A nanomicellar ophthalmic formulation, and methods of making and using the same

Abstract

The present application relates to a kind of nanomicelle ophthalmic preparation and its preparation method and application, the nanomicelle ophthalmic preparation is with cyclosporine, solubilizing agent and aqueous vehicle as raw material, is prepared by film hydration method, the solubilizing agent is polyoxyethylene hydrogenated castor oil.The ophthalmic preparation product of the present application is creatively designed with a specific formula and is matched with specific preparation process, and the solubilizing agent used only has polyoxyethylene hydrogenated castor oil this single component, without adding other solubilizing agent, organic solvent or oily solvent in formula, so that cyclosporine can be stably present in aqueous solution with higher concentration, it is favorable for the higher concentration accumulation of cyclosporine in ocular tissue.At the same time this greatly improves the use safety of product, reduces manufacturing cost.Polyoxyethylene hydrogenated castor oil can form long-term stable nanomicelle system with cyclosporine in aqueous solvent under the preparation process, micelle particle size is less than 50nm, system is clear and transparent.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to a nanomicelle ophthalmic formulation, its preparation method, and its application. Background Technology

[0002] Cyclosporin A (CsA), also known as cyclosporine or cyclosporine, is a cyclic polypeptide compound composed of 11 amino acids. It is a potent immunosuppressant. Cyclosporin can be used to treat eye diseases such as dry eye. However, systemic administration of cyclosporin can cause serious toxic side effects such as kidney damage, central nervous system damage, and liver damage, thus greatly limiting its use. These toxic side effects can be avoided by using topical administration methods such as eye drops.

[0003] Cyclosporine is a highly lipid-soluble drug, appearing as a white powder. It dissolves readily in organic solvents such as acetonitrile and ethanol, but its water solubility is only 12 ng / mL (25°C). However, when administered as eye drops, the conjunctival sac volume of each eye typically does not exceed 30 μL. Therefore, increasing the concentration of cyclosporine to enhance the effective drug delivery to the eye and thereby improve the drug concentration in ocular tissues for better efficacy is a direction that urgently needs research.

[0004] To improve the water solubility of cyclosporine, many solubilizers are used in the preparation of cyclosporine ophthalmic formulations. However, most of these formulations add an oil phase or other organic solvents such as ethanol. Oils or organic solvents typically cause strong burning sensations and irritation when used topically in the eye. Some formulations also use solubilizers with a certain degree of toxicity or high cost, limiting their widespread use. Furthermore, some formulations, while exhibiting high cyclosporine solubility, suffer from poor long-term stability; after prolonged storage at room temperature or extreme temperatures, cyclosporine undergoes a crystal form change, leading to crystal precipitation or sedimentation. Therefore, there is an urgent need to develop new, safe, effective, long-term stable, and low-cost high-concentration cyclosporine eye drops. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a nanomicelle ophthalmic formulation, its preparation method, and its application.

[0006] To achieve this objective, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides a nanomicelle ophthalmic formulation, wherein the nanomicelle ophthalmic formulation is prepared by a thin-film hydration method using cyclosporine, a solubilizer and an aqueous medium as raw materials, wherein the solubilizer is polyoxyethylene hydrogenated castor oil.

[0008] Addressing the shortcomings of existing cyclosporine ophthalmic formulations, such as poor safety, poor long-term stability, high preparation costs, or low cyclosporine concentrations, this invention creatively designs an ophthalmic formulation with a specific formulation and preparation process. This formulation uses only one solubilizer—polyoxyethylene hydrogenated castor oil—eliminating the need for additional solubilizers and any organic solvents such as ethanol or methanol, as well as any oily solvents. This allows cyclosporine to exist stably at a high concentration in aqueous solution, promoting higher concentrations of cyclosporine in ocular tissues and thus facilitating its faster efficacy. Simultaneously, this significantly improves product safety and reduces manufacturing costs.

[0009] The nanomicelle ophthalmic formulation involved in this invention is prepared using a thin-film hydration method. Polyoxyethylene hydrogenated castor oil can form a long-term stable nanomicelle system with cyclosporine in an aqueous solvent. The micelle size is less than 50 nm, and the system is clear and transparent. If other preparation processes, such as aqueous solution methods, are used, the long-term stability of the product is poor, and significant precipitation will occur after prolonged storage.

[0010] Preferably, the degree of polymerization of polyoxyethylene in the polyoxyethylene hydrogenated castor oil is 30-80, such as polyoxyethylene 35 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil, etc.

[0011] Preferably, the aqueous medium includes water or a phosphate buffer solution.

[0012] Preferably, the mass ratio of the solubilizer to cyclosporine is not less than 5:1, for example, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 15:1, etc. More preferably, the mass ratio is not less than 9:1.

[0013] In the ophthalmic formulations involved in this invention, the amount of solubilizer used relative to cyclosporine is relatively small. As long as the mass ratio of solubilizer to cyclosporine is not less than 5:1, cyclosporine can be stably present in aqueous solution at a high concentration. Long-term stability is even better when the mass ratio is not less than 9:1.

[0014] Preferably, the mass ratio of the aqueous medium to cyclosporine is not less than 333:1, such as 350:1, 400:1, 450:1, 500:1, 600:1, 700:1, 800:1, 1000:1, 1500:1, etc. More preferably, the mass ratio is not less than 800:1.

[0015] The ophthalmic formulations involved in this invention achieve a low relative level of aqueous mediator compared to cyclosporine, meaning that cyclosporine can be stably present in aqueous solutions at a high concentration. Long-term stability is further enhanced when the mass ratio is not less than 800:1.

[0016] Preferably, the drug-loaded micelles prepared by the thin-film hydration method have a particle size of less than 50 nm.

[0017] The micelles in the nanomicelle ophthalmic formulation of this invention have small and uniform particle size, good tissue permeability, and high bioavailability.

[0018] In a second aspect, the present invention provides a method for preparing a nanomicelle ophthalmic formulation according to the first aspect, the method comprising:

[0019] An organic solution containing polyoxyethylene hydrogenated castor oil and cyclosporine is desolventized to form a thin film, which is then mixed with an aqueous medium and hydrated to form a clear and transparent system, namely the nanomicelle ophthalmic formulation.

[0020] The preparation method of the nanomicelle ophthalmic formulation involved in this invention is simple and easy to operate, and is very suitable for large-scale industrial production.

[0021] Preferably, the solvent includes any one or a combination of at least two of ethanol, methanol, acetonitrile, acetone, chloroform, or dichloromethane.

[0022] Preferably, the solvent removal process includes rotary evaporation or vacuum distillation.

[0023] Preferably, the hydration treatment method includes oscillation treatment or ultrasonic treatment.

[0024] The formulation formed after the above hydration treatment is a solution, which can also be further freeze-dried to obtain a powder for preservation.

[0025] Thirdly, the present invention provides the use of the nanomicelle ophthalmic formulation according to the first aspect in the preparation of cyclosporine eye drops.

[0026] Fourthly, the present invention provides a cyclosporine eye drop, wherein the raw materials for preparing the cyclosporine eye drop include the nanomicelle ophthalmic formulation described in the first aspect and pharmaceutically acceptable excipients.

[0027] Preferably, the excipients include any one or a combination of at least two of the following: osmotic pressure regulators, pH regulators, thickeners, or preservatives.

[0028] Preferably, the osmotic pressure regulator comprises any one or a combination of at least two of sodium chloride, mannitol, sorbitol, glucose, glycerol, polyethylene glycol, or propylene glycol.

[0029] Preferably, the pH adjuster comprises any one or a combination of at least two of the following: phosphate buffer, boric acid, sodium borate, tromethorphan, tromethorphan hydrochloride buffer, sodium hydroxide, hydrochloric acid, citric acid, or sodium citrate.

[0030] Preferably, the thickener comprises any one or a combination of at least two of hyaluronic acid or its salt, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, polyvinylpyrrolidone, chitosan, carbomer, glycerin, or polyoxyethylene.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] Addressing the shortcomings of existing cyclosporine ophthalmic formulations, such as poor safety, poor long-term stability, high preparation costs, or low cyclosporine concentrations, this invention creatively designs an ophthalmic formulation with a specific formulation and preparation process. This formulation uses only one solubilizer—polyoxyethylene hydrogenated castor oil—eliminating the need for additional solubilizers and any organic solvents such as ethanol or methanol, as well as any oily solvents. This allows cyclosporine to exist stably at a high concentration in aqueous solution, promoting higher concentrations of cyclosporine in ocular tissues and thus facilitating its faster efficacy. Simultaneously, this significantly improves product safety and reduces manufacturing costs.

[0033] The nanomicelle ophthalmic formulation involved in this invention is prepared using a thin-film hydration method. Polyoxyethylene hydrogenated castor oil can form a long-term stable nanomicelle system with cyclosporine in an aqueous solvent. The micelle size is less than 50 nm, and the system is clear and transparent. If other preparation processes, such as aqueous solution methods, are used, the long-term stability of the product is poor, and significant precipitation will occur after prolonged storage. Detailed Implementation

[0034] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0035] The cyclosporine mentioned below was purchased from Shanghai Yuanye Biotechnology Co., Ltd.; the polyoxyethylene hydrogenated castor oil was purchased from BASF.

[0036] The instruments used in the following description include: laser particle size analyzer (Malvin, Zetasizer ZSP); high performance liquid chromatograph (Shimadzu LC-20-AT).

[0037] Cyclosporine content was determined using the external standard method. Before testing, the sample was centrifuged to obtain the supernatant. The high-performance liquid chromatography (HPLC) conditions were as follows: Agilent Zorbax C18 column, 5 μm, 4.6 × 250 mm, flow rate 1.0 mL / min, column temperature 70℃, detection wavelength 210 nm, injection volume 20 μL. The mobile phase was water:acetonitrile:tert-butyl methyl ether:phosphoric acid solution (85%) = 520:430:50:1 (v / v), with isocratic elution.

[0038] Example 1

[0039] This embodiment provides a nanomicelle ophthalmic formulation, the preparation method of which is as follows:

[0040] 9 mg of cyclosporine and 45 mg of polyoxyethylene hydrogenated castor oil were placed in a 100 mL round-bottom flask, and 10 mL of anhydrous ethanol was added. After dissolving completely, the anhydrous ethanol was removed using a rotary evaporator to obtain a uniformly dispersed film. Then, 10 mL of purified water was added for hydration treatment to dissolve the film and obtain a micelle solution. The micelle solution was filtered through a 0.22 μm microporous membrane to remove insoluble particles, thus obtaining a nano-micelle ophthalmic formulation.

[0041] Example 2

[0042] This embodiment provides a nanomicelle ophthalmic formulation, the preparation method of which is as follows:

[0043] 9 mg of cyclosporine and 200 mg of polyoxyethylene hydrogenated castor oil were placed in a 100 mL round-bottom flask, and 10 mL of dichloromethane was added. After dissolving completely, the dichloromethane was removed using a rotary evaporator to obtain a uniformly dispersed film. Then, 5 mL of purified water was added for hydration treatment to dissolve the film and obtain a micelle solution. The micelle solution was filtered through a 0.22 μm microporous membrane to remove insoluble particles, thus obtaining a nano-micelle ophthalmic formulation.

[0044] Example 3

[0045] This embodiment provides a nanomicelle ophthalmic formulation, the preparation method of which is as follows:

[0046] 9 mg of cyclosporine and 250 mg of polyoxyethylene hydrogenated castor oil were placed in a 100 mL round-bottom flask, and 10 mL of methanol was added. After dissolving completely, the methanol was removed using a rotary evaporator to obtain a uniformly dispersed film. Then, 3 mL of water was added for hydration treatment to dissolve the film and obtain a micelle solution. The micelle solution was filtered through a 0.22 μm microporous membrane to remove insoluble particles, thus obtaining a nano-micelle ophthalmic formulation.

[0047] Example 4

[0048] This embodiment provides a nanomicelle ophthalmic formulation, the preparation method of which is as follows:

[0049] 9 mg of cyclosporine and 120 mg of polyoxyethylene hydrogenated castor oil were placed in a 100 mL round-bottom flask, and 10 mL of methanol was added. After dissolving completely, the methanol was removed using a rotary evaporator to obtain a uniformly dispersed film. Then, 10 mL of water was added for hydration treatment to dissolve the film and obtain a micelle solution. The micelle solution was filtered through a 0.22 μm microporous membrane to remove insoluble particles, thus obtaining a nano-micelle ophthalmic formulation.

[0050] Comparative Example 1

[0051] This comparative example provides a nano-micelle ophthalmic formulation, the preparation method of which is as follows:

[0052] 120 mg of polyoxyethylene hydrogenated castor oil was placed in a glass bottle and heated at 40 °C until the polyoxyethylene hydrogenated castor oil was completely melted. Then, 9 mg of cyclosporine was added and stirred thoroughly at 40 °C until the cyclosporine was evenly dispersed. Then, 10 mL of purified water was added and stirred thoroughly at 25 °C until the system became clear and transparent, thus obtaining a micelle solution. The micelle solution was filtered through a 0.22 μm microporous membrane to remove insoluble particles, thus obtaining a nano-micelle ophthalmic formulation.

[0053] Comparative Example 2

[0054] This comparative example provides a nano-micelle ophthalmic formulation, the preparation method of which is as follows:

[0055] 120 mg of polyoxyethylene hydrogenated castor oil was placed in a glass bottle and heated at 55 °C until the polyoxyethylene hydrogenated castor oil was completely melted. Then, 9 mg of cyclosporine was added, and the mixture was stirred at 55 °C for 5 min. The mixture was then cooled to 35 °C, and 10 mL of purified water was added. The mixture was stirred thoroughly at 25 °C until it became clear and transparent, thus obtaining a micelle solution. The micelle solution was filtered through a 0.22 μm microporous membrane to remove insoluble particles, thus obtaining a nano-micelle ophthalmic formulation.

[0056] Comparative Example 3

[0057] This comparative example provides a nano-micelle ophthalmic formulation, the preparation method of which is as follows:

[0058] 120 mg of polyoxyethylene hydrogenated castor oil was placed in a glass bottle and heated at 55 °C until the polyoxyethylene hydrogenated castor oil was completely melted. Then, 9 mg of cyclosporine was added, and the mixture was stirred at 55 °C for 5 min. The mixture was then cooled to 35 °C, and 5 mg of octylphenol polyoxyethylene ether-40 and 10 mL of purified water were added. The mixture was stirred thoroughly at 25 °C until the system became clear and transparent, thus obtaining a micelle solution. The micelle solution was filtered through a 0.22 μm microporous membrane to remove insoluble particles, thus obtaining a nano-micelle ophthalmic formulation.

[0059] Comparative Example 4

[0060] This comparative example provides a nano-micelle ophthalmic formulation, the preparation method of which is as follows:

[0061] 120 mg of polyoxyethylene hydrogenated castor oil was placed in a glass bottle, and 10 mL of pure water was added. The mixture was heated at 40 °C until the polyoxyethylene hydrogenated castor oil was completely dissolved in the water. Then, 9 mg of cyclosporine was added, and the mixture was stirred thoroughly at 40 °C until the cyclosporine was evenly dispersed and the system became clear and transparent, thus obtaining a micelle solution. The micelle solution was then filtered through a 0.22 μm microporous membrane to remove insoluble particles, thus obtaining a nano-micelle ophthalmic formulation.

[0062] Comparative Example 5

[0063] This comparative example provides a nano-micelle ophthalmic formulation, the preparation method of which is as follows:

[0064] 120 mg of polyoxyethylene hydrogenated castor oil was placed in a glass bottle, and 10 mL of pure water was added. The mixture was heated at 40 °C until the polyoxyethylene hydrogenated castor oil was completely dissolved in the water. Then, 9 mg of cyclosporine was added, and the mixture was stirred thoroughly at 25 °C until the cyclosporine was evenly dispersed and the system became clear and transparent, thus obtaining a micelle solution. The micelle solution was filtered through a 0.22 μm microporous membrane to remove insoluble particles, thus obtaining a nano-micelle ophthalmic formulation.

[0065] Test Example 1

[0066] The particle size of the products obtained in Examples 1-4 and Comparative Examples 1-5 was characterized using a laser particle size analyzer, and the results are shown in Table 1.

[0067] Table 1

[0068] sample Particle size (nm) PDI Example 1 28.10 0.239 Example 2 32.87 0.183 Example 3 32.55 0.231 Example 4 30.23 0.205 Comparative Example 1 30.37 0.105 Comparative Example 2 33.61 0.106 Comparative Example 3 32.43 0.225 Comparative Example 4 32.11 0.195 Comparative Example 5 28.19 0.183

[0069] As can be seen from the data in Table 1, the micelles in the nanomicelle ophthalmic formulation system involved in this invention have small and uniform particle sizes.

[0070] Test Example 2

[0071] The products obtained in Examples 1-4 and Comparative Examples 1-5 were placed at 35°C for 30 days, and their appearance was recorded. The cyclosporine content (mg / mL) was determined by high performance liquid chromatography, and the results are shown in Table 2.

[0072] Table 2

[0073]

[0074] As shown in Table 2, the nanomicelle ophthalmic formulation system involved in this invention has good stability. After being placed at 35°C for 30 days, the cyclosporine content remained basically unchanged, while the cyclosporine content of the comparative product decreased significantly, indicating poor stability.

[0075] Test Example 3

[0076] The products obtained in Examples 1-4 were placed at 35°C for 12 months, and the cyclosporine content (mg / mL) was determined by high performance liquid chromatography at 0 months, 1 month, 2 months, 3 months, 6 months and 12 months. The results are shown in Table 3.

[0077] Table 3

[0078] sample 0 months 1 month 2 months 3 months 6 months 12 months Example 1 0.883 0.865 0.459 / / / Example 2 1.754 1.733 0.715 / / / Example 3 2.903 2.809 0.613 / / / Example 4 0.885 0.871 0.863 0.863 0.921 0.914

[0079] As shown in Table 3, the nanomicelle ophthalmic formulation system of Example 4 of this invention has the best long-term stability. After being placed at 35°C for 12 months, the cyclosporine content showed no significant change.

[0080] Application Example 1

[0081] This application example provides a cyclosporine eye drop, the preparation method of which is as follows:

[0082] Dissolve 48 mg of disodium hydrogen phosphate (dihydrate), 52 mg of anhydrous sodium dihydrogen phosphate, and 48 mg of sodium chloride in 1 mL of purified water; dissolve 30 mg of thickener PVP-K90 in 1 mL of purified water; mix the product from Example 4 with the aforementioned two solutions thoroughly, and add purified water to reach a final volume of 10 mL. Filter the solution through a 0.22-micron filter to remove insoluble particles, obtaining cyclosporine eye drops.

[0083] Test case

[0084] Eye irritation test was conducted on the product manufactured in accordance with use case 1:

[0085] Five healthy rabbits were used. 50 μL of the test product was instilled into the left eye of each rabbit, and 50 μL of physiological saline was administered into the right eye. The eyelids were gently closed for 10 seconds. The medication was administered four times daily for seven consecutive days (cyclosporine eye drops). Local reactions of the cornea, iris, and conjunctiva were observed before each administration and at 1, 2, 4, 24, 48, and 72 hours after the last administration. The total score (average score) was calculated. Irritation scores for physiological saline were all 0. The scoring criteria and methods are shown in the table below.

[0086]

[0087]

[0088] The criteria for determining the results are shown in the table below:

[0089] Stimulation Level Total Score Judgment criteria 1 0-3 points Non-irritating 2 4-8 points Mild irritation 3 9-12 points moderate irritation 4 13-16 points Intensive irritation

[0090] The eye irritation test result was 0. This indicates that the nanomicelle ophthalmic formulation and cyclosporine eye drops involved in this invention have no significant irritating effect on the rabbit eyes and are safe and mild.

[0091] The applicant declares that the technical solution of this invention is illustrated by the above embodiments, but this invention is not limited to the above embodiments, that is, it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials for the products of this invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

[0092] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0093] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable way without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A nanomicellar ophthalmic formulation, characterized in that, The nanomicellar ophthalmic preparation is prepared by a thin film hydration method using cyclosporine, a solubilizer, and an aqueous vehicle, wherein the solubilizer is polyoxyl hydrogenated castor oil; The mass ratio of the solubilizer to cyclosporine is not less than 5:

1. The preparation method of the nanomicellar ophthalmic preparation comprises: The organic solution containing polyoxyl hydrogenated castor oil and cyclosporine is subjected to solvent removal treatment to form a thin film, and then mixed with an aqueous vehicle to perform hydration treatment to form a clear and transparent system, i.e., the nanomicellar ophthalmic preparation.

2. The nanomicellar ophthalmic formulation of claim 1, wherein, The polyoxyl in the polyoxyl hydrogenated castor oil has a polymerization degree of 30-80.

3. The nanomicellar ophthalmic formulation of claim 1, wherein, The aqueous vehicle comprises water or a phosphate buffer.

4. The nanomicellar ophthalmic formulation of claim 1, wherein, The mass ratio of the aqueous vehicle to cyclosporine is not less than 333:

1.

5. The nanomicellar ophthalmic formulation of claim 1, wherein, The drug-loaded micelles prepared by the thin film hydration method have a particle size of less than 50 nm.

6. The method of preparing a nanomicellar ophthalmic formulation according to any one of claims 1-5, wherein, The preparation method comprises: The organic solution containing polyoxyl hydrogenated castor oil and cyclosporine is subjected to solvent removal treatment to form a thin film, and then mixed with an aqueous vehicle to perform hydration treatment to form a clear and transparent system, i.e., the nanomicellar ophthalmic preparation.

7. The method of claim 6, wherein the nanomicellar ophthalmic formulation is prepared by, The solvent comprises any one or a combination of at least two of ethanol, methanol, acetonitrile, acetone, chloroform, or dichloromethane.

8. The method of claim 6, wherein the nanomicellar ophthalmic formulation is prepared by, The solvent removal treatment comprises a rotary evaporation method or a reduced pressure distillation method.

9. The method of claim 6, wherein the nanomicellar ophthalmic formulation is prepared by, The hydration treatment comprises oscillation treatment or ultrasonic treatment.

10. Use of the nanomicellar ophthalmic preparation according to any one of claims 1-5 in the preparation of a cyclosporine eye drop.

11. An eye drop of cyclosporin, characterized by, The preparation raw materials of the cyclosporine eye drop comprise the nanomicellar ophthalmic preparation according to any one of claims 1-5 and a pharmaceutically acceptable excipient.

12. The cyclosporine eye drop of claim 11, wherein, The excipient comprises any one or a combination of at least two of an osmotic pressure regulator, a pH regulator, a thickening agent, or a preservative.

13. The cyclosporine eye drop of claim 12, wherein, The osmotic pressure regulator comprises any one or a combination of at least two of sodium chloride, mannitol, sorbitol, glucose, glycerol, polyethylene glycol, or propylene glycol.

14. The cyclosporine eye drop of claim 12, wherein, The pH regulator comprises any one or a combination of at least two of a phosphate buffer salt, boric acid, sodium borate, tromethamine, tromethamine hydrochloride buffer salt, sodium hydroxide, hydrochloric acid, citric acid, or sodium citrate.

15. The cyclosporine eye drop of claim 12, wherein, The thickening agent comprises any one or a combination of at least two of hyaluronic acid or a salt thereof, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, polyvinylpyrrolidone, chitosan, carbomer, glycerol, or polyethylene oxide.

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