Compounds, polymers, gel dressings, methods of making the same, and uses thereof

Abstract

The application provides a functional monomer shown in formula (I), a preparation method thereof, a gel prepared from the functional monomer, a gel dressing and application of the gel dressing. The application uses polyvinyl alcohol, polyglutamic acid and acrylic acid as gel raw materials, adds sodium chloride as an effective component, adds initiators and crosslinking agents, grafts a compound shown in formula (I) containing a disulfide bond, forms an interpenetrating gel network, and the prepared gel dressing can be quickly attached to the skin and can be easily and completely removed from the skin surface. The gel dressing solves the problem of poor patient compliance, and the gel dressing can be attached to the common warts when used, which is simple and convenient, does not contain preservatives, is completely non-toxic and non-side effect to the human body, and is safe and reliable. Experimental results show that the gel dressing provided by the application can be quickly attached to the skin and form stable adhesion, and can be easily and completely separated from the skin under the action of sodium bicarbonate and glutathione after the warts disappear.

Description

Technical Field

[0001] This invention relates to the field of medical materials technology, and in particular to a compound, polymer, gel dressing, its preparation method and its application. Background Technology

[0002] Common warts are benign skin tumors caused by human papillomavirus (HPV) infection. They most commonly appear on the fingers, toes, soles of the feet, and backs of the hands. They are contagious and have a high recurrence rate. Current treatments for common warts primarily focus on destroying the wart itself; the goal of treatment is to remove the wart.

[0003] Existing techniques (such as "Treatment of 52 Cases of Common Warts with Saturated Saline Immersion") disclose soaking or applying a suitable amount of saturated saline solution to common warts once a day for 30 minutes each time. After 4 weeks of observation, the overall effective rate was 100%. This method mainly relies on the dehydrating effect of sodium chloride ions, resulting in a high osmotic pressure environment on the warts. This may damage or cause dysfunction of host cells, thereby affecting the viral replication process, viral stability, transmission, and infectivity. However, this method requires soaking or applying a wet compress, which is inconvenient in terms of operation. Summary of the Invention

[0004] In view of this, the present invention provides a compound, a polymer, a gel dressing, a method for preparing the same, and its application. The gel dressing provided in this application is easy to use, can be quickly adhered to the skin, and can be easily detached from the skin after treatment.

[0005] This application provides the functional unit shown in formula (I):

[0006]

[0007] This application also provides a method for preparing the functional monomer shown in formula (I), comprising the following steps:

[0008] 1,4,5-O-dithiocyclohexane-2,7-dione and 2-hydroxyethyl methacrylate react in the presence of an organic base to give the dithiocarboxylic acid ester compound shown in formula (1).

[0009]

[0010] The dithiocarboxylic acid ester compound shown in formula (1) reacts with N,N'-carbonyldiimidazole to obtain the functional monomer shown in formula (I);

[0011]

[0012] This application also provides a gel prepared from polyvinyl alcohol, acrylic acid, polyglutamic acid, the compound shown in formula (I), an initiator, and a crosslinking agent:

[0013]

[0014] In some specific implementations, the mass ratio of polyvinyl alcohol, acrylic acid, polyglutamic acid, the compound shown in formula (I), initiator and crosslinking agent is 1-20:10-50:0.1-1:0.1-5:0.1-1:0.01-1.

[0015] In some specific implementations, the initiator is selected from at least one of α-ketoglutaric acid, α-hydroxyphosphate, peroxide, xylyl ketone, benzoyl propylene glycol, and benzoyl ethylene glycol.

[0016] The crosslinking agent is selected from at least one of polyethylene methacrylate, dimethacrylate, epoxy acrylate, polyvinylpyrrolidone, and epoxy vinyl ether;

[0017] The number average molecular weight of the polyvinyl alcohol is 5 to 1,000,000 Daltons.

[0018] This application also provides a gel dressing comprising a gel prepared from polyvinyl alcohol, acrylic acid, polyglutamic acid, a compound of formula (I), an initiator, and a crosslinking agent, and sodium chloride loaded in the gel:

[0019]

[0020] In some specific implementations, the mass ratio of polyvinyl alcohol, acrylic acid, polyglutamic acid, the compound shown in formula (I), initiator, crosslinking agent and sodium chloride is 1-20:10-50:0.1-1:0.1-5:0.1-1:0.01-1:5-25.

[0021] In some specific implementations, the initiator is selected from at least one of α-ketoglutaric acid, α-hydroxyphosphate, peroxide, xylyl ketone, benzoyl propylene glycol, and benzoyl ethylene glycol.

[0022] The crosslinking agent is selected from at least one of polyethylene methacrylate, dimethacrylate, epoxy acrylate, polyvinylpyrrolidone, and epoxy vinyl ether;

[0023] The number average molecular weight of the polyvinyl alcohol is 5 to 1,000,000 Daltons.

[0024] In some specific implementations, the gel dressing further includes a protective layer laminated onto the gel.

[0025] The use of the gel and / or the gel dressing described in the above technical solutions in the preparation of drugs for treating common warts and / or for antibacterial and bacteriostatic purposes.

[0026] This application uses polyvinyl alcohol, polyglutamic acid, and acrylic acid as gel raw materials, sodium chloride as the active ingredient, and adds initiators and cross-linking agents to graft compounds containing disulfide bonds as shown in formula (I) to form an interpenetrating gel network. The prepared gel dressing can rapidly adhere to the skin after absorbing water through hydrogen bonding and electrostatic interaction. Subsequently, the compound shown in formula (I) in the gel dressing can form stable covalent amide bonds with the amine groups in the skin, stably adhering to the skin. Sodium chloride ions in the gel contact the wart lesion with water molecules, resulting in a high osmotic pressure environment, thereby affecting the viral replication process, viral stability, transmission, and infectivity. The gel contains disulfide bonds. When the sodium chloride ions inside the gel are completely released, the disulfide bonds can be broken using a dissociation solution containing sodium bicarbonate and glutathione, thereby easily and thoroughly removing the gel dressing from the skin surface. This gel dressing solves the problem of poor patient compliance. When using it, the gel dressing is simply applied to the wart lesion, which is simple and convenient, preservative-free, completely non-toxic to the human body, and safe and reliable. In addition, the gel dressing provided by this application has good bactericidal effect. Experimental results show that the gel dressing provided in this application can quickly adhere to the skin and form a stable adhesion. After the warts disappear, they can easily and completely detach from the skin under the action of sodium bicarbonate and glutathione. Attached Figure Description

[0027] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0028] Figure 1 The application principle and method of using the gel dressing provided in this application. Detailed Implementation

[0029] It should be understood that the expression “one or more of…” individually includes each of the objects described after the expression, as well as various different combinations of two or more of the described objects, unless otherwise understood from the context and usage. The expression “and / or” combined with three or more described objects should be understood to have the same meaning, unless otherwise understood from the context.

[0030] The terms “including,” “having,” or “containing,” including the use of their grammatical synonyms, should generally be understood as open-ended and non-restrictive, for example, not excluding other unstated elements or steps, unless otherwise specifically stated or understood from the context.

[0031] It should be understood that the order of the steps or the order in which certain actions are performed is not important as long as the invention remains operational. Furthermore, two or more steps or actions can be performed simultaneously.

[0032] The use of any and all instances or exemplary language such as “e.g.” or “including” in this document is merely intended to better illustrate the invention and is not intended to limit the scope of the invention unless the claims are made. No language in this specification should be construed as indicating that any unclaimed element is essential to the practice of the invention.

[0033] Furthermore, the numerical ranges and parameters used to define the present invention are approximate values, and the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any value inevitably contains standard deviations due to individual test methods. Therefore, unless explicitly stated otherwise, it should be understood that all ranges, quantities, values, and percentages used in this disclosure are modified with the word "approximately." Here, "approximately" generally means an actual value within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range.

[0034] This application provides the functional unit shown in formula (I):

[0035]

[0036] The functional monomer shown in formula (I) is an N,N'-carbonyldiimidazole compound containing a disulfide bond. This compound can react with the primary amine group on the skin surface to form an amide bond, thereby adhering firmly to the skin surface. At the same time, the disulfide bond can be broken by the action of sodium bicarbonate and L-glutathione, easily and completely detaching from the skin surface.

[0037] This application also provides a method for preparing the functional monomer shown in formula (I), comprising the following steps:

[0038] 1,4,5-O-dithiocyclohexane-2,7-dione and 2-hydroxyethyl methacrylate react in the presence of an organic base to give the dithiocarboxylic acid ester compound shown in formula (1).

[0039]

[0040] The dithiocarboxylic acid ester compound shown in formula (1) reacts with N,N'-carbonyldiimidazole to obtain the functional monomer shown in formula (I);

[0041]

[0042] This application uses 1,4,5-oxodithiacyclohexane-2,7-dione and 2-hydroxyethyl methacrylate as raw materials, reacting them under the action of an organic base to obtain the dithiocarboxylic acid ester compound shown in formula (1). Both 1,4,5-oxodithiacyclohexane-2,7-dione and 2-hydroxyethyl methacrylate are commercially available raw materials, and this application does not impose any special restrictions on their source. In some specific implementations, the mass ratio of 1,4,5-oxodithiacyclohexane-2,7-dione to 2-hydroxyethyl methacrylate is 1:1 to 5, preferably 1:1.2. In some specific implementations, the organic base includes, but is not limited to, 4-dimethylaminopyridine, triethylamine, N,N-dimethylacetamide, etc., and can be one or more of these. When the organic base is a combination of multiple specific substances, this application does not impose any special restrictions on the proportion of each substance. In some specific implementations, the reaction is carried out in a solvent, which includes, but is not limited to, dichloromethane, carbon tetrachloride, dimethyl ether, benzene, etc., with dichloromethane being preferred. In some specific implementations, the reaction is preferably carried out at room temperature, and the reaction time is preferably 10 h to 30 h.

[0043] After the reaction is complete, the resulting reaction product is acidified, extracted, dried, concentrated, and purified to obtain the dithiocarboxylic acid ester compound shown in formula (1). This application does not have any special requirements for the acidification, extraction, drying, concentration, and purification processes; those skilled in the art can select them according to their needs.

[0044] After obtaining the dithiocarboxylic acid ester compound shown in formula (1), it is reacted with N,N'-carbonyldiimidazole to obtain the acylimidazole compound shown in formula (I). In some specific implementations, the mass ratio of the dithiocarboxylic acid ester compound shown in formula (1) to N,N'-carbonyldiimidazole is 1:1 to 2, preferably 1:1.5. In some specific implementations, the reaction is carried out in a solvent, which includes, but is not limited to, dichloromethane, chloroform, dimethyl thionamide, acetonitrile, etc., preferably dichloromethane. In some specific implementations, the reaction is preferably carried out at room temperature, and the reaction time is preferably 10 h to 30 h.

[0045] After the reaction is complete, the resulting reaction product is purified to obtain the acylimidazole compound shown in formula (I). This application does not impose any particular limitations on the purification process; purification can be performed using a mixture of dichloromethane and methanol as the eluent and employing a chromatographic column.

[0046] This application also provides a gel prepared from polyvinyl alcohol, acrylic acid, polyglutamic acid, the compound shown in formula (I), an initiator, and a crosslinking agent:

[0047]

[0048] This application uses polyvinyl alcohol, acrylic acid, polyglutamic acid, and the compound shown in formula (I) as raw materials. Under the action of the crosslinking agent of the initiator, polyvinyl alcohol, acrylic acid, and polyglutamic acid are grafted onto the compound shown in formula (I) to form an interpenetrating gel network, which can be used as a gel dressing.

[0049] In some specific implementations, the mass ratio of polyvinyl alcohol, acrylic acid, polyglutamic acid, the compound shown in formula (I), initiator and crosslinking agent is 1-20:10-50:0.1-1:0.1-5:0.1-1:0.01-1, preferably 5-15:15-45:0.2-0.9:0.5-3:0.2-0.9:0.05-0.8.

[0050] The gel raw materials provided in this application include polyvinyl alcohol (PVA), which, as the main component forming the gel, preferably has a number-average molecular weight of 5 to 1,000,000 Daltons, more preferably 100,000 to 900,000 Daltons. The gel raw materials provided in this application include acrylic acid, which is copolymerized with PVA to form a gel network. The gel raw materials provided in this application include polyglutamic acid, which can enhance the moisture content of the gel and increase the loading of sodium chloride. The gel raw materials provided in this application include compounds of formula (I), which will not be described further herein.

[0051] The gel raw material provided in this application also includes an initiator. In some specific implementations, the initiator is selected from at least one of α-ketoglutaric acid, α-hydroxyphosphate, peroxide, xylyl methyl ketone, benzoyl propylene glycol and benzoyl ethylene glycol. When the initiator is multiple of these, this application does not have any special restrictions on the proportion of each specific substance.

[0052] The gel raw material provided in this application also includes a crosslinking agent. In some specific implementations, the crosslinking agent is selected from at least one of polyethylene methacrylate, dimethacrylate, epoxy acrylate, polyvinylpyrrolidone, and epoxy vinyl ether. When the initiator is one of multiple substances, this application does not impose any special restrictions on the proportion of each specific substance.

[0053] This application does not impose any particular limitation on the preparation method of the gel. Polyvinyl alcohol, acrylic acid, polyglutamic acid crosslinking agent, and initiator are mixed in a first solvent to obtain a reaction stock solution; the compound shown in formula (I) is dissolved in an organic solvent and mixed with the reaction stock solution to obtain a precursor fluid; the precursor fluid is then cured to obtain the gel dressing. In some specific implementations, the first solvent is selected from deionized water, and the organic solvent is selected from acetone. In some specific implementations, the curing is preferably ultraviolet curing, with a wavelength preferably between 280 nm and 320 nm, and a power preferably between 10 W and 120 W.

[0054] This application also provides a gel dressing comprising a gel prepared from polyvinyl alcohol, acrylic acid, polyglutamic acid, a compound of formula (I), an initiator, and a crosslinking agent, and sodium chloride loaded in the gel. Compared to a gel, the gel dressing provided in this application loads sodium chloride in the gel, making the gel dressing more suitable for treating diseases such as common warts.

[0055] In some specific implementations, the mass ratio of polyvinyl alcohol, acrylic acid, polyglutamic acid, the compound shown in formula (I), initiator, crosslinking agent and sodium chloride is 1-20:10-50:0.1-1:0.1-5:0.1-1:0.01-1:5-25, preferably 5-15:15-45:0.2-0.9:0.5-3:0.2-0.9:0.05-0.8:10-20.

[0056] The other components of the gel dressing are the same as those described above, and will not be repeated here.

[0057] The preparation method of the gel dressing differs from that of the gel in that sodium chloride is mixed simultaneously with the stock solution when mixing the raw materials. Other steps and parameters are basically the same, and will not be described in detail here.

[0058] In some specific implementations, the gel dressing further includes a protective layer laminated onto the gel.

[0059] The gel provided in this application and / or the gel dressing described in the above technical solutions can be used to treat common warts and / or antibacterial and antimicrobial drugs.

[0060] The principle of use of the gel dressing provided in this application is as follows: Figure 1 As shown, Figure 1 The application provides the principle and method of using the gel dressing, wherein... Figure 1 (a) is a schematic diagram of applying a gel dressing to the skin. Figure 1 (b) is a schematic diagram showing the release of sodium chloride ions after the gel dressing adheres to the skin. Figure 1 (c) is a schematic diagram of removing the gel dressing using a dissociation solution. The gel dressing provided in this application can absorb water and quickly adhere to the skin through hydrogen bonding and electrostatic interaction. Subsequently, the compound shown in formula (I) in the gel dressing can form stable covalent amide bonds with amine groups in the skin, thus adhering stably to the skin. Sodium chloride ions in the gel come into contact with the wart lesion along with water molecules, resulting in a high osmotic pressure environment, thereby affecting the viral replication process, viral stability, transmission, and infectivity. The gel contains disulfide bonds. When the sodium chloride ions inside the gel are completely released, the disulfide bonds can be broken using a dissociation solution containing sodium bicarbonate and glutathione, thereby easily and thoroughly removing the gel dressing from the skin surface.

[0061] This application also provides a dissociation solution comprising sodium bicarbonate, glutathione, and phosphate buffer. This application does not impose any particular limitation on the phosphate buffer, but preferably it is a phosphate buffer with a pH of 7–7.4. In some specific implementations, the concentration of sodium bicarbonate is 5–15 g / mL, preferably 8–10 g / mL; the concentration of glutathione is 0.5–3 g / mL, preferably 1–2.5 g / mL. The dissociation solution is used to dissociate the aforementioned gel dressing from the skin surface.

[0062] The gel dressing provided in this application also has bactericidal and bacteriostatic functions and can be used for wound treatment.

[0063] This application uses polyvinyl alcohol, polyglutamic acid, and acrylic acid as gel raw materials, sodium chloride as the active ingredient, and adds an initiator and a cross-linking agent to graft a compound containing disulfide bonds as shown in formula (I). The resulting gel dressing can be quickly applied to the skin surface and treats common warts by releasing sodium chloride. Furthermore, the gel contains disulfide bonds, which can be broken under the action of sodium bicarbonate and glutathione, allowing the gel to easily detach from the skin. Experimental results show that the gel dressing provided in this application can quickly adhere to the skin, and after the warts disappear, it can easily and completely detach from the skin under the action of sodium bicarbonate and glutathione.

[0064] The following examples further illustrate the compounds, gels, gel dressings, their preparation methods, and their applications provided in this application.

[0065] Example 1

[0066] 1.5 g of 1,4,5-oxodithiacyclohexane-2,7-dione oil was transferred into a mixture of 1.9 g of 2-hydroxyethyl methacrylate, 12 mg of 4-dimethylaminopyridine, and 15 mL of anhydrous dichloromethane. The mixture was stirred overnight at room temperature, and 30 mL of saturated sodium bicarbonate solution was added to complete the reaction. The mixture was then acidified to pH 2 with 1 M HCl, extracted with dichloromethane, dried on sodium sulfate, concentrated under reduced pressure, and the crude product was purified in a chromatographic column to the dithiocarboxylic acid ester compound shown in formula (1).

[0067]

[0068] 1.08 g of the purified product was dissolved in 30 mL of anhydrous dichloromethane and reacted with 1.5 g of CDI (N,N'-carbonyldiimidazole) overnight to obtain a crude product. The crude product was purified by eluing with a mixture of dichloromethane and methanol in a volume ratio of 85:15 to obtain the acylimidazole compound shown in formula (I).

[0069]

[0070] Example 2: Preparation of Gel Dressing

[0071] Step (1) Prepare a gel solution containing sodium chloride:

[0072] The stock solution was prepared by dissolving 7% (w / v) polyvinyl alcohol, 35% (w / v) acrylic acid, 5% (w / v) sodium chloride, 0.5% (w / v) polyglutamic acid, 0.2% (w / v) α-ketoglutarate and 0.03% (w / v) polyethylene methacrylate in deionized water.

[0073] Step (2) Grafting disulfide bonds:

[0074] Dissolve 100 mg of the acylimidazolium compound of formula (2) prepared in Example 1 in acetone, and add 10 mL of the stock solution obtained in step (1) to obtain the precursor solution;

[0075] Step (3) Curing:

[0076] The precursor solution prepared in step (2) was poured onto a mold and cured under ultraviolet light with a wavelength range of 280 nm to 320 nm and a power of 100 W to obtain a gel.

[0077] Step (4) uses:

[0078] The gel obtained in step (3) is applied to the warts and kept moist until the sodium chloride is completely released. The gel provided in this application can be quickly applied to the skin surface. On the second day after application, the warts begin to dry, peel, and gradually shrink in size until the warts disappear completely, thus achieving the treatment of warts.

[0079] Preparation of dissociation solution: Dissolve 9.585g sodium bicarbonate and 1.5366g glutathione in 100mL phosphate buffer solution to obtain dissociation solution; remove the gel dressing in the dry or shrunken state using the dissociation solution, and the gel will completely detach from the skin without residue.

[0080] Example 3: Preparation of gel dressing:

[0081] The difference from Example 2 is that the proportions of the raw materials in step (1) are different, specifically: 7% (w / v) polyvinyl alcohol, 35% (w / v) acrylic acid, 10% (w / v) sodium chloride, 0.5% (w / v) polyglutamic acid, 0.2% (w / v) α-ketoglutarate and 0.03% (w / v) polyethylene methacrylate. All other steps are the same.

[0082] Example 4: Preparation of gel dressing:

[0083] The difference from Example 2 is that the proportions of the raw materials in step (1) are different, specifically: 7% (w / v) polyvinyl alcohol, 35% (w / v) acrylic acid, 18% (w / v) sodium chloride, 0.5% (w / v) polyglutamic acid, 0.2% (w / v) α-ketoglutarate and 0.03% (w / v) polyethylene methacrylate. All other steps are the same.

[0084] Experimental Example 1

[0085] Test bacteria: Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 25922).

[0086] Experimental methods:

[0087] Take a petri dish, pour in the culture medium, and after it solidifies, place it flat. Then, pour in the culture medium containing the soaking solution of the gel dressings from Examples 1, 2, and 3, respectively. After solidification, evenly spread the selected bacteria on top. Place the petri dish in a 37°C incubator and incubate for 24 hours. Observe the growth of the bacteria to determine the concentration range within which Examples 1, 2, and 3 have an inhibitory effect on the bacterial species. The results are shown in Table 1, which presents the antibacterial test results of the gel dressings from Examples 1 to 3.

[0088] Table 1. Antibacterial test results of gel dressings in Examples 1-3

[0089]

[0090] As shown in Table 1, the gel dressing provided by the present invention has a good antibacterial effect.

[0091] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The functional unit shown in equation (I):

2. A method for preparing the functional monomer shown in formula (I), comprising the following steps: 1,4,5-O-dithiocyclohexane-2,7-dione and 2-hydroxyethyl methacrylate react in the presence of an organic base to give the dithiocarboxylic acid ester compound shown in formula (1). The dithiocarboxylic acid ester compound shown in formula (1) reacts with N,N'-carbonyldiimidazole to obtain the functional monomer shown in formula (I); 3. A gel prepared from polyvinyl alcohol, acrylic acid, polyglutamic acid, a compound of formula (I), an initiator, and a crosslinking agent:

4. The gel according to claim 3, characterized in that, The mass ratio of polyvinyl alcohol, acrylic acid, polyglutamic acid, the compound shown in formula (I), initiator and crosslinking agent is 1-20:10-50:0.1-1:0.1-5:0.1-1:0.01-1.

5. The gel according to claim 3, characterized in that, The initiator is selected from at least one of α-ketoglutaric acid, α-hydroxyphosphate, peroxide, xylmethyl ketone, benzoylpropanedione, and benzoyl ethylenedione; The crosslinking agent is selected from at least one of polyethylene methacrylate, dimethacrylate, epoxy acrylate, polyvinylpyrrolidone, and epoxy vinyl ether; The number average molecular weight of the polyvinyl alcohol is 5 to 1,000,000 Daltons.

6. A gel dressing comprising a gel prepared from polyvinyl alcohol, acrylic acid, polyglutamic acid, a compound of formula (I), an initiator, and a crosslinking agent, and sodium chloride loaded in the gel:

7. The gel dressing according to claim 6, characterized in that, The mass ratio of polyvinyl alcohol, acrylic acid, polyglutamic acid, the compound shown in formula (I), initiator, crosslinking agent and sodium chloride is 1~20:10~50:0.1~1:0.1~5:0.1~1:0.01~1:5~25.

8. The gel dressing according to claim 6, characterized in that, The initiator is selected from at least one of α-ketoglutaric acid, α-hydroxyphosphate, peroxide, xylmethyl ketone, benzoylpropanedione, and benzoyl ethylenedione; The crosslinking agent is selected from at least one of polyethylene methacrylate, dimethacrylate, epoxy acrylate, polyvinylpyrrolidone, and epoxy vinyl ether; The number average molecular weight of the polyvinyl alcohol is 5 to 1,000,000 Daltons.

9. The gel dressing according to claim 6, characterized in that, It also includes a protective layer laminated onto the gel.

10. Use of the gel according to any one of claims 3 to 5 and / or the gel dressing according to any one of claims 6 to 9 in the preparation of medicaments for treating common warts and / or for antibacterial and bacteriostatic purposes.

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