JP7638485B2 - Gel-in-water type emulsion, its manufacturing method and transdermal absorption agent - Google Patents

Description

Article 30, Paragraph 2 of the Patent Act applied Kyushu University Faculty of Engineering, Department of Materials Science and Engineering, Chemical Process and Life Science Course Published in the 2018 Graduation Thesis Abstracts

The present invention relates to a gel-in-water type emulsion, its manufacturing method, and a transdermal absorption agent.

Oil-in-water emulsions, in which oil is dispersed in water, have traditionally been used as raw materials for cosmetics and pharmaceuticals. Oil-in-water emulsions have the advantage that the active ingredients of cosmetics and pharmaceuticals can be encapsulated in the oil and stabilized.

For example, Patent Document 1 describes that an oil-in-water (O/W) emulsion having a specific composition can improve the penetration of cosmetic active ingredients.

JP 2017-114800 A

However, conventional oil-in-water emulsions, including those described in Patent Document 1, generally tend to lose dispersibility when stored for long periods due to particle settling and aggregation.

The present invention aims to provide a gel-in-water type emulsion that can be used as an alternative to oil-in-water type emulsions, in which particle settling and aggregation are suppressed and dispersion stability is excellent even when stored for a long period of time, a method for producing the same, and a transdermal absorption agent containing the gel-in-water type emulsion.

As a result of extensive research, the inventors have discovered that dispersion stability can be improved by gelling the oil in an oil-in-water emulsion that satisfies certain requirements.

That is, the present invention provides the following [1] to [5].
[1] A gel-in-water type emulsion comprising a gelling agent, an oil gelled by the gelling agent, a surfactant, and water, wherein the average particle size of gel particles in the emulsion is 500 nm or less.
[2] The gel-in-water type emulsion according to [1], comprising a poorly water-soluble drug in the gelled oil.
[3] The gel-in-water type emulsion according to [1] or [2], wherein the gelling agent comprises at least one selected from the group consisting of higher fatty acids and beeswax.
[4] A transdermal absorption agent containing the gel-in-water type emulsion according to any one of [1] to [3].
[5] A method for producing a gel-in-water type emulsion, comprising the steps of emulsifying a mixture containing a gelling agent, an oil, a surfactant, and water at a temperature equal to or higher than the melting point of the gelling agent, and cooling the mixture after the emulsification to a temperature below the melting point of the gelling agent.

The present invention provides a gel-in-water type emulsion having excellent dispersion stability and sustained release properties, a method for producing the same, and a transdermal absorption agent containing the gel-in-water type emulsion.

FIG. 1 shows the results of antitumor activity evaluation for Examples 19 and 20 and Comparative Example 1. FIG. 1 shows the results of antitumor activity evaluation for Example 21 and Comparative Example 2. FIG. 13 shows the results of skin permeability evaluation for Example 23.

One embodiment of the present invention is described in detail below, but the present invention is not limited to this.

The gel-in-water type emulsion (hereinafter also referred to as "G/W type emulsion") of this embodiment contains a gelling agent, oil gelled by the gelling agent, a surfactant, and water. The G/W type emulsion of this embodiment may also contain a poorly water-soluble drug in the gelled oil, as necessary. Note that the G/W type emulsion is an emulsion in which gel particles derived from gelled oil are dispersed in water.

The average particle size of the gel particles in the emulsion is 500 nm or less. This improves the dispersion stability. From the viewpoint of further improving the dispersion stability, the average particle size of the gel particles in the emulsion is preferably 400 nm or less, more preferably 300 nm or less, and even more preferably 200 nm or less. The lower limit of the average particle size of the gel particles is not particularly limited, but can be, for example, 50 nm or more. The average particle size of the gel particles is the particle size measured by dynamic light scattering.

The components of the G/W emulsion of this embodiment are described in detail below.

(Gelling Agent)
The gelling agent is not particularly limited as long as it can gel the oil, but it is possible to use one that is solid at room temperature and melts when heated. The melting point of the gelling agent can be, for example, 50 to 100° C. It is preferable that the gelling agent is one that is generally acceptable for use in pharmaceutical preparations.

The gelling agent is preferably a wax, a higher fatty acid, a fatty acid ester, a metal soap, an amino acid-based gelling agent, or a hydrocarbon. The gelling agent may be used alone or in combination of two or more.

Specific examples of waxes include hydrogenated oil, candelilla wax, carnauba wax, rice wax, Japan wax, beeswax, montan wax, ozokerite, ceresin, paraffin wax, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax, and ethylene-propylene copolymer.

Specific examples of higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid (12-HSA), palmitoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, docosahexaenoic acid, eicosapentaenoic acid, isohexadecanoic acid, anteisohenicosanoic acid, long-chain branched fatty acids, dimer acid, and hydrogenated dimer acid.

Specific examples of hydrocarbons include α-olefin oligomers, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, petrolatum, and solid paraffin.

Fatty acid esters include cholesterol fatty acid esters, sugar fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, etc., and specific examples of sugar fatty acid esters include dextrin palmitate, dextrin myristate, dextrin isostearate, fructooligosaccharide stearate, inulin stearate, dibenzylidene sorbitol, etc.

Specific examples of metal soaps include calcium stearate, lithium stearate, aluminum stearate, calcium palmitate, lithium palmitate, aluminum palmitate, calcium 2-ethylhexanoate, lithium 2-ethylhexanoate, aluminum 2-ethylhexanoate, calcium 12-hydroxystearate, lithium 12-hydroxystearate, and aluminum 12-hydroxystearate.

Specific examples of amino acid gelling agents include N-lauroyl glutamic acid di-n-butylamide.

Of these, it is more preferable that the gelling agent is a higher fatty acid or beeswax.

From the viewpoint of making the gel particle size smaller, the content of the gelling agent is preferably 2 to 20 mass %, more preferably 3 to 15 mass %, and even more preferably 4 to 12 mass %, based on the total amount of oil in the G/W type emulsion.

(oil)
Examples of oils include vegetable oils, animal oils, neutral lipids (mono-substituted, di-substituted or tri-substituted glycerides), fatty acid ester oils, synthetic oils and fats, liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, sterol derivatives, lactate esters, polycarboxylic acid esters, 2-cetyl ethylhexanoate, silicone, lipiodol, etc. One type of oil may be used alone, or two or more types may be used in combination. The oil is preferably one that is liquid at room temperature and generally acceptable for pharmaceutical preparations.

Specific examples of vegetable oils include coconut oil, palm oil, soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, sunflower oil, olive oil, rapeseed oil, perilla oil, fennel oil, cacao oil, cinnamon oil, peppermint oil, and bergamot oil.
Specific examples of animal oils include fish oil and whale oil.
Specific examples of neutral lipids include medium-chain fatty acid triglycerides, triolein, trilinolein, tripalmitin, tristearin, trimyristin, and triarachidonin.
Specific examples of fatty acid ester oils include isopropyl myristate, octyldodecyl myristate, cetyl myristate, ethyl oleate, ethyl linoleate, isopropyl linoleate, isopropyl palmitate, and butyl stearate.
A specific example of the synthetic oil is Azone.
Specific examples of sterol derivatives include cholesteryl oleate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmitate, and cholesteryl arachidate.
Specific examples of lactate esters include ethyl lactate and cetyl lactate.
Specific examples of polyvalent carboxylates include triethyl citrate, diisopropyl adipate, diethyl sebacate, and diisopropyl sebacate.

Among these, the oil is preferably isopropyl myristate, soybean oil, or lipiodol.

From the viewpoint of making the gel particles smaller, the mass ratio of the oil and water content in the G/W type emulsion is preferably 1:1 to 1:50, more preferably 1:2 to 1:40, and even more preferably 1:4 to 1:10.

Fluorescent substances may be added to the oil to confirm the penetration of active ingredients such as drugs by fluorescent observation. Fluorescent substances include hydrophobic fluorescent substances such as coumarin 6, calcein, fluorescein dyes, and rhodamine dyes.

(Surfactant)
The surfactant may be a nonionic surfactant, an anionic surfactant, a cationic surfactant, an amphoteric surfactant, or a bile salt. The surfactant is preferably one that is generally acceptable for use in pharmaceutical preparations.

Surfactants have hydrophilic and hydrophobic groups in the molecule, and are classified as hydrophilic or hydrophobic depending on the balance between the hydrophilic and hydrophobic groups (HLB value). Specifically, those with an HLB value of more than 10 are classified as hydrophilic, and those with an HLB value of 10 or less are classified as hydrophobic. These surfactants can be used without particular restrictions, but hydrophilic surfactants are preferred. Surfactants can be used alone or in combination of two or more types.

Specific examples of hydrophilic surfactants include alkyl sulfate salts, alkyl sulfonates, alkyl sulfosuccinates, polyoxyethylene alkyl ethers, polyoxyalkylene alkyl ethers, lauryl alcohol alkoxylates, glycerin fatty acid esters, saponin, sucrose fatty acid esters (sucrose erucate, etc.), glycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, polysorbates, lecithin (rapeseed lecithin, soybean lecithin, egg yolk lecithin, etc.), polyoxyethylene hydrogenated castor oil (HCO-40, HCO-60, HCO-80, HCO-100, etc.), polyoxyethylene-polyoxypropylene block polymers, etc. Among these, from the viewpoint of improving skin permeability, it is preferable to apply lecithin. Furthermore, from the viewpoint of application to a drug delivery system described later, surfactants having a polyoxyethylene chain as a hydrophilic part, such as polyoxyethylene hydrogenated castor oil, are preferred. Compounds with polyoxyethylene chains introduced are less likely to be captured by organs such as the liver (high stealth properties), which can increase the likelihood of the drug being delivered to the affected area.

From the viewpoint of making the particle size of the gel particles smaller, the content of the surfactant is preferably 10 to 1000 mg, more preferably 20 to 600 mg, and even more preferably 25 to 400 mg per mL of oil in the G/W type emulsion.

(Poorly water-soluble drugs)
A poorly water-soluble drug is a drug that has low solubility in water, and for example, refers to a drug whose solubility in ion-exchanged water at 20° C. is 10 mg/mL or less.

Specific examples of poorly water-soluble drugs include anti-inflammatory and/or antipyretic/analgesic drugs (NSAIDs) such as acemetacin, indomethacin, diflunisal, ibuprofen, ketoprofen, mefenamic acid, naproxen, piroxicam, and aspirin; steroid anti-inflammatory drugs such as fluorometholone, dexamethasone, hydrocortisone, prednisolone, and betamethasone; medroxyprogesterone acetate, methotrexate, paclitaxel, mercaptopurine, mitomycin C, tamoxifen citrate, and cisplatin. anti-cancer drugs such as docetaxel hydrate, immunosuppressants such as cyclosporine A and tacrolimus hydrate, antibiotics such as enoxacin and norfloxacin, antifungal agents such as itraconazole and griseofulvin, antiviral agents such as acyclovir, antihyperlipidemic drugs such as clofibrate, probucol and simvastatin, antihypertensive and/or antiangina drugs such as dipyridamole, nifedipine, pindolol, prazosin hydrochloride, reserpine, verapamil hydrochloride and atenolol, and anti-cardiac drugs such as digitoxin and digoxin. antipsychotics or hypnotics/sedatives such as diazepam, nitrazepam, haloperidol, droperidol, sulpiride, triazolam, etc.; antiepileptic drugs such as phenytoin, phenobarbital, etc.; antihistamines such as clemastine fumarate, terfenadine, cyproheptadine hydrochloride, etc.; gastric and duodenal ulcer treatment drugs such as cimetidine, famotidine, omeprazole, lansoprazole, oxethazaine, sucralfate, gefarnate, rebamipide, metoclopramide, etc.; Examples of poorly water-soluble drugs include vitamins such as rabine, pyridoxal phosphate, mecobalamin, folic acid, tocopherol acetate, phytonadione, and menatetrenone, diuretics such as furosemide, indapamide, and spironolactone, asthma treatment drugs such as theophylline and tranilast, cough suppressants and expectorants such as bromhexine hydrochloride, hormone acting drugs such as chlormadinone acetate, danazol, and methylprednisolone, gout treatment drugs such as benzbromarone and allopurinol, diabetes treatment drugs such as tolbutamide, and Parkinson's disease treatment drugs such as levodopa. One type of poorly water-soluble drug can be used alone, or two or more types can be used in combination.

The content of the poorly water-soluble drug can be, for example, 0.1 to 10 mg per 1 mL of oil in the G/W emulsion.

The G/W type emulsion of this embodiment can also be dispersed in oil and used as a gel-in-water-in-oil (G/W/O) type multiphase emulsion. The oil used here may contain a surfactant. Before dispersing in oil, the G/W type emulsion may be dialyzed to remove excess hydrophilic surfactant. By forming it into a G/W/O type multiphase emulsion, it is possible to improve penetration into the stratum corneum.

(Method for producing G/W type emulsion)
The method for producing the G/W type emulsion is not particularly limited, but for example, the emulsion can be produced by a method having a step of emulsifying a mixture containing a gelling agent, an oil, a surfactant, and water at a temperature equal to or higher than the melting point of the gelling agent (emulsion processing step), and a step of cooling the mixture after the emulsification process to a temperature lower than the melting point of the gelling agent (cooling step). When preparing a mixture containing a gelling agent, an oil, a surfactant, and water, it is preferable to prepare the mixture by mixing the gelling agent and the oil at a temperature equal to or higher than the melting point of the gelling agent to form an organosol, and then mixing the mixture with water heated to a temperature equal to or higher than the melting point of the gelling agent. At this time, the surfactant may be mixed in the organosol, may be mixed in the water, or may be added separately from the organosol and water.

In the emulsion processing step, a conventionally known method can be applied to the emulsification process, such as a method using an ultrasonic homogenizer, a method using a high-pressure homogenizer, a method using an ultra-high-speed homogenizer, a method using a microchannel, a method using a homomixer, etc. In addition, the temperature during the emulsification process may be equal to or higher than the melting point of the gelling agent, and the upper limit of the temperature is not particularly limited, but can be, for example, 110°C or lower or 100°C or lower.

In the cooling step, the cooling method is not particularly limited, but from the viewpoint of energy efficiency, it is preferable to allow the mixture to cool to room temperature in the atmosphere. Also, from the viewpoint of stabilizing gelation, it is preferable to leave the mixture at the temperature after cooling.

(Transdermal absorption agent)
The transdermal absorbent of this embodiment contains the above-mentioned G/W type emulsion. Such a transdermal absorbent may contain the G/W type emulsion as the above-mentioned G/W/O type multiphase emulsion. Since such a transdermal absorbent contains a G/W type emulsion, it has excellent sustained release properties. The dosage form of the transdermal absorbent may be any that can maintain the shape of the G/W type emulsion, and examples of such dosage forms for external use include liquids (including lotions and sprays), ointments, creams, gels, emulsions, and sticks. Furthermore, one of the preferred forms is to add the dispersion of the G/W type emulsion of this embodiment to an adhesive or a thermoplastic elastomer to prepare a coating liquid, and apply the coating liquid to a support and/or a release liner to use it as a patch.

When used as a transdermal absorption agent, a transdermal absorption enhancer, an antioxidant, a flavoring agent, a colorant, etc. may be added as necessary. When used as a patch, a tackifier, an excipient, etc. may be further added. In the patch, the content of the G/W type emulsion relative to the total amount of the G/W type emulsion and the tackifier is preferably 10% by mass or more, more preferably 25% by mass or more, and even more preferably 40% by mass or more.

The patch can be produced, for example, by a method including the following steps (1) to (3).
(1) preparing a G/W emulsion;
(2) A step of increasing the concentration of the G/W emulsion by concentrating the G/W emulsion, removing the supernatant, or the like;
(3) A step of adding a patch imparting agent and additives to the G/W type emulsion to prepare a coating liquid, and applying the coating liquid to a support or a release liner.

The amount of the transdermal agent used in this embodiment varies depending on the type of disease, the severity of symptoms, and the size of the affected area, and cannot be generally determined. It is usually used by applying an appropriate amount to the affected area once or several times a day.

(Other dosage forms)
The G/W type emulsion and G/W/O type multiphase emulsion of the present embodiment can be used not only as a dermatological drug as the above-mentioned transdermal absorption agent, but also as external medications such as eye drops, eye ointments, nasal drops, oral medications, and suppositories, and internal medications and injectables such as capsules, granules, tablets, pills, chewable tablets, and sugar-coated tablets.

(Drug delivery system)
A drug delivery system (DDS) is a technology/system that controls the pharmacokinetics of drugs to the ideal level in order to maximize their effectiveness, and aims to supply the minimum amount of drug to the required place at the required time. On the other hand, the EPR (Enhanced Permeability and Retention) effect is a phenomenon in which polymers administered to plasma proteins or blood naturally accumulate selectively in tumors, and DDS utilizing this EPR effect are being investigated.

The G/W emulsion containing the poorly water-soluble drug of this embodiment is expected to efficiently deliver the drug to the diseased site due to the EPR effect caused by the microparticulation of the gel particles, and to stabilize the poorly water-soluble drug by carrying it in the gel particles, allowing for sustained release at the diseased site.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

(Examples 1 to 18)
A surfactant and a gelling agent were added to the oil (oil phase) in the formulations shown in Tables 1 to 3, and dissolved by shaking in a water bath at 80° C. Water at 80° C. was added to the resulting solution so as to achieve the ratio of oil phase:water phase shown in Tables 1 to 3, and emulsions were obtained by treating with an ultrasonic homogenizer for 20 minutes while the container was immersed in a thermostatic bath at 80° C. The resulting emulsion was allowed to cool at room temperature, whereby the dispersed oil phase gelled, and a G/W type emulsion was obtained.
The emulsion was diluted 600 times with water, and the average particle size and polydispersity were measured by dynamic light scattering using a Zertasizer Nano-ZS (Marvern Panalytical Ltd.).
In Tables 1 to 3, the following oils, surfactants and gelling agents were used.
<Oil>
IPM: Isopropyl myristate Lipiodol: Iodized poppy seed oil fatty acid ethyl ester <Surfactant>
Soy lecithin HCO-60; Polyoxyethylene hydrogenated castor oil (Nikko Chemicals) (fatty acid ester with PEG chain)
<Gelling Agent>
Beeswax (melting point: approx. 65°C)
12-HSA: 12-hydroxystearic acid (higher fatty acid) (melting point: about 75°C)

<Evaluation of antitumor activity of G/W type emulsion containing anticancer drug (paclitaxel)>
(Example 19)
An anticancer drug-containing G/W type emulsion was prepared in the same manner as in Example 17, except that paclitaxel with a saturated solubility (concentration: about 2 mg/ml) was dissolved in advance in Lipiodol.

(Example 20)
An anticancer drug-containing G/W type emulsion was prepared in the same manner as in Example 18, except that paclitaxel with a saturated solubility (concentration: about 2 mg/ml) was dissolved in advance in Lipiodol.

(Antitumor activity evaluation)
A549 cells (human alveolar basal epithelial adenocarcinoma cells) were seeded in a 96-well plate at 5000 cells/ ^cm2 and cultured in an incubator at 37°C for 24 hours. After removing the medium from the wells, 80 μl/well of the anticancer drug-containing G/W emulsion of Example 19 or 20 diluted 1000-fold with DMEM medium was added and cultured at 37°C. After 24 hours and 48 hours, the medium was replaced with DMEM medium containing 10% WST-8 (a dye that stains living cells), and then cultured at 37°C for 3 hours. Next, 8 μl/well of 0.1 M hydrochloric acid was added to stop the reaction, and the absorbance was measured at a measurement wavelength of 450 nm.
The results of the same procedure except that the anticancer drug-containing G/W type emulsion was not used are shown as Comparative Example 1. These results are shown in FIG.

As is clear from Figure 1, both Examples 19 and 20 had lower absorbance after 24 hours and 48 hours than Comparative Example 1, and it was confirmed that there were fewer live A549 cells. This result indicates that the anticancer drug-containing G/W type emulsion has antitumor activity (has an effect of inhibiting tumor cell proliferation).

<Antitumor activity evaluation using tumor-bearing mice>
(Example 21)
An anticancer drug-containing G/W type emulsion was prepared in the same manner as in Example 18, except that paclitaxel (concentration: about 144 mg/ml) was dispersed in advance in Lipiodol.

(Antitumor activity evaluation)
The anticancer drug-containing G/W type emulsion prepared in Example 21 was diluted with PBS (phosphate buffered saline) so that the PTX (paclitaxel) concentration was 1.8 mg/ml. B16F10 cells (2.0 x 10 ⁵ cells/individual) were transplanted into the flank of the cancer-bearing mice (ICR, male, 6 weeks old) to make them cancer-bearing. 24 hours after transplantation, 100 μl (equivalent to 0.18 mg of PTX) of the above anticancer drug-containing G/W type emulsion was subcutaneously administered every 2 days around the tumor of the cancer-bearing mice. In addition, the results of the same operation except that the anticancer drug-containing G/W type emulsion was not used were set as Comparative Example 2. The results of measuring the tumor volume every 2 days using a caliper are shown in FIG. 2. As is clear from FIG. 2, the increase in tumor volume was suppressed in Example 21 more than in Comparative Example 2, indicating that the anticancer drug-containing G/W type emulsion has antitumor activity even in a living body environment.

(Example 22)
The G/W emulsions obtained in Examples 3, 15, and 16 were placed in sample tubes and stored at room temperature for 30 days. After that, the state of the G/W emulsions was visually inspected, but no settling or aggregation of particles was observed, making it clear that the emulsions had excellent dispersion stability.

<Evaluation of skin permeability using mouse skin>
(Example 23)
An oil phase was prepared by adding 0.03% by weight of coumarin 6, a hydrophobic fluorescent substance, and 8% by weight of 12-HSA (12-hydroxystearic acid), a gelling agent, to Lipiodol and dissolving them while shaking in a water bath at 80° C. Pure water containing 150 mg/mL of surfactant HCO-60 was mixed with this oil phase at a ratio of 1:7, and treated with an ultrasonic homogenizer for 20 minutes while immersing the container in a thermostatic bath at 80° C. to obtain a coumarin 6-containing G/W type emulsion (average particle size: 47.7 nm, polydispersity: 0.214).
2 ml of the resulting G/W type emulsion was placed in a dialysis tube (molecular weight cutoff: 1 kDa) and dialyzed in pure water for 4 hours to remove excess surfactant.
The dialyzed G/W type emulsion was mixed with IPM containing 50 mg/ml of sucrose erucate (manufactured by Mitsubishi Chemical Foods Corporation, "ER-290"), a surfactant, in a ratio of 1:2, and treated with an ultrasonic homogenizer for 10 minutes to obtain a coumarin 6-containing G/W/O type emulsion (average particle size: 139.9 nm, polydispersity index: 0.126).

(Skin permeability evaluation)
After lightly shaving the hair on the back of the mouse with a razor, the remaining hair was removed cleanly using a hair remover, and the skin was washed with ultrapure water. The mouse skin was excised in full thickness and cut into about 2 cm squares with scissors, and then the skin was attached to a diffusion cell so that the stratum corneum was on the donor side and the dermis was on the reservoir side. PBS was added to the reservoir side of the diffusion cell to the extent that the underside of the skin was in contact, and 200 μl of the above-mentioned coumarin 6-containing G/W/O type emulsion was added to the donor side. The permeation test was performed by placing it in an incubator and leaving it at 37 ° C for 1 day. The skin was collected, the surface was lightly wiped with a professional wipe, the skin was cut into small pieces, embedded in OCT compound (manufactured by Sakura Finetech Japan Co., Ltd.), frozen at -80 ° C, and 20 μm tissue pieces were prepared with a microtome. The tissue pieces were adsorbed onto a slide glass and subjected to phase contrast observation and fluorescence observation. The results are shown in Figure 3. It was confirmed that when coumarin 6 was used alone as an IPM solution, the hydrophobic substance penetrated deep into the skin when a coumarin 6-containing G/W/O type emulsion was used.

Claims (3)

An eye drop , eye ointment, nasal drop, oral medication, suppository, internal medicine, injection, or patch, which contains a gel-in-water type emulsion containing a gelling agent, an oil gelled by the gelling agent, a poorly water-soluble drug contained in the oil, a surfactant, and water ,
The emulsion comprises gel particles having an average particle size of 500 nm or less, and is used as an eye drop, eye ointment, nasal drop, oral medication, suppository, internal medicine, injection, or patch . 2. The eye drop, eye ointment, nasal drop, oral medication, suppository, internal medicine, injection, or patch according to claim 1, wherein the gelling agent comprises at least one selected from the group consisting of higher fatty acids and beeswax. A step of emulsifying a mixture containing a gelling agent, an oil, a poorly water-soluble drug contained in the oil, a surfactant, and water at a temperature equal to or higher than the melting point of the gelling agent;
and cooling the mixture after the emulsification treatment to a temperature below the melting point of the gelling agent to obtain a gel- in-water type emulsion.
The method, wherein the poorly water-soluble drug is contained in the gelled oil in the gel-in-water emulsion.

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