Topical preparations containing rapamycin

Abstract

[Problem] To provide an external preparation that contains rapamycin, has high stability and is efficacious in treating skin diseases. [Solution] An external preparation that contains (a) rapamycin, (b) at least one member selected from the group consisting of ethylene glycol salicylate, diethyl sebacate and triacetin, and (c) propylene glycol and / or polyethylene glycol, an external preparation that further contains an antioxidant, and an external preparation that further contains a solution of an antioxidant in a lipophilic solvent.

Description

[Technical Field]

[0001] The present invention relates to an external preparation containing rapamycin, and more particularly to an external preparation containing rapamycin, which has excellent stability and is effective in treating skin diseases. [Background technology]

[0002] Rapamycin (generic name: sirolimus) is a macrolide produced by microorganisms. Because of its immunosuppressive properties, rapamycin has been used to treat a variety of diseases. For example, it is used as an oral medication for the treatment of lymphangioleiomyomatosis, and more recently, it has also been used as a topical agent for the treatment of skin lesions associated with tuberous sclerosis complex.

[0003] On the other hand, although rapamycin dissolves in some organic solvents such as ethanol, it is practically insoluble or poorly soluble in many solvents such as water.

[0004] When rapamycin is used as an external preparation, it is necessary to dissolve it in a solvent and disperse it in an ointment base, etc. As mentioned above, rapamycin is practically insoluble in most solvents, except for some solvents such as ethanol. However, since alcohol is a skin irritant, the solvent must be carefully selected.

[0005] Rapamycin is also susceptible to oxidative degradation and decomposition in the presence of water, and while pharmaceutical formulations combining rapamycin with antioxidants have been developed, it has been difficult to disperse lipid-soluble antioxidants in alcohol-free solutions of rapamycin.

[0006] Patent Document 1 discloses an alcohol-free composition for treating skin diseases, which contains rapamycin and polyethylene glycol. Patent Document 2 discloses an anhydrous composition for treating skin diseases, which contains an mTOR inhibitor such as rapamycin, an antioxidant, and a gelling agent. In this document, propylene glycol or the like is used as a solvent. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO2018 / 031789 publication [Patent Document 2] WO2018 / 129364 publication Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention has been made in view of the above circumstances, and aims to provide an external preparation that does not contain alcohol, has guaranteed stability, and contains an effective amount of rapamycin. [Means for solving the problem]

[0009] The inventors have investigated various combinations of solvents that do not contain alcohol, that ensure the stability of rapamycin, and that can contain an effective amount of rapamycin, and have found that the above problems can be solved by combining specific solvents, thereby completing the present invention.

[0010] That is, the present invention provides: (a) rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin, and (c) An external preparation containing propylene glycol and / or polyethylene glycol.

[0011] The present invention also provides (a) rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin; (c) propylene glycol and / or polyethylene glycol, and (d) an antioxidant.

[0012] Furthermore, the present invention provides (a) rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin; (c) propylene glycol and / or polyethylene glycol, and (d1) An external preparation comprising a lipophilic solvent solution of an antioxidant.

[0013] Furthermore, the present invention provides (i)(d1) dissolving an antioxidant in a lipophilic solvent; and (ii) A method for producing an external preparation, comprising the step of mixing the solution obtained in (i) with a solution containing the following (a), (b), and (c): (a) rapamycin (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin; (c) propylene glycol and / or polyethylene glycol.

[0014] The present invention provides (i) a mixture obtained by dissolving an antioxidant in a lipophilic solvent; (ii) A topical preparation obtained by mixing a solution containing the following (a), (b), and (c): (a) rapamycin (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin; (c) propylene glycol and / or polyethylene glycol. [Effects of the Invention]

[0015] According to the present invention, it is possible to provide a highly stable preparation, particularly an external preparation, in which rapamycin is present stably without precipitating during storage of the preparation and in which decomposition within the preparation is suppressed. [Brief explanation of the drawings]

[0016] [Figure 1A] FIG. 1 is a graph showing the stability (residual rate) of sirolimus in an aqueous ethanol solution of sirolimus and various sirolimus-BHT blend solutions at 40° C. [Figure 1B] FIG. 1 is a graph showing the stability (residual rate) of sirolimus in an aqueous ethanol solution of sirolimus and various sirolimus-BHT blend solutions at 50° C. [Figure 2] FIG. 1 is a graph showing the stability (residual rate) of sirolimus at 40° C. or 50° C. when BHT is added at concentrations of 1% to 10%. DETAILED DESCRIPTION OF THE INVENTION

[0017] Topical preparations containing rapamycin The topical preparation of the present invention comprises: (a) rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin, and (c) propylene glycol and / or polyethylene glycol.

[0018] (a) Rapamycin is known generically as sirolimus and is commercially available. In this specification, rapamycin and sirolimus are used synonymously.

[0019] Instead of rapamycin, everolimus or temsirolimus, which are known as derivatives of rapamycin, can also be used in place of rapamycin or in combination with rapamycin.

[0020] The amount of rapamycin used can be 0.05 to 1% by weight, preferably 0.1 to 0.8%, and particularly preferably 0.1 to 0.5%, based on the total weight of the preparation.

[0021] As the solvent (b), at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin is used, and they may be mixed in any ratio for use.

[0022] As the solvent (c), propylene glycol, polyethylene glycol, or a mixture thereof is used, and in particular, a mixture of propylene glycol and polyethylene glycol (macrogol 400) is preferred, and they may be mixed in any ratio for use.

[0023] The mixing ratio of solvent (b) to solvent (c) is not particularly limited, but examples thereof include a weight ratio of (b):(c)=2:1 to 2:6, and a particularly preferred ratio of (b):(c)=2:5 is recommended.

[0024] On the other hand, the mixing ratio of (a) rapamycin to solvent (c) is not limited as long as rapamycin dissolves in the mixture of solvents (b) and (c), but examples thereof include a weight ratio of (a):(c)=1:20 to 1:70, preferably (a):(c)=1:60, and examples thereof include a weight ratio including solvent (b) of (a):(b):(c)=1:20 to 80:20 to 70, preferably (a):(b):(c)=1:25:60.

[0025] The topical preparation of the present invention may further contain an antioxidant (d). Adding an antioxidant to the topical preparation prevents the decomposition of rapamycin and ensures long-term storage stability. Specific examples of antioxidants include dibutylhydroxytoluene (BHT), tocopherol, and ascorbic acid, with dibutylhydroxytoluene (BHT) being preferred.

[0026] The amount of antioxidant used is, for example, 1 to 10% by weight, preferably 1 to 5%, and particularly preferably 1 to 2% based on the total weight of the preparation.

[0027] The antioxidant can be added directly to the formulation containing (a), (b), and (c), but it is preferred to add a solution (d1) of the antioxidant dissolved in a lipophilic solvent to the formulation containing (a), (b), and (c).

[0028] Such lipophilic solvents include liquid paraffin, a mixture of liquid paraffin and polyethylene (gelled hydrocarbon), etc., with liquid paraffin being preferred.

[0029] The amount of lipophilic solvent used relative to the antioxidant is, for example, a weight ratio of antioxidant:lipophilic solvent=1:10 to 3:10, preferably 3:10.

[0030] A surfactant may be further added to the solution (d1) in which the antioxidant is dissolved in the lipophilic solvent. Preferred examples of the surfactant include surfactants with an HLB of 4 to 7, and preferably one or more surfactants with an HLB of 5 to 6.

[0031] The addition of such surfactants further stabilizes the resulting formulation.

[0032] The surfactant may be, for example, at least one, preferably at least two selected from the group consisting of polyoxyethylene cetyl ether, glycerin monostearate, and polyoxyethylene hydrogenated castor oil.

[0033] Specific examples of surfactants include: - POE cetyl ether: glycerin monostearate = 1:4 (weight ratio), - Glycerin monostearate: POE hydrogenated castor oil = 4:1 (weight ratio) is exemplified.

[0034] The topical preparation of the present invention may contain other excipients or additives that are commonly used to prepare pharmaceutical dosage forms, as long as they do not impair the effects of the present invention. For example, gelling agents, thickeners, pH adjusters, inorganic salts, etc. may be used.

[0035] Examples of gelling agents include water-soluble cellulose-derived polymers such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylhydroxyethylcellulose, methylcellulose, and carrageenan. Examples of thickeners include hydroxypropylcellulose. Examples of pH adjusters include acidic additives such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, malic acid, mesylic acid, tosylic acid, and besylic acid, as well as buffers containing alkali metal salts, alkaline earth metal salts, and ammonium salts. Examples of inorganic salts include calcium chloride, sodium chloride, calcium oxide, and magnesium sulfate.

[0036] Furthermore, other medicinal ingredients can be added to the topical preparation of the present invention as long as they do not interfere with the effects of the main active ingredient, rapamycin. Examples of such other medicinal ingredients include tacrolimus and steroids.

[0037] Manufacturing method of topical preparation The topical preparation of the present invention can be produced as follows.

[0038] for example, (a) rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin; (c) Propylene glycol and / or polyethylene glycol are mixed.

[0039] When antioxidants are used, (i)(d1) dissolving an antioxidant in a lipophilic solvent; and (ii) The solution obtained in (i) and the following (a), (b), and (c) (a) rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin; (c) Mixing a solution containing propylene glycol and / or polyethylene glycol.

[0040] In order to obtain a more stable topical preparation, for example, (i)(d2) dissolving an antioxidant in a lipophilic solvent to prepare a mixed solution, and then adding one or more surfactants having an HLB of 5 to 7 to the mixed solution; and (ii) The solution obtained in (i) and the following (a) rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin; (c) mixing a solution containing propylene glycol and / or polyethylene glycol (hereinafter, also referred to as "a solution of rapamycin in a hydrophilic solvent").

[0041] In particular, by adding one or more surfactants having an HLB of 5 to 7 to the mixture of the antioxidant dissolved in the lipophilic solvent in step (d2) of step (i) above, it is possible to further enhance the compatibility between the mixture of the antioxidant and the lipophilic solvent in step (ii) above and the solution of rapamycin in the hydrophilic solvent.

[0042] In order to obtain the topical preparation of the present invention in an optimal administration form, for example, a cream, paste, jelly, gel, emulsion, liquid, or other form, such as an ointment, liniment, or lotion, the topical preparation of the present invention may contain, in addition to the other excipients or additives described above, sodium alginate; gelatin, corn starch, tragacanth gum, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, polyvinylpyrrolidone, or the like. Any polymer; beeswax, olive oil, cocoa oil, sesame oil, soybean oil, camellia oil, peanut oil, beef fat, pork fat, lanolin; petrolatums such as white petrolatum and yellow petrolatum; paraffin, a mixture of liquid paraffin and polyethylene (gelled hydrocarbon); stearic acid; lauric acid ester, myristate ester, octanoic acid ester; cetyl alcohol, stearyl alcohol; polyethylene glycol; dimethyl sulfoxide, dodecylpyrrolidone; urea; azone; olive oil; kaolin, bentonite, zinc oxide, titanium oxide, etc. may be appropriately added.

[0043] How to use topical medications The topical preparation containing rapamycin of the present invention has an immunosuppressive effect and can therefore be used, for example, to treat skin diseases.

[0044] Specific examples of skin diseases include dermatitis, contact dermatitis, psoriasis, atopic dermatitis, seborrheic dermatitis, nummular eczema, vitiligo, rosacea, keloid, autosensitization dermatitis, stasis dermatitis, asteatotic eczema, tuberous sclerosis skin tumor, seborrheic keratosis, and Recklinghausen's disease skin tumor.

[0045] The dosage of the pharmaceutical product using the topical preparation of the present invention can be changed depending on the patient's sex, age, physiological condition, pathological condition, etc., but when used as a topical preparation, for example, the dosage is 0.01 to 100 mg / m2 of rapamycin per day for an adult. 2 (body surface area) can be administered by application. [Example]

[0046] The present invention will be described below with reference to specific embodiments, but it will be understood that the present invention is not limited to these embodiments, and that various changes and modifications therein can be made by those skilled in the art without departing from the scope or spirit of the present invention as defined in the appended claims.

[0047] Reference example 1 Sirolimus was mixed with each of the solvents shown in Table 1 at a sirolimus:solvent ratio of 1:50 (by weight), heated in a water bath at approximately 50°C, irradiated with ultrasound, and the solubility was confirmed by visual observation. As a result, as shown in Table 1, no single solvent was found to dissolve sirolimus. [Table 1]

[0048] (Quantitative test of sirolimus) An HPLC test was carried out under the following conditions, and the amount of sirolimus was determined by comparing the area of ​​the sirolimus peak in the test substance with the area of ​​the sirolimus peak in a sirolimus standard substance.

[0049] Detector: ultraviolet absorption photometer (measurement wavelength: 278 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm, packed with octadecylsilanized silica gel for chromatography. Column temperature: constant temperature around 40°C Mobile phase: acetonitrile / 0.02 mol / L ammonium acetate buffer (pH 6.0) = 13 / 7 Flow rate: 0.8 mL / min

[0050] Example 1, Comparative Example 1 Various formulations were prepared by mixing each of the solvents listed in Table 1 with propylene glycol in a weight ratio of 1:50:25 (sirolimus:solvent:propylene glycol), heating in a water bath at approximately 50°C, and irradiating with ultrasound. The solubility of the resulting formulations was confirmed by visual observation.

[0051] The solubility results are shown in Table 2. The dissolution of sirolimus was confirmed using ethylene glycol salicylate, diethyl sebacate, and a mixture of triacetin and propylene glycol. [Table 2]

[0052] The same effect can be obtained by preparing an external preparation using polyethylene glycol instead of propylene glycol.

[0053] Reference Examples 2 and 3 (Study of antioxidant formulation) A solution of sirolimus dissolved in a 50% ethanol solution at a ratio of 0.2% (hereinafter referred to as an ethanolic sirolimus solution) and a solution of sirolimus ethanol solution blended with BHT at a concentration of 0.1% (hereinafter referred to as a sirolimus-BHT blend solution) were prepared. Furthermore, a solution was prepared by adding sodium EDTA or sodium tocopherol acetate to the sirolimus-BHT blend solution. The ethanolic sirolimus solution and the various sirolimus-BHT blend solutions were stored at 40°C and 50°C, and samples were quantified after 7 and 30 hours using the method described in the "Quantitative Test" section above to calculate the residual sirolimus rate.

[0054] The composition of the sample solution is shown in Table 3, and the results are shown in Table 4 and Figures 1A and 1B. At all temperatures, the residual rate of the ethanol aqueous solution of sirolimus decreased over time (Reference Example 2). On the other hand, for the various sirolimus-BHT compound solutions, the decrease in the residual rate was significantly suppressed at all temperatures (Reference Example 3).

[0055] [Table 3] [Table 4]

[0056] Reference Example 4 (Study of the amount of BHT blended) Solutions were prepared by blending various concentrations of BHT into ethanol solutions of sirolimus, and the solutions were stored at 40°C and 50°C for 2 weeks. After storage, the amount of sirolimus in the samples was quantified in the same manner as in Reference Example 2, and the residual rate was calculated. The results are shown in Table 5 and Figure 2. It was confirmed that the stability of sirolimus was maintained by blending BHT at a concentration of 1% or more.

[0057] [Table 5]

[0058] Example 2 (Mixing of thickened sirolimus solution with BHT solution) A solution was prepared by dissolving sirolimus in a mixture of triacetin and propylene glycol (5:7) to a concentration of 1.6%. Hydroxypropyl cellulose was added to this solution to a concentration of 1.6% by weight to thicken the solution (hereinafter referred to as the thickened sirolimus solution). Separately, a solution (hereinafter referred to as BHT solution) was prepared by dissolving BHT in liquid paraffin to a concentration of 23%.

[0059] The thickened sirolimus solution and the BHT solution were mixed in a ratio of 70:30 and incubated for 11,000 min. -1 The resulting solution was left to stand for 3 hours and then visually observed. The results showed that the solution, which appeared homogeneous immediately after stirring, gradually separated into two phases.

[0060] Example 3 (Mixing Thickened Sirolimus Solution with BHT / Surfactant Solution) Various substances known as surfactants were mixed in the proportions shown in Table 6 to prepare surfactants with various HLB values. The BHT solution was heated (50-60°C) to add the various surfactants prepared to a concentration of 13%, and the resulting solution was mixed with the thickened sirolimus solution in a ratio of 62:38, followed by high-speed stirring at 11,000 min-1 to obtain a formulation. The resulting formulation was then left to stand for 22 hours, and the state of the liquid was observed visually.

[0061] Visual observation showed that formulations using surfactants a and b maintained a stable, cloudy mixture without phase separation. On the other hand, formulations using surfactants with an HLB value of 7.25 or higher experienced phase separation. These results suggest that surfactants with an HLB value of 5 to 7 are preferable for preventing phase separation.

[0062] [Table 6]

[0063] Example 4 and Comparative Example 2 An ointment was prepared as follows, and stored at 50°C. The residual rate of sirolimus was measured after 2 and 4 weeks.

[0064] Example 4 A solution of rapamycin dissolved in a triacetin / propylene glycol / polyethylene glycol mixture (a mixture of approximately equal amounts of triacetin, propylene glycol, and polyethylene glycol) was added to the gelling hydrocarbon so that the rapamycin content was 0.2% relative to the final formulation. A BHT solution in liquid paraffin was then mixed with the mixture in the presence of a surfactant (a mixture of glycerin monostearate and polyoxyethylene hydrogenated castor oil, mixed to an HLB of approximately 6) so that the BHT content was 1.5% relative to the final formulation. The gelling hydrocarbon content was adjusted to approximately 75% of the final formulation, resulting in a gel-like ointment.

[0065] (Comparative Example 2) A solution of rapamycin dissolved in triacetin / propylene glycol was added to the gelling hydrocarbon so that the rapamycin content was 0.2% of the final formulation. The gelling hydrocarbon content was adjusted to approximately 80% of the final formulation, resulting in a gel-type ointment.

[0066] The results are shown in Table 7. This table shows that the amount of remaining sirolimus in the ointment containing no BHT (Comparative Example 2) decreased rapidly over the storage period, whereas the amount of remaining sirolimus in the ointment containing BHT (Example 4) was suppressed from decreasing and remained stable.

[0067] [Table 7]

[0068] Example 5 Ointment penetration test Using the sirolimus ointment prepared in Example 4 as the test substance and the EFT-400 kit manufactured by MetTec Corporation as the skin model, a test for the penetration of the ointment into the skin model was carried out. The skin model cells were transferred to a 6-well plate into which EFT-400 assay medium had been dispensed, and incubated overnight (16 to 18 hours) in a carbon dioxide incubator (37°C, 5% CO2, humidified conditions).

[0069] Approximately 50 mg of the test substance was applied to the center of the cultured skin cells and spread evenly over the cells. This was incubated for 24 hours in a carbon dioxide incubator (37°C, 5% CO2, humidified conditions). After incubation, the test substance on the cells was wiped three times with absorbent cotton moistened with phosphate-buffered saline, and the surface moisture was removed. The dermis layer was peeled off and the surface was washed with phosphate-buffered saline, after which the surface moisture was removed and the mass was measured.

[0070] The collected dermis layer was cut into small pieces, and 1 mL of methanol was added and vigorously stirred. This was centrifuged (20,400 × g, 5 minutes, 4 °C), and the supernatant was used as the sample solution. A solution prepared in the same manner as above, but without applying the test substance, was used as the blank matrix. Separately, a methanol solution of ascomycin (20 ng / mL) was prepared and used as the internal standard solution.

[0071] The sample solution was then diluted 10-fold with blank matrix, and 20 μL of the diluted solution was placed in a PP tube. This was mixed with 20 μL of acetonitrile, 20 μL of internal standard solution, and 50 μL of methanol, and subjected to LC / MS / MS under the following conditions to quantify the sirolimus concentration in the measurement sample. The mass of sirolimus transferred to the dermis layer was calculated from the obtained sirolimus concentration value and the mass of the dermis layer used to prepare the sample solution. The transfer rate to the dermis layer (% of the applied dose) was calculated from the mass of sirolimus transferred to the dermis layer and the mass of sirolimus in the applied test substance. The transfer rate of sirolimus to the dermis layer was 1.402 (% of the applied dose), confirming that sufficient skin permeability was maintained.

[0072] (LC conditions) Column: A stainless steel tube with an inner diameter of 2.0 mm and a length of 50 mm, packed with octadecylsilanized silica gel for chromatography. Column temperature: constant temperature around 50°C Flow rate: 0.6mL / min Mobile phase: 5mmol / L ammonium formate (liquid A) and methanol (liquid B) mixed under the following gradient conditions [Table 8] (MS / MS conditions) Ionization method: ESI Polarity: Positive Scan type: MRM (multiple reaction monitoring) Confirming ion species (m / z, Q1>Q3): Sirolimus (931>864) :Ascomycin (809>756) [Industrial Applicability]

[0073] The present invention makes it possible to provide a stable topical preparation of rapamycin that has excellent solubility and a high transfer rate to the dermis layer, thereby enabling the treatment of skin diseases with rapamycin to be carried out more widely and effectively.

Claims

1. (a) rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin; (c) propylene glycol and / or polyethylene glycol, and (d) dibutylhydroxytoluene (BHT), one or more surfactants having an adjusted HLB of 5 to 7, and a lipophilic solvent; A topical preparation comprising:

2. 2. The topical preparation according to claim 1, wherein the weight ratio of (a) to (c) is 1:20 to 1:

70.

3. 2. The external preparation according to claim 1, wherein the weight ratio of (b) to (c) is 2:1 to 2:

6.

4. 2. The external preparation according to claim 1, wherein the weight ratio of (a), (b), and (c) is 1:20-80:20-70.

5. The topical preparation according to any one of claims 1 to 4, wherein the one or more surfactants having an adjusted HLB of 5 to 7 are at least two selected from the group consisting of polyoxyethylene cetyl ether, glycerin monostearate, and polyoxyethylene hydrogenated castor oil.

6. (i) (d1) A process for dissolving dibutylhydroxytoluene (BHT) in a lipophilic solvent, and mixing the resulting solution with one or more surfactants having an adjusted HLB of 5 to 7; (ii) A method for producing the external preparation according to any one of claims 1 to 5, comprising a step of mixing the solution obtained in (i) with a solution containing the following (a), (b), and (c): (a) rapamycin (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin (c) propylene glycol and / or polyethylene glycol

7. The method for producing an external preparation according to claim 6, wherein the one or more surfactants having an HLB of 5 to 7 after adjustment are at least two selected from the group consisting of polyoxyethylene cetyl ether, glycerin monostearate, and polyoxyethylene hydrogenated castor oil.

8. (i) a mixed solution obtained by dissolving dibutylhydroxytoluene (BHT) in a lipophilic solvent, the mixed solution containing one or more surfactants having an adjusted HLB of 5 to 7; (ii) An external preparation obtained by mixing a solution containing the following (a), (b), and (c): (a) rapamycin (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin (c) propylene glycol and / or polyethylene glycol

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