, such as powder or solution. Of these forms, powder is preferred because it allows for a high concentration of sacran in the scar formation inhibitor.

[0035] The average particle size of sacran powder is not particularly limited, but from the viewpoint of preventing aggregation of sacran powder and improving the dispersion stability of sacran, it is preferably 0.05 μm or larger, and from the viewpoint of uniformly applying (coating) the scar formation inhibitor to human skin, it is preferably 500 μm or smaller. The average particle size of sacran powder can be measured using a laser diffraction particle size distribution analyzer.

[0036] A typical example of a sacran solution is an aqueous solution of sacran, but the present invention is not limited to such examples. The aqueous solution of sacran may contain water-soluble compounds, such as ethanol, to the extent that the objectives of the present invention are not hindered. The concentration of sacran in the sacran solution is not particularly limited and is preferably adjusted as appropriate according to the actual form of use of the scar formation inhibitor.

[0037] The scar formation inhibitor of the present invention contains sacran as an active ingredient. The scar formation inhibitor of the present invention may consist solely of sacran, or it may contain other ingredients as long as the objective of the present invention is not hindered.

[0038] The scar formation inhibitor of the present invention exhibits a novel and remarkably superior effect, inhibiting scar formation not only in erosions and shallow skin ulcers but also in skin ulcers that extend to the mid-dermis, thereby healing such ulcers without leaving scars. Therefore, it is expected to be used, for example, in the treatment of burns, trauma, and skin ulcers after skin grafting surgery.

[0039] The scar formation inhibitor of the present invention can be used as is or dissolved or dispersed in a solvent, but it is preferable to use it in a dosage form such as an ointment from the viewpoint of improving usability on the skin and retention on the skin. The following describes in detail an embodiment in which the dosage form of the scar formation inhibitor of the present invention is an ointment, but the scar formation inhibitor of the present invention is not limited to this dosage form.

[0040] 〔ointment〕 The ointment of the present invention contains the scar formation inhibitor of the present invention and petrolatum. Because the ointment of the present invention contains the scar formation inhibitor of the present invention, it can suppress scar formation not only for erosions and shallow skin ulcers, but also for skin ulcers that extend to the middle layer of the dermis, thereby healing the skin ulcers without leaving scars.

[0041] Vaseline is a paraffinic hydrocarbon that is semi-solid at room temperature. Examples of Vaseline include white Vaseline and yellow Vaseline, but white Vaseline is preferred in the present invention. Vaseline is the remainder of the scar formation inhibitor, silver ions (described later), and additives.

[0042] The ointment of the present invention can be easily obtained by mixing the scar formation inhibitor of the present invention with petrolatum and stirring the resulting mixture to obtain a uniform composition.

[0043] The sacran content in the ointment of the present invention is preferably 0.1 to 1.0% by mass, more preferably 0.3 to 0.5% by mass, from the viewpoint of obtaining an ointment useful for suppressing scar formation and healing skin ulcers that extend to the middle layer of the dermis, as well as erosions and shallow skin ulcers, without leaving scars.

[0044] It is preferable that the ointment of the present invention contains silver ions. When the scar formation inhibitor of the present invention contains silver ions, the silver ions inhibit the progression of skin ulcers caused by bacterial and fungal infections, and furthermore, the effect of healing skin ulcers without leaving scars can be further enhanced by the synergistic effect with the scar formation inhibitory effect of sacran contained in the ointment of the present invention.

[0045] The World Health Organization (WHO)'s "Guidelines for drinking-water quality" states that even when silver ions are used to disinfect drinking water, a concentration of silver ions of 100 ppb in drinking water is not harmful to human health. Silver ions are typically used as silver ion water. The main methods for producing silver ion water are generally known to be electrolysis and chemical methods, which involve adding chemicals such as silver nitrate to water. Of these methods, electrolysis is preferred from the viewpoint of preparing high-concentration silver ion water. Silver ion water can be readily obtained commercially, for example, as a product manufactured by Antimicrobial Chemicals Co., Ltd., trade name: High-Concentration Silver-Based Liquid Antimicrobial Agent (silver ion concentration: 500 ppm), and commercially available silver ion water may be used in this invention.

[0046] While there is no particular upper limit to the concentration of silver ions in silver ion water, from the viewpoint of easily preparing silver ion water of a desired concentration by diluting high-concentration silver ion water with water, for example, the stock solution of silver ion water may be around 5000 ppm.

[0047] The silver ion content in the ointment of the present invention is preferably 3 to 100 ppm, more preferably 5 to 50 ppm, from the viewpoint of suppressing scar formation and healing skin ulcers that extend to the middle layer of the dermis, as well as erosions and shallow skin ulcers, without leaving scars.

[0048] The ointment of the present invention may contain pharmaceutically acceptable additives, provided that the objectives of the present invention are not hindered. Examples of such additives include alcohols such as glycerin, lauryl alcohol, cetyl alcohol, cetostearyl alcohol, oleyl alcohol, and isostearyl alcohol; fatty acid esters such as glycerin fatty acid esters and isopropyl myristate; paraffin; liquid paraffin; ceresin; squalane; lauric acid; myristic acid; oleic acid; isostearin; olive oil; castor oil; various vitamins; maltose; dextrose; dextrin; xylitol; and colorants. However, the present invention is not limited to these examples.

[0049] As described above, the scar formation inhibitor and the ointment containing the present invention both contain sacran obtained from Suizenji-nori, which is used for food, as a raw material, and are therefore highly safe for the human body. They can suppress scar formation not only for erosions and shallow skin ulcers, but also for skin ulcers that reach the middle layer of the dermis, and heal such skin ulcers without leaving scars. Therefore, they are expected to be widely used as a scar formation inhibitor and ointment to replace conventional scar formation inhibitors. [Examples]

[0050] Next, the present invention will be described in more detail based on examples, but the present invention is not limited to such examples.

[0051] Example 1 As the sacran used, we used sacran obtained from Green Science Material Co., Ltd. [sacran represented by formula (I) above, weight-average molecular weight: 3 million].

[0052] The sacran was ground so that the average particle size of the sacran was between 0.05 μm and 500 μm, and the resulting sacran powder was used as a scar formation inhibitor.

[0053] 5 g of the scar formation inhibitor obtained above was added to 95 g of white petrolatum (Japanese Pharmacopoeia), and kneaded until the sacran was uniformly dispersed in the white petrolatum, thereby obtaining 100 g of ointment (hereinafter referred to as sacran ointment) with a sacran powder content of 5% by mass. In the same manner as above, an amount of sacran ointment corresponding to the number of subjects shown below was prepared.

[0054] Next, the sacran ointment obtained above was applied to subjects with skin ulcers based on the following method, and the effect of sacran ointment on inhibiting scar formation was investigated.

[0055] ·Case 1 (traumatic skin ulcer) Figure 1 shows before and after photographs of a 2-year-old girl with a traumatic skin ulcer on her face that reached the mid-dermis, after applying Sacran ointment at a dose of approximately 0.5g twice a day for 3 months.

[0056] In Figure 1, (a) is a substitute photograph of the girl before the simple application of Sacran ointment, and (b) is a substitute photograph of the girl after the simple application of Sacran ointment for three months.

[0057] As shown in Figure 1, before the application of Sacran ointment, scar formation due to skin ulcers reaching the mid-dermis was observed. However, when Sacran ointment of the present invention was applied to a traumatic skin ulcer on the face of a girl, although slight scarring was observed on the upper lip after 3 months from the start of application, the skin ulcer was completely healed without leaving any scarring. This indicates that scar formation was effectively suppressed and the scar disappeared.

[0058] Case 2 (Traumatic skin ulcer on the face caused by scratching with fingernails) Figure 2 shows before and after photos of a 5-year-old boy with a traumatic facial ulcer caused by fingernail scratching, treated with simple application of Sacran ointment at a rate of approximately 0.3g twice a day for two weeks.

[0059] In Figure 2, (a) is a substitute photograph of the boy before the simple application of Sacran ointment, and (b) is a substitute photograph of the boy after the simple application of Sacran ointment for two weeks.

[0060] As shown in Figure 2, before the application of Sacran ointment, shallow, wide scars were observed on the upper part of the eyebrows and on the eyelids. Based on experience, such scars are not expected to disappear completely but are likely to remain as scars. However, when Sacran ointment of the present invention was applied to scratches on the face of a boy, the scars disappeared after two weeks, and the scratches were almost completely healed. This indicates that scar formation is effectively suppressed and the scars disappear.

[0061] Furthermore, in cases 1 and 2, no skin irritation or contact dermatitis was observed as a result of using Sacran ointment.

[0062] Example 2 An ointment (hereinafter referred to as Sacran Silver Ointment) was prepared in the same manner as in Example 1, except that silver ion water with a silver ion concentration of 500 ppm was added to the Sacran Ointment obtained in Example 1 so that the silver ion content in the ointment was 20 ppm.

[0063] Next, using the sacran silver ointment obtained above, the effect of sacran silver ointment on inhibiting scar formation was investigated based on the following method.

[0064] • Case 3 (Erosion of the neck) Figure 3 shows before and after photographs of a 1-year-old boy with a neck erosion treated with sacran silver ointment, applied twice a day at a rate of approximately 1g per application for 8 days.

[0065] In Figure 3, (a) is a substitute photograph of the boy before the application of silver sacran ointment, and (b) is a substitute photograph of the boy after simple application of silver sacran ointment for 8 days.

[0066] As shown in Figure 3, before the application of sacran silver ointment, erosions accompanied by exudate were observed throughout the neck. However, when the sacran silver ointment of the present invention was applied to the neck of a boy, no bacterial infection was observed in the neck after 8 days from the start of application of the sacran silver ointment. Although mild erythema was slightly observed, scar formation was suppressed, and the condition improved to the point where no scars were visible.

[0067] Case 4 (Acne-like rash) Figure 4 shows before and after photographs of a 35-year-old woman with acne-like facial rashes treated with sacran silver ointment, applied twice a day at a rate of approximately 1g per application for 4 weeks.

[0068] In Figure 4, (a) is a substitute photograph of the woman before the application of sacran silver ointment, and (b) is a substitute photograph of the woman after simple application of sacran silver ointment for 4 weeks.

[0069] As shown in Figure 4, before application of sacran silver ointment, acne-like rashes were observed around the lips on the face. However, when the sacran silver ointment of the present invention was applied to the area around the lips on the face of a woman, the acne-like rashes were completely healed without leaving scars after two weeks from the start of application, indicating that scar formation was effectively suppressed.

[0070] Case 5 (Acne vulgaris and acneiform rash) Ten patients (average age: 25.8 years, 2 males, 8 females) suffering from acne vulgaris or acneiform rash were given sacran silver ointment at a dose of approximately 1-2 g twice a day for one month. One month after the start of application, the affected areas of acne vulgaris or acneiform rash were visually observed. As a result, scar formation was suppressed in all patients with acne vulgaris or acneiform rash, and no new scars were formed, confirming that sacran silver ointment has an excellent effect in suppressing scar formation.

[0071] Furthermore, in cases 3-5, no skin irritation or contact dermatitis was observed as a result of using silver sacran ointment.

[0072] From the results above, it was confirmed that the ointment using the scar formation inhibitor of the present invention, because it contains sacran as an active ingredient, is effective in suppressing scar formation not only for erosions and shallow skin ulcers, but also for skin ulcers that extend to the middle layer of the dermis, thereby healing the skin ulcers without leaving scars. [Industrial applicability]

[0073] The scar formation inhibitor of the present invention effectively suppresses scar formation not only in erosions and shallow skin ulcers, but also in skin ulcers that extend to the middle layer of the dermis. Therefore, it is expected to be used as a substitute for conventionally used scar formation inhibitors.

Claims

1. A scar formation inhibitor containing sacran as an active ingredient.

2. An ointment containing the scar formation inhibitor and petrolatum described in claim 1.

3. Furthermore, the ointment according to claim 2 contains silver ions.

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