JPH0723303B2 - Microemulsion formulation containing poorly soluble drug - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to a poorly soluble drug-containing microemulsion formulation having excellent stability and transdermal absorbability. The poorly soluble drug in the present invention means a poorly soluble drug in water,
The same applies to the following description.

[Conventional technology]

The poorly soluble drug in the present invention means a drug which is poorly soluble in water as described above, and many drugs belong to this. Many of these poorly soluble drugs are generally oil-soluble, and ointment bases, liquids containing an organic solvent, emulsion bases, etc. have conventionally been often used to formulate them. .

As the ointment base, there are oil-soluble bases such as petrolatum, paraffin and plastibase, and hydrophilic bases such as macrogol and FAPG, and a poorly soluble drug is mixed and used.
However, the ointment base is not sticky on the coated surface, and the transdermal absorbability of the drug on the coated surface is not always sufficient. Further, the ointment base has the drawback that it is easily retained by the application surface and can be easily removed by clothing, and the drug in the formulation does not reach the affected area sufficiently.

Further, since a poorly soluble drug is generally dissolved in an organic solvent such as ethanol, methyl ethyl ketone, or acetone, a liquid formulation containing these organic solvents as a solvent has been conventionally used. However, these preparations do not necessarily have sufficient transdermal absorbability, because the solvent is easily volatilized, and thus drug crystals are easily deposited on the coated surface. Further, these liquid agents have a drawback that the coated surface becomes red due to temporary irritation due to the organic solvent.

Further, a formulation in which a poorly soluble drug is mixed with an emulsion base has also been used. These formulations, compared to the ointments and liquids,
Although usability and irritation were improved, stability and transdermal absorbability were still insufficient.

[Problems to be solved by the invention]

As for emulsion bases, this is disclosed in JP-B-60-3336 and JP-B
57-8085, JP-B-56-30327, JP-A-57-2
09213, JP55-62008, JP54-1190
As seen in Japanese Patent No. 24, the drug must be dissolved in a highly polar oil and emulsified. Generally, to obtain a stable emulsion base by emulsifying highly polar oil,
It was extremely difficult. Furthermore, it is desirable to increase the concentration of the drug in the oil phase (supersaturation ratio above the saturated solubility) in order to increase the release of the drug from the base. Since it is easy to precipitate, the stability of the emulsion base tends to deteriorate. That is, in order to enhance the transdermal absorbability, it is desirable to mix the drug into the oil phase at a saturated solubility or at a saturated solubility or higher and emulsify it, but the conventional emulsified base has a drawback that the stability becomes poor. was there.

Therefore, as a result of intensive studies to develop a poorly soluble drug-containing emulsion formulation having excellent stability and transdermal absorbability, the present inventors have found that the poorly soluble drug is saturated in the oil phase at room temperature with a saturated solubility or We have found a remarkably stable emulsion formulation even when it is mixed up to a saturated solubility or higher. This formulation was found from the fact that a microemulsion having a remarkably fine emulsified particle size was obtained by emulsifying a poorly soluble drug under specific conditions, and surprisingly, this microemulsion formulation was It was remarkably stable and sufficiently endured a long-term stability test. Furthermore, this microemulsion formulation exhibited significantly higher transdermal absorbability than the conventional emulsion base containing a poorly soluble drug.

[Means for Solving Problems and Their Actions]

That is, according to the present invention, the poorly soluble drug, IOB, is 0.22
A microemulsion preparation containing a poorly soluble drug is provided, which comprises an oil content of ˜0.85, an oil content of IOB of 0 to 0.20, a hydrophilic surfactant and water, and has an average particle size of emulsified particles of 0.5 μm or less. Examples of the poorly soluble drug that is incorporated into the micro-emulsion preparation of the present invention to promote percutaneous absorption and increase the expression of effects include the following.

Steroid anti-inflammatory agents: For example, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate, prednisolone, methylprednisolone, methylprednisolone acetate, prednisolone valerate acetate, dexamethasone, fluorometholone,
Betamethasone, triamcinolone, betamethasone valerate, betamethasone butyrate, betamethasone propionate, triamcinolone acetonide, fludroxycortide, clobetasone butyrate, betamethasone dipropionate, clobetasol propionate, halcinonide, amcinonide,
Fluocinolone acetonide, fluocinonide, desoxymethasone, dexamethasone acetate, flumethasone pivalate, diflucordron valerate, beclomethasone propionate, fludrocortisone acetate, parameterzone,
Flumethasone, dichlorisone, etc. Analgesic and anti-inflammatory agents: acetaminophen, aspirin, salicylic acid, methyl salicylate, choline salicylate, glycol salicylate, l-menthol, camphor, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, Naproxen, pranoprofen, fenoprofen, salindac, fenbufen, kridanac, flurbiprofen, indoprofen, butyric acid, fenthiazac, tolmethine, thiaprofenic acid, benzaduck, bufexamac, piroxicam,
Phenylbutazone, Oxyphenbutazone, Clofezone, Bentazocine, Meperizole, Glycyrrhizin, Glycyrrhetinic acid, Azulene, Ibufenac, Ibuprofen piconol, Benzitamine, Isothibenzyl, Dipotassium glycyrrhizinate, Camphor, Thymol, Tesit, etc. Antihistamines: Diphenhydramine, Diphenhydramine hydrochloride Triperenamine, Tondialumine, Chlorpheniramine maleate, Chlorpheniramine, Isocybenzylcremizole, Diphenylimidazole,
Periactin, carbinoxamine, diphenylpyraline, fenbenzamine, incybenzyl, promethazine, promethazine hydrochloride, tridylamine hydrochloride, metzirazine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, etc. antifungal agents: clotrimazole, pentachlor Phenol, trichlorophenolcaproate, tribromphenolcaproate, lauryltriphenylphosphonium bromide, dianthazole hydrochloride, paraacetylaminophenylrodane, thimerosal, undecylenic acid,
Zinc undecylenate, dermasid, barithione, pyrrolenitrin, siccanin, miconazole, econazole, isoconazole, sulconazole, thioconazole, bifonazole, oxyconazole, ketoconazole, ciclopirox olamine, tolcyclate, naphthifin, griseofulvin, 5-fluorocytosine, etc. Local anesthetics: dibucaine hydrochloride, pyridoxine hydrochloride,
Ethyl aminobenzoate, procaine hydrochloride, dimethisoquine hydrochloride, pramoxine hydrochloride, lidocaine, benzocaine,
Procaine, dibucaine, tetracaine hydrochloride, lidocaine hydrochloride, piperocaine acetate, bramoocin hydrochloride, hexothiocaine hydrochloride, benzyl alcohol, thecaine hydrochloride, mepivacaine hydrochloride, pubilucaine hydrochloride, cocaine hydrochloride, catakine hydrochloride, probitocaine hydrochloride, butanicaine hydrochloride, oxybutanicaine hydrochloride, hydrochloric acid Mebryl butanicaine, piperocaine hydrochloride, chlorobutanol, mebrilukaine hydrochloride, epilocaine hydrochloride, thecaine, etc.Sulfa drugs: homosulfamine, sulfamine, sulfisoxazole, sulfisoxazole sodium, sulfamethoxazole, sulfisomidine, sulfadiazine, Sulfisomidine sodium, sulfamethoxazole sodium, sulfamonomethoxine,
Sulfamethazole, sulfapyridine, sulfamethoxypyridine, sulfamethoxine, sulfanilamide, sulfamethoxypyridazine etc. Antibiotics: chloramphenicol, demethylchlortetracycline hydrochloride, fradiomycin, trichomycin sulfate, bacitracin, sulfate Colistin, colistin sodium methanesulfonate, lactobioerythromycin, cefmetazole, penicillin, cephalexin,
Clindamycin, tetracycline, erythromycin, kanamycin, metronidazole, cephalosporin, streptomycin, cefatrizine, amphotericin, chlamicidine, oxytetracycline, metacycline, doxycycline, minocycline, lincomycin, nystatin, cephalotin, nitrofurantoin, etc. Acid warenylamide, nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, zingerone, cantharisin tincture,
Ictamol, caffeine, tannic acid, α-borneol, tocopherol nicotinate, inositol hexanicotinate, cyclandrate, cinnarizine, tolazoline, acetylcholine, verapamil, etc.Insect repellents: N, N-diethylamide, bisethylenetetrahydrofurfural, butoxide, If necessary, the above-mentioned drugs such as di-n-propylisocincoronate and diethyltoluamide can be used alone or in combination of two or more kinds. Further, the above-mentioned drugs can be used in the free state, those capable of salt formation can be used in the form of acid or base salts, and those having a carboxylic acid group can be used in the form of their esters. Examples of the above acid include organic acids (lactic acid,
Acetic acid, tartaric acid, fumaric acid, maleic acid, etc.) and inorganic acids (hydrochloric acid, phosphoric acid, sulfuric acid, etc.), and as bases, organic bases (ammonia, triethylamine, etc.) and inorganic bases (sodium hydroxide, potassium hydroxide, etc.) ) Is mentioned. Further, examples of the ester include alkyl ester and aryl ester.

The amount of the poorly soluble drug in the microemulsion formulation of the present invention is generally 0.0001 to 30 with respect to the entire formulation.
%, Preferably 0.05 to 15% by weight. This blending amount may be an amount sufficient for manifestation of drug efficacy, and may be appropriately increased or decreased depending on the type of drug, the purpose of treatment, the age and weight of the patient, the degree of disease progression, and the like. However, if the content of the drug is too small, it is easy to formulate, but it is not preferable because the pharmacological effect is inferior. Conversely, if the content is too large, it is necessary to use a large amount of oil to dissolve the drug, and thus a microemulsion. It is not preferable because it becomes difficult to maintain the stability of the preparation.

IOB blended in the microemulsion formulation of the present invention
The oil content of 0.22 to 0.85 can be widely selected from natural to synthetic ones.For example, adipic acid dialkyl ester having 12 to 22 carbon atoms, pimelic acid dialkyl ester having 13 to 23 carbon atoms, and total carbon number Suberic acid dialkyl ester having 14 to 24 carbon atoms, azelaic acid dialkyl ester having 13 to 21 carbon atoms, sebacic acid dialkyl ester having 14 to 22 carbon atoms and phthalic acid dialkyl ester having 14 to 24 carbon atoms ( However, the alkyl group may be linear or branched, and the alkyl groups of dialkyl may be the same or different) and the like, carboxylic acid dialkyl ester, propylene glycol fatty acid ester having 9 to 15 carbon atoms (however, , Fatty acids may be linear or branched), glycerin fatty acid diesters having 15 to 27 total carbon atoms or groups having 21 to 39 total carbon atoms. Serine fatty acid triester (provided that the fatty acid may be linear or branched), sorbitan fatty acid ester having a total carbon number of 12 to 18 (provided that the fatty acid may be linear or branched), total carbon number A polyhydric alcohol fatty acid ester such as a pentaerythritol fatty acid triester having 23 to 41 or a pentaerythritol fatty acid tetraester having a total carbon number of 29 to 53 (however, the fatty acid may be linear or branched), 2-octyl Dodecanol, isostearic acid, castor oil, β-phenethyl alcohol, crotamiton, triethyl citrate, benzyl alcohol and the like, which can be used alone or as an arbitrary mixture.

The oil content of these IOB is 0.22 to 0.85 is 0.5 to 60% by weight, preferably 1 to 40% by weight in the microemulsion preparation.
It is mixed in the ratio of. If the amount of these oil components is too small, the poorly soluble drug will be deposited, which is not preferable, and if it is too large, the polarity of the oil phase will be high and stable microemulsion production cannot be achieved, which is not preferable.

IOB blended in the microemulsion formulation of the present invention
Examples of the oil content of 0 to 0.2 include triglycerides such as olive oil, soybean oil, rapeseed oil, coconut oil, and beef tallow, oleyl oleate, synthetic ester oils such as isopropyl myristate, liquid paraffin, squalane, and silicone oil, These can be used alone or as an arbitrary mixture. These oils preferably have a molecular weight of about 200 or more, and are preferably liquid at room temperature from the viewpoint of handling.

The amount of these IOBs in oil-based microemulsion formulations of 0 to 0.2 is the above-mentioned poorly soluble drug and IO.
B. 0.22 to 0.85 times the total amount of oil content, 1/200 times to 1
The amount is 00 times, preferably 1/100 times to 10 times. If the amount of these oil components is too small, the resulting microemulsion formulation tends to be unstable, which is not preferable, and if too large, the solubility of the poorly soluble drug tends to be poor, which is not preferable.

The IOB (Inorganic Organic Balance) value is an inorganic or organic value calculated according to the calculation method by Fujita shown in "Chemistry Area" Vol. 11, No. 10, pp. 719-725 (1957). Ratio, that is, a numerical value represented by the following equation.

As the hydrophilic surfactant blended in the microemulsion preparation of the present invention, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, Polyoxyalkylene-based compounds such as polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyglycerin fatty acid ester,
Hydrophilic nonionic surfactant having HLB of 10 or more such as sugar ester, or alkyl sulfate, polyoxyethylene alkyl ether sulfate, N-acyl amino acid, N
-Anionic surfactants such as acylamino acid salts, N-acylmethyl taurine salts, alkyl phosphates, polyoxyethylene alkyl ether phosphates and fatty acid soaps, or casein, saponin, phospholipids, glycopeptides, alginic acid, soybean protein A hydrophilic surfactant derived from a natural product such as is used.

The content of the hydrophilic surfactant in the microemulsion preparation of the present invention is usually in the range of 0.1 to 25% by weight, particularly 0.5 to 15% by weight.
Weight percent is preferred. If the blending amount of these hydrophilic surfactants is too small, a stable microemulsion formulation cannot be obtained, and if too large, it is not preferable because stickiness increases and usability deteriorates. In addition, in the present invention, the hydrophilic surfactants may be used alone or as an arbitrary mixture.

The microemulsion formulation according to the present invention incorporates water as an essential ingredient. The amount of water to be added is not particularly limited,
Preferably 40 to 95% by weight (in the case of emulsion) or 20 to 40% by weight (in the case of cream) is blended.

The microemulsion preparation containing a poorly soluble drug according to the present invention includes, in addition to the above essential components, a wetting agent, a general fat and oil that is miscible with the oil phase, a lower alcohol such as ethanol, and a thickening agent for a polymer compound and the like. Agents and the like can be blended as desired.

As the wetting agent optionally added to the microemulsion preparation of the present invention, it is preferable to use a water-soluble polyhydric alcohol having two or more hydroxyl groups in the molecule. As such polyhydric alcohol, specifically, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, dipropylene glycol, glycerin, diglycerin, triglycerin, tetraglycerin, glucose,
Maltose, maltose, sucrose, fructose, xylitol, sorbitol, mavit, sorbit, maltotriose, threitol, erythritol, starch-decomposing sugar, starch-decomposing sugar reducing alcohol and the like can be mentioned, and the amount thereof is 0.5 to 50% by weight. Is preferred.

The microemulsion preparation of the present invention may optionally contain a lower alcohol such as ethanol for the purpose of improving "wetting" on the skin and providing a refreshing feeling. The amount of lower alcohol such as ethanol is generally about 0.5 to 30% by weight.

Furthermore, if necessary, the micro-emulsion formulation containing a poorly soluble drug according to the present invention may further appropriately contain a bactericide, an isotonicity agent, a buffering agent, a solubilizing agent, an absorption promoter, an antiseptic, and a stabilizer. You can

The poorly soluble drug-containing microemulsion preparation according to the present invention can be produced by any method. For example, a poorly soluble drug dissolves an oil component having an IOB of 0.22 to 0.85, and further I.
An oil phase having an OB of 0 to 0.2 is added to prepare an oil phase. on the other hand,
The aqueous phase is prepared, for example, by adding a hydrophilic surfactant to a wetting agent, heating if necessary to dissolve it, and then adding water thereto. Next, a microemulsion preparation containing a poorly soluble drug can be obtained by performing emulsification with stirring while adding the oil phase to the aqueous phase. In addition, if necessary, a part of water may be added to the aqueous phase component, and after stirring and emulsifying treatment, the remaining water may be added while stirring.

In the emulsification of the microemulsion formulation containing the poorly soluble drug of the present invention, it can be carried out by a usual stirrer or a homomixer (for example, manufactured by Tokushu Kika Kogyo Co., Ltd.), but it is preferably Mantongaurin homogenizer (manton Gaurin manufactured by USA). High speed rotary emulsifier such as pressure emulsifier such as Type15M-8TA), ultrasonic emulsifier such as Ultrasonic homogenizer (U.S. Ultrasonic), Polytron emulsifier (Type50 / 6ST manufactured by Kinematica, Switzerland) If you emulsify under high speed stirring with an emulsifying machine such as a machine,
A microemulsion formulation having a finer particle size can be obtained.

Further, the microemulsion preparation containing the poorly soluble drug of the present invention is composed of fine emulsified particles having a diameter of 0.5 μm or less, and is extremely excellent in physical stability over time.

The microemulsion containing the poorly soluble drug according to the present invention can be used as a dosage form such as cream and emulsion.

〔Example〕

Needless to say, the present invention will be described in more detail with reference to Examples or the scope of the present invention will not be limited to these Examples.

In the following examples, "%" means "% by weight" unless otherwise specified. The particle size of the microemulsion was measured using NICOMP model 270 (manufactured by Nozaki Sangyo Co., Ltd.).

Example 1 Emulsion (Method) Dexamethasone Acetate 0.05% Diisopropyl adipate 3 Olive oil 0.5 Squalane 0.3 POE (55) Stearate 1 Hydrogenated lecithin 0.5 Propylene glycol 3 Glycerin 2 Ethanol 5 Preservatives Purified water Residue (Production method) The ingredients were added to the ingredients and dissolved by heating. While cooling to 40 ° C, the ingredients were sequentially added to this to prepare an oil phase.
On the other hand, the component was added to a mixture of the components and dissolved by heating, and the components and were sequentially added while cooling to 40 ° C. to prepare an aqueous phase. Next, while adding the oil phase to the water phase,
As a preliminary emulsification, a homomixer was used to perform emulsification at 10,000 revolutions for 2 minutes, and then a manganese-gauline homogenizer was used to perform 6 treatments at 200 kg / cm ² to obtain a target microemulsion emulsion having a particle size of 0.05 μm.

Example 2 Cream (Method) Triamcinolone acetonide 0.5% β-glycyrrhetinic acid 0.2 Castor oil 30 Diethyl sebacate 10 Liquid paraffin 5 POE (45) stearate 10 Potassium stearate 0.5 Glycerin 10 1,3-Butylene glycol 5 Citric acid Buffer solution Appropriate amount Preservative Appropriate amount Purifying agent Residual (manufacturing) Ingredients were added to the ingredients and dissolved by heating, and the ingredients were added to this while cooling to 35 ° C to prepare an oil phase.
On the other hand, the components were added to a mixture of the components, dissolved by heating, and the components ,,, were added while cooling to 35 ° C. to prepare an aqueous phase. Next, it was emulsified for 10 minutes using an Ultrasonic homogenizer to obtain the desired microemulsion cream having a particle size of 0.5 μm.

Example 3 Emulsion (Method) Tolucyclate 3% Diphenhydramine 0.5 Dibutyl phthalate 30 Oribu oil 3 Liquid paraffin 2 Decaglycerin monooleate 7 POE (60) Hydrogenated castor oil 3 Propylene glycol 5 Glycerin 2 Ethanol 7 Preservative Appropriate amount Purified water Residue (Production method) The components were added to the components and dissolved by heating. While cooling to 40 ° C, the components and were sequentially added to this to prepare an oil phase. On the other hand, the component was added to a mixture of the components and dissolved by heating, and the components and were sequentially added while cooling to 40 ° C. to prepare an aqueous phase. Next, while adding the oil phase to the aqueous phase, emulsification was performed for 2 minutes at 10,000 revolutions using a homomixer as preliminary emulsification, and further, using a Manton Gaulin homogenizer, it was treated 8 times at 250 Kg / cm ² to obtain a particle size of 0.1. A target microemulsion emulsion having a thickness of μm was obtained.

Example 4 Cream Miconazole 1% Glycerine tricaprylate 40 Castor oil 10 Squalane 5 Liquid paraffin 7 POE (55) stearate 4 Decaglycerin monostearate 1 1,3-Butylene glycol 10 Glycerin 5 Ethanol 3 Carbopol 940 (US Good) (Manufactured by Rich Co., Ltd.) 0.2 Sodium hydroxide 0.01 Preservative Appropriate amount Purified water Residual (Production method) Ingredients were added to ingredients and dissolved by heating. While cooling to 30 ° C, ingredients were added to this to prepare an oil phase. .
On the other hand, the ingredients were added to the mixture of ingredients, and dissolved by heating, while cooling to 30 ° C., the ingredients, and were sequentially added, and a part of the previously added solution was added to the mixture. The aqueous phase was prepared. Next, it was emulsified for 5 minutes using a Polytron emulsifying machine to obtain a target microemulsion cream having a particle size of 0.5 μm.

Example 5 Emulsion (Method) Butyl mefenamic acid 4% l-Menthol 1 Dibutyl adipate 20 β-Phenethyl alcohol 5 Isopropyl myristate 3 Liquid paraffin 2 POE (120) hydrogenated castor oil 5.5 DK ester S-160N (first) Industrial) 1.5 Propylene glycol 12 Ethanol 6 Preservative Suitable amount Purified water Residual (process) Add the components to the ingredients and heat to dissolve, and while cooling to 35 ° C, add the ingredients and prepare the oil phase. did. On the other hand, add the ingredients to the ingredients, dissolve by heating, and
While cooling to ℃, part of component 12 (30%),
Were sequentially added to prepare an aqueous phase. Next, while adding the oil phase to the water phase, use a homomixer to pre-emulsify 10,000
Emulsify for 2 minutes by rotation, further process with Manton Gaulin homogenizer at 200 Kg / cm ² for 6 times, and add the rest of the components with stirring to obtain the desired microemulsion emulsion with a particle size of 0.2 μm. It was

Example 6 Emulsion (Method) ibuprofen piconol 3% propylene glycol dicaprylate 15% dibutyl sebacate 4 oleyloleate 1.5 squalane 3.5 decaglycerin monostearate 7 1,3-butylene glycol 12 preservative proper amount purified water residue ( Manufacturing method) Ingredients were added to the ingredients and dissolved by heating. While cooling to 40 ° C, the ingredients were sequentially added to this to prepare an oil phase. On the other hand, the ingredients were added to the ingredients and dissolved by heating, and the ingredients were added while cooling to 40 ° C. to prepare an aqueous phase. Next, the oil phase was added to the aqueous phase and emulsified with an Ultrasonic homogenizer for 10 minutes to obtain a target microemulsion emulsion having a particle size of 0.1 μm.

Example 7 Emulsion (Method) Methyl salicylate 8% Diphenhydramine 5 Procaine hydrochloride 2 Diisopropyl adipate 23 Glycerin tricaprylate 10 Olive oil 2.5 Liquid paraffin 3.5 POE (45) Stearate 5 Soybean saponin 0.5 1,3- Butylene glycol 10 Sorbit (70%) 5 Ethanol 8 Preservative Appropriate amount Purified water Residue (production method) Ingredients were dissolved in the ingredients, and the ingredients were added to prepare an oil phase. On the other hand, the component was added to the component, dissolved by heating, and the component, was added while cooling to 30 ° C. to prepare an aqueous phase. Then, the oil phase was added to the aqueous phase and treated with 200 Kg / cm ² of 10 times using a Manton Gaulin homogenizer to obtain a target microemulsion emulsion having a particle size of 0.05 μm.

Example 8 Emulsion (formulation) Clotrimazole 1% Diphenhydramine 0.5% Dibutyl phthalate 15% Olivine oil 2.5% Liquid paraffin 9.5% Decaglycerin monooleate 5% Glycerin 5% Ethanol 5% Preservative suitable amount Purified water Residual (production method) ) A component was added to the above components and dissolved by heating. While cooling to 40 ° C, the components and were sequentially added to this to prepare an oil phase. On the other hand, the components were added to the components, dissolved by heating, and the components and were sequentially added while cooling to 40 ° C. to prepare an aqueous phase. While adding the oil phase prepared above to the aqueous phase, emulsification was performed for 2 minutes at 10,000 revolutions using a homomixer as preliminary emulsification, and further processed 6 times at 300 kg / cm ² using a Manton Gaulin homogenizer to obtain a particle size. A target clotrimazole-containing microemulsion emulsion of 0.1 μm was obtained.

Example 9 Emulsion (formulation) Clotrimazole 0.5% Salicylic acid 0.2% 2-Octyldodecanol 12% β-phenethyl alcohol 2% Squalane 5% Isopropyl myristate 2% Hexaglycerin monolaurate 3% POE (60) hydrogenated castor oil 3% Polyethylene glycol 400 4% 1,3-Butylene glycol 2.5% Ethanol 1.5% Preservative Appropriate amount Purified water Residue (Manufacturing method) Add the above ingredients to the ingredients while heating and dissolving, and cool to 40 ℃. The ingredients were sequentially added to prepare an oil phase. On the other hand, the ingredients were added to the mixture of the ingredients and dissolved by heating, and while cooling to 40 ° C., the ingredients,
, Were sequentially added to prepare an aqueous phase. Next, the oil phase was added to the aqueous phase and emulsified for 10 minutes using an Ultrasonic homogenizer to obtain a target clotrimazole-containing microemulsion having a particle size of 0.2 μm.

Example 10 Emulsion (prescription) Clotrimazole 2% Kakikin tincture 2% Castor oil 20% Diisobutyl adipate 5% Methylpolysiloxane 2% Liquid paraffin 3% Decaglycerin monostearate 15% Sorbite (70%) 3% Propylene Glycol 5% Ethanol 7% Preservative Appropriate amount Purified water Residue (Production method) The ingredients were added to the ingredients and dissolved by heating, and the ingredients were sequentially added to this while cooling to 40 ° C to prepare an oil phase. On the other hand, the components were added to a mixture of the components and dissolved by heating, and the components and were sequentially added while cooling to 40 ° C. to prepare an aqueous phase. Next, the oil phase was added to the aqueous phase and emulsified at 22,000 rpm for 10 minutes using a Polytron emulsifier to obtain a target clotrimazole-containing microemulsion emulsion having a particle size of 0.5 μm.

Example 11 Emulsion (formulation) clotrimazole 5% β-glycyrrhetinic acid 0.1% dibutyl phthalate 30% oleyl oleate 2.5% liquid paraffin 1.5% pentacosanglycerin diisostearate 12% POE (55) stearate 2% lecithin 0.5 % Propylene glycol 5% Glycerin 2% Ethanol 10% Preservative Appropriate amount Purified water Residual (preparation method) Add ingredients to the ingredients while heating and dissolve, and while cooling to 40 ° C, add ingredients, and in order to add oil. The phases were prepared. On the other hand, the ingredients were added to the mixture of the ingredients, and dissolved by heating, and while cooling to 40 ° C., the ingredients,
Were sequentially added to prepare an aqueous phase. Next, while adding the oil phase to the water phase, use a homomixer to pre-emulsify 10,000
Emulsify for 2 minutes by rotation, and further process with Manton-Gaulin homogenizer 8 times at 250 kg / cm ² to obtain a particle size of 0.2 μm.
The target clotrimazole-containing microemulsion emulsion was obtained.

Example 12 Emulsion (formulation) clotrimazole 0.5% dibucaine hydrochloride 0.3% dibutyl phthalate 4% isostearic acid 1% isopropyl myristate 2% squalane 2% decaglycerin monostearate 1% saponin 0.5% glycerin 15% ethanol 5% preservative Agent Proper amount Purified water Residue (Production method) Ingredients were added to the ingredients and dissolved by heating. While cooling to 40 ° C, the ingredients were sequentially added to this to prepare an oil phase. On the other hand, add the ingredients to the ingredients, dissolve by heating, and
While cooling to ℃, some of the ingredients (30%),
Were sequentially added to prepare an aqueous phase. Next, while adding the oil phase to the water phase, emulsify for 10 minutes at 22,000 rotations using a Polytron emulsifier, and add the rest of the ingredients with stirring to add the target clotrimazole-containing microparticles with a particle size of 0.3 μm. An emulsion emulsion was obtained.

Example 13 Emulsion (formulation) Clotrimazole 1.5% Diethyl sebacate 12% Olive oil 2% Squalane 6% Pentadecaglycerin monostearate 7% Dipropylene glycol 7% 1,3-Butylene glycol 5% Ethanol 0.5% Preservative Appropriate amount Purified water Residue (manufacturing method) The components were added to the components and dissolved by heating. While cooling to 40 ° C, the components were sequentially added to this to prepare an oil phase.
On the other hand, the components were added to a mixture of the components, and dissolved by heating, and while cooling to 40 ° C., the components, and were sequentially added to prepare an aqueous phase. Next, while adding the oil phase to the water phase,
As pre-emulsification, emulsify for 2 minutes at 10,000 rpm using a homomixer, and further process 6 times at 300 kg / cm ² using a Mantongaurin homogenizer to obtain the target clotrimazole-containing microemulsion with a particle size of 0.2 μm. Obtained.

Example 14 Cream (formulation) Clotrimazole 2% Kakikin tincture 0.5% Castor oil 30% Diethyl sebacate 10% Oleyloylate 5% Squalane 8% POE (45) Stearate 15% DK ester S-160N (Mitsubishi Kasei Foods) 3% glycerin 12% 1,3-butylene glycol 3% preservative proper amount purified water Residue (manufacturing method) Add the ingredients to the ingredients, dissolve by heating, and cool to 30 ° C while adding the ingredients. An oil phase was prepared by adding them sequentially. On the other hand, the components were added to a mixture of the components, dissolved by heating, and the components were added while cooling to 30 ° C. to prepare an aqueous phase. Then, it was emulsified for 10 minutes using an Ultrasonic homogenizer to obtain the target clotrimazole-containing microemulsion cream having a particle size of 0.5 μm.

Next, Comparative Examples 1 to 6 were produced in order to compare the stabilizing effect and the transdermal absorbability of the microemulsion preparation containing the poorly soluble drug according to the present invention with that of the conventional one.

Comparative Example 1 Emulsion (treatment) Dexamethasone acetate 0.05% Diethyl phthalate 6 Stearic acid 3 Cetanol 1 Propylparaben 0.05 Propylene glycol 10 Carboxyvinyl polymer 0.15 Sodium hydroxide 0.3 Methylparaben 0.2 Purified water Residual (manufacturing) Were dissolved, and the ingredients, and were added, and the mixture was heated to 70 ° C. to prepare an oil phase. On the other hand, the ingredients,
,, and were mixed and heated to 70 ° C. to prepare an aqueous phase. Then, while adding the oil phase to the aqueous phase, emulsification was performed at 10,000 rpm for 2 minutes using a homomixer, and this was cooled to room temperature to obtain an emulsion of Comparative Example.

Comparative Example 2 Cream (treatment) Dexamethasone acetate 0.05% Diethyl phthalate 12 Stearic acid 4 POE (20 mol) sorbitan 3 Glycerin monostearate 1 Carboxyvinyl polymer 0.5 Sodium hydroxide 0.2 Sodium hexametaphosphate 0.05 Propylparaben 0.3 Propylene Glycol 7 Purified water Residual (manufacturing) Add ingredients to the ingredients and dissolve them.
Was added and heated to 70 ° C. to prepare an oil phase. On the other hand, add the ingredients ,,,, to the ingredients and mix, and mix this at 70 ℃.
The mixture was warmed to prepare an aqueous phase. Then add the oil phase to the water phase, emulsify for 3 minutes at 7,000 rpm with a homomixer,
This was cooled to room temperature to obtain a cream of Comparative Example.

Comparative Example 3 Emulsion (treatment) Tolucyclate 3% Diphenhydramine 0.5 Dibutyl phthalate 15 Stearic acid 5 Cetanol 2 Butylparaben 0.02 Propylene glycol 16 Carboxyvinyl polymer 0.15 Sodium hydroxide 0.5 Ethylparaben 0.3 Purified water Residual (manufacturing) component The ingredients were added and dissolved by heating, and the ingredients and were further added and heated to 70 ° C. to prepare an oil phase. On the other hand, the components ,,, were mixed and heated to 70 ° C. to prepare an aqueous phase. Then, while adding the oil phase to the aqueous phase, emulsification was performed at 10,000 rpm for 2 minutes using a homomixer, and this was cooled to room temperature to obtain an emulsion of Comparative Example.

Comparative Example 4 Cream (treatment) Torsiclate 3% Diphenhydramine 0.5 Dibutyl phthalate 30 Stearic acid 5 Glycerin monostearate 5 POE (20 mol) sorbitan monostearate 3.8 Sorbitan monostearate 1.2 Propylene glycol 10 Methylparaben 0.1 Propylparaben 0.05 Edetic acid Sodium 0.05 Purified water Residual (manufacturing method)
, And were added and heated to 70 ° C. to prepare an oil phase. On the other hand, ingredients ,,, were added to the ingredients and mixed, and this was heated to 70 ° C. to prepare an aqueous phase. Then, the oil phase was added to the water phase, and the mixture was emulsified with a homomixer at 7,000 rpm for 3 minutes and cooled to room temperature to obtain a cream of Comparative Example.

Comparative Example 5 Emulsion (formulation) Clotrimazole 1% Diethyl phthalate 8% Stearic acid 3% Cetanol 1% Propylparaben 0.05% Propylene glycol 10% Carboxyvinyl polymer 0.15% Sodium hydroxide 0.3% Methylparaben 0.2% Purified water Residual (manufacturing method) ) The ingredients were added to the ingredients and dissolved by heating, the ingredients, and were added, and the mixture was heated to 70 ° C. to prepare an oil phase. On the other hand, the ingredients,
,, and were mixed and heated to 70 ° C. to prepare an aqueous phase. Then, while adding the oil phase to the aqueous phase, emulsification was performed for 2 minutes at 10,000 rpm using a homomixer, and this was cooled to room temperature to obtain a clotrimazole-containing emulsion.

Comparative Example 6 Cream (prescription) Clotrimazole 1% Crotamiton 4% Isopropyl myristate 10% Stearic acid 3% POE monostearate (15 mol) sorbitan 2% Glycerin monostearate 0.8% Carboxyvinyl polymer 0.3% Sodium hydroxide 0.1 % Sodium hexametaphosphate 0.05% Ethylparaben 0.3% Propylene glycol 10% Purified water Residual (manufacturing method) Add ingredients to the ingredients and dissolve by heating.
, And were added and heated to 70 ° C. to prepare an oil phase. On the other hand, add ingredients ,,,, to the ingredients and mix,
This was heated to 70 ° C. to prepare an aqueous phase. Then, the oil phase was added to the aqueous phase and emulsified at 7,000 rpm for 3 minutes with a homomixer, and this was cooled to room temperature to obtain a clotrimazole-containing cream.

〔The invention's effect〕

The poorly soluble drug-containing microemulsion preparation of the present invention has not only excellent physical stability over time, but also remarkably good transdermal absorbability.

First, regarding the physical stability over time, the microemulsion preparations containing the poorly soluble drugs of Examples 1 to 14 according to the present invention are extremely stable even after 6 months from the preparation, and are observed by a polarization microscope. By observation, no crystals of each drug were observed. In addition, even in microemulsion preparations that had been stored under severe conditions (50 ° C, 40 ° C, 5 ° C, 0 ° C, -5 ° C) for 2 months, crystals of each drug were not observed, and were extremely stable. . The results are shown in Table-1.

Next, it was confirmed by an animal experiment that the microemulsion preparation containing the poorly soluble drug according to the present invention has significantly better transdermal absorbability as compared with the conventional emulsion base. As an example, the anti-inflammatory action and antifungal action will be described below.

(Anti-inflammatory action test) From the carrageenin paw edema inhibitory rate test using rats, it was confirmed that there was a significant difference in the transdermal absorption agent due to the difference in the base.

In this test, 6-week-old Wistar rats were used as one group consisting of 5 rats. The paw edema volume was measured using a rat hindlimb footpad edema volume measuring device KM-357 (Natsume Seisakusho).

After measuring the rat right hindlimb volume, sample 0 on the right hind footpad.
2g was applied. Two hours later, 0.05 ml of 1% carrageenin sodium salt was subcutaneously injected into the same site. The volume of the right hind limb was measured 3 hours after injection of carrageenin sodium salt, and the difference from the volume of the right hind limb before application of the sample was defined as the paw edema volume.

However, Vc and Vt represent the average paw edema volume of the control group and the test sample application group, respectively. The above test results were as shown in Table-2.

As is clear from the above examples, the microemulsion preparation of the present invention was more effective than the conventional emulsified base.

(Antifungal Action Test) Next, it was confirmed from the in vivo anti-trichophyton screening test using guinea pigs that there was a significant difference in transdermal absorbability due to the difference in the base.

In this study, guinea pigs were used as infected animals and weighed 450
A total of 30 males and 15 females weighing ˜500 g were used. The inoculum used was Trichophyton mentagropes, which was reverse-cultured from a freshly isolated strain of human origin.
hytes) was used to prepare 2 × 10 ⁸ conidia / ml with 0.1% Tween 80-physiological saline. The hair of the guinea pig was shaved on the back, the hair was removed with a hair removing wax, and the stratum corneum was peeled off twice with gum tape. Then, 0.025 ml of the bacterial solution prepared in a circular shape with a diameter of 2 cm, 4 places on each back of each guinea pig
I glued each. (Number of conidia: 1.59 × 10 ⁶ pieces / cm ² ) Each guinea pig was divided into 3 groups of 10 animals, and one group was applied with a liquid agent having the same composition as the microemulsion according to the present invention except that the group did not contain torsiclate ( The control group) and the remaining two groups were defined as two prescription groups A and B shown in Table 3, respectively. Drug application for 2 weeks from the 5th day after inoculation, 1
Once a day, 0.25 ml was applied to each site. The determination of the lesion area is
It is performed every day due to the spread of erythema, the formation of scales, and the formation of skin, and the criteria for its determination are as shown in Table 4
Stein) method.

The first is the therapeutic effect of each prescription carried out by the above method.
Shown in the figure. The control group reached a plateau on the 9th day of inoculation, and no improvement of the lesion was observed until the 18th day, after which the spontaneous healing was started.

In addition, the formulations containing torsiclate were significantly more effective than the control group. The therapeutic effect obviously differs depending on the bases in the course after 5 days from the drug application, and the torucyclate-containing microemulsion preparation (formulation B) according to the present invention is more effective than the conventional emulsion base (formulation A). , Because the transdermal absorbability is far superior, the therapeutic effect is
At a significance level of 0.1%, the effect was clearly high.

In addition, with respect to another antifungal agent, clotrimazole, an in vivo Trichophyton action test using guinea pigs was carried out in the same manner.

The therapeutic effect of each prescription over time is shown in FIG.

The control group reached a plateau on the 11th day after the bacterial inoculation, and no improvement in the lesion area was observed until the 18th day, after which the self-healing treatment was started. In addition, each of the formulations containing clotrimazole showed a significant therapeutic effect as compared with the control group.

The course of treatment on and after the 8th day after application of the drug was obviously different in the therapeutic effect depending on the respective bases.
Showed that the therapeutic effect was significantly higher at a significance level of 0.1% at any time point because it was far superior to the conventional emulsion base (formulation D) in transdermal absorbability. .

[Brief description of drawings]

1 is a graph showing the therapeutic effect over time of a torucyclate-containing microemulsion preparation according to the present invention and a control preparation thereof, and FIG. 2 is a graph showing the therapeutic effect over time of a conventional torucyclate-containing preparation. FIG. 6 is a graph showing the therapeutic effect over time of a clotrimazole-containing microemulsion preparation according to the above and its control preparation and the therapeutic effect over time of a conventional clotrimazole-containing preparation.

Claims (1)

[Claims] 1. A poorly soluble drug, oil content of IOB 0.22 to 0.85,
A micro-emulsion preparation containing a poorly soluble drug, which contains an oil component having an IOB of 0 to 0.20, a hydrophilic surfactant and water, and has an average particle diameter of emulsified particles of 0.5 μm or less.