KR102394599B1 - Pharmaceutical composition for topical administration containing efinaconazole - Google Patents

Abstract

It relates to a pharmaceutical composition for topical administration in the form of a solution comprising efinaconazole or a pharmaceutically acceptable salt thereof, and comprising a fat-soluble permeation enhancer and a water-soluble permeation enhancer, the composition comprising: It can be usefully used for the prevention or treatment of onychomycosis because it significantly increases the permeability and has excellent safety.

Description

Pharmaceutical composition for topical administration containing efinaconazole

It relates to a pharmaceutical composition for topical administration comprising efinaconazole or a pharmaceutically acceptable salt thereof. The pharmaceutical composition for topical administration according to the present invention can be usefully used for the prevention or treatment of onychomycosis because it significantly increases the penetration rate and permeability of efinaconazole and has excellent safety.

Dermatomycosis is a group of diseases caused by a fungal infection in the stratum corneum of the epidermis, the outermost layer of the skin, hair, and nails. can

Depending on the causative organism, there are dermatophytosis, aspergillosis, candidiasis, sporotolithosis, mycosis nigricans (chromomysis), and cryptococcosis.

Dermatomycosis is a generic term for skin diseases caused by fungal infections, and it is treated with antifungal drugs. Antifungal drugs may have side effects, so the treatment method is topical except for chronic cases where the infection site is too extensive or topical application treatment fails. Dispensing is the principle.

Ringworm onyi, also called ringworm onycho or onychomycosis, is a type of dermatomycosis, the most common fungal disease, and is known to occur in about 6 to 8% of the adult population. In particular, it is one of the most common nail diseases that occur in about 100 million patients in Europe and North America, and is known to occur in 10% of the total population and more than 25% in those over 50. Onychomycosis can occur in both fingernails and toenails, causing thickening, brittleness, and opacification of the toenails.

Onychomycosis is usually caused by the fungus infiltrating the inner surface of the nail, that is, the surface of the nail in contact with the keratinous skin layer (nail bed) and multiplying by feeding the keratin that constitutes the nail, gradually becoming the outer surface of the nail (nail plate). As a spreading disease, there has been a continuous demand for a topical therapeutic agent that has fewer side effects by directly applying the drug to a desired site in the treatment regimen. In order for a topical treatment agent to show effective drug efficacy, when the drug is applied to the outside (nail plate), it must be delivered to the inside (nail base) that needs treatment. It is about 100 times thicker than the stratum corneum, so there is a limitation in that drug penetration is not easy.

Fungi, as eukaryotes, have cell walls like bacteria, but antibacterial agents are not effective because there is no peptidoglycan present in the cell walls of bacteria. Accordingly, antifungal agents are the most common types of antifungal agents that target ergosterol, a component of a fungal-specific cell membrane. )-based compounds.

The azole compound has an imidazole ring and a triazole ring, and inhibits lanosterol 14 α-demethylase, which converts lanosterol to ercosterol, thereby inhibiting fungi The lack of ergosterol in the cell membrane of the cell membrane collapses and growth is inhibited.

Representative azole compounds include imidazole-based ketoconazole and triazole-based fluconaxole and itraconazole.

Itraconazole was developed in 1984, has a triazole ring, has a side chain structure similar to that of ketoconazole, and has a longer blood half-life. Due to its low bioavailability, cyclodextran is used to increase solubility. Similar to ketoconazole, it is effective in the treatment of oral, vaginal and esophageal candidiasis, tinea corpuscle, tinea pedis, fungal keratitis and systemic fungal infection, and is particularly used for the treatment of aspergillosis.

Arylamine-based compounds exhibit antifungal activity by inhibiting squalene epoxidase involved in ergosterol synthesis, and a representative arylamine-based compound includes terbinafine.

Efinaconazole is a triazole antifungal agent having the structure of Formula 1 below, and the chemical name is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine- 1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol[(2R,3R)-2-(2,4-difluorophenyl)-3-(4- methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol]. It has been reported that efinaconazole has excellent inhibitory activity of lanosterol 14α-demethylase in the ergosterol biosynthesis pathway.

[Formula 1]

For the treatment of onychomycosis, a topical solution formulation containing efinaconazole at a concentration of 10% (trade name: JUBLIA ^TM , Kaken Pharmaceutical Co., Ltd.) is commercially available. The topical solution formulations, together with efinaconazole, include ethanol as a volatile solvent; cyclomethicone in oily phase as a wetting agent; and diisopropyl adipate and C12-C15 alkyl lactate, which are highly lipid-soluble as permeation enhancers (U.S. Patent Nos. 7,214,506 (Patents relating to a method for treating onychomycosis), 8,039,494, 8,486,978, 9,302,009 Nos., 9,566,272, 9,861,698, and 9,877,955 (patents relating to compositions for treating nail diseases including non-volatile solvents, wetting agents, etc.) Solution formulations contain a volatile solvent such as ethanol as a basic medium after application Since it does not show sticky or gluey and the solution dries within a short time, it has the advantage that there is no inconvenience in daily life.However, in the case of JUBLIA ^TM (Kaken Pharmaceutical Co., Ltd.), the conventional solution formulation uses a solvent after application. Although it volatilizes quickly and is convenient to use, there is a problem that the penetration rate and permeability of the drug into the skin and nail are still unsatisfactory.

Domestic Patent No. 10-2060546 discloses efinaconazole, ethanol and cyclomethicone as a volatile solvent, and diethylene glycol monoethyl ether with strong fat solubility as a penetration enhancer to improve the skin and nail penetration rate and permeability of efinaconazole. A pharmaceutical composition for topical administration comprising a combination of isopropyl myristate has been disclosed. This technology also uses a volatile solvent as the basic medium as in JUBLIA ^TM , and has a common feature of combining cyclomethicone, diethylene glycol monoethyl ether, and isopropyl myristate as a fat-soluble permeation accelerator. The composition also has a problem in that the nail penetration rate and permeability are still unsatisfactory like JUBLIA ^TM .

The present inventors have found that, unlike a composition containing only a fat-soluble permeation enhancer, when a water-soluble permeation enhancer is combined with a fat-soluble permeation enhancer, it helps the nail, which is a dry tissue with a very low moisture content, hydrdation, and micropores It was hypothesized that it would be possible to improve the nail penetration rate and permeability of efinaconazole by helping the formation. As a result of various studies afterward, when formulated by combining a fat-soluble permeation enhancer and a water-soluble permeation enhancer, in particular, propylene glycol dicaprolate/dicaprate (hereinafter Labrafac PG, Gattefosse) as a fat-soluble permeation enhancer and hydroxypropyl as a water-soluble permeation enhancer When formulated in combination with beta cyclodextrin (hereinafter referred to as HP-β-CD), it was found that the nail penetrating rate and permeability of efinaconazole were significantly increased and stabilized, and the present invention was completed.

One object of the present invention is to

To provide a pharmaceutical composition comprising efinaconazole or a pharmaceutically acceptable salt thereof as an active ingredient, and excellent nail permeability when applied topically, and a method for preparing the same.

In order to achieve the above object,

The present invention provides a pharmaceutical composition for topical administration in the form of a solution comprising efinaconazole or a pharmaceutically acceptable salt thereof, a volatile solvent, a fat-soluble permeation enhancer and a water-soluble permeation enhancer.

Also, the present invention

adding and dissolving efinaconazole and a fat-soluble permeation enhancer in a volatile solvent (step 1);

dissolving the water-soluble permeation enhancer in water (step 2); and

It provides a method for preparing the pharmaceutical composition comprising a; mixing the solvent dissolved in steps 1 and 2 to be medicated (step 3).

The pharmaceutical composition for topical administration of efinaconazole according to the present invention is a composition with significantly improved nail permeability, and can significantly increase the skin and nail permeability and permeability of efinaconazole, and has excellent stability, so it is in solution form It can be usefully used as a composition for topical administration of, and can be usefully used in the treatment of onychomycosis using the composition.

1 shows the results of comparative evaluation of nail permeability over time of compositions according to Examples 2 and Comparative Examples 1 to 3;
2 is a photograph showing the results of evaluation of the properties of the composition according to Example 2.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for topical administration in the form of a solution comprising efinaconazole or a pharmaceutically acceptable salt thereof, a volatile solvent, a fat-soluble permeation enhancer and a water-soluble permeation enhancer.

Efinaconazole may be contained in a therapeutically effective amount, for example, in the range of 8 to 12% by weight, preferably in an amount of about 10% by weight, based on the total weight of the composition. It is not limited.

The composition may contain an antifungal active material in addition to efinaconazole, examples of the antifungal active material are as follows, and these active materials may be free acids or bases themselves, or may be in the form of salts thereof. Specifically, polyene antimycotic agents as imidazole compounds as miconazole, ketoconazole, clotrimazole, econazole, bifonazole, butoconazole ( butoconazole), penticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, or tioconazole; As a triazole compound, fluconazole, itraconazole, ravuconazole, posaconazole, voriconazole, efinaconazole or terconazole ), etc.

Since the nail plate (nail plate) is a structure in which keratinocytes are irregularly stacked, this structure acts as an obstacle to drug permeation in drug delivery through the nail. Since the causative bacteria of onychomycosis proliferate on the nail bed under the nail plate and cause disease, the antifungal agent must secure the nail plate permeability in order to show a therapeutic effect on the causative bacteria of onychomycosis. To this end, the pharmaceutical composition according to the present invention includes a fat-soluble permeation enhancer and a water-soluble permeation enhancer, and in particular, it is characterized in that it contains both a fat-soluble permeation enhancer and a water-soluble permeation enhancer. The fat solubility and water solubility of the permeation enhancer can be classified by miscibility with water. The oil-soluble permeation enhancer listed in the present invention has a characteristic of being separated into two phases without mixing with water, and the water-soluble permeation enhancer is characterized by being completely mixed into one phase when mixed with water.

The pharmaceutical composition can significantly increase the nail permeability of efinaconazole by including a fat-soluble permeation enhancer. The oil-soluble permeation enhancer includes a hydrophobic excipient and a hydrophobic emulsifier, which have non-polar properties, so that they are soluble in non-polar solvents rather than polar solvents and are hardly soluble in water-soluble solvents. Since the lipid content in the nail plate is less than 1%, the fat-soluble permeation enhancer does not interact very much with the nail plate. It can help the stability of the drug by preventing the back, and it can increase the hydration of the nail plate by preventing the evaporation of moisture by being absorbed into the nail plate or forming a film on the plate.

The fat-soluble permeation enhancer may be at least one selected from the group consisting of alkylene glycol fatty acid esters, alkyl fatty acid esters, fatty acid glycerides, glycerides, fatty acids, fatty alcohols, hydrocarbons, minerals, and oils;

said alkylene is methylene, ethylene, propylene or butylene;

The alkyl is C _1-10 straight or branched chain alkyl; and

The fatty acid ester may be a saturated or unsaturated fatty acid ester of C _6-30 .

The fatty acid may be a C _6-30 saturated or unsaturated fatty acid.

In this case, the unsaturated fatty acid ester means containing at least one double bond. The fatty acid ester may be a mono (mono-), di (di-) or tri (tri-) fatty acid ester. The fatty acid glyceride may be a fatty acid mono-, di-, or tri-glyceride.

The alkyl may be C _1-10 , C _2-8 , or C _3-6 , but is not limited thereto. The fatty acid ester or fatty acid may be, for example, each independently C _6-28 , C _8-26 , or C _9-25 , but is also not necessarily limited to the number of carbon atoms.

For example, minerals such as ceresin and ozokerite as a fat-soluble permeation enhancer; Corn oil, sesame oil, soybean oil, olive oil, jojoba oil, grapeseed oil, macadamia ternifolia nut oil, hydrogenated coriander -hydrogenated hi-erucic acid rape seed oil, safflower oil, hybrid sunflower(Helian thus annuus) oil, neen(melia azadirachta) seed oil or wild rose oils such as dog rose (rosa canina) lips oil, yellow wax, white wax, petrolatum, mineral oil, paraffin, lanolin, and the like; fatty acid alcohols such as lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and behenyl alcohol; capric acid, lauric acid, myristic acid, tetradecanoic acid, palmitic acid, stearic acid, arachidic acid, Fatty acids such as behenic acid, alpha-linolenic acid, oleic acid, ethyl oleate, gamma linolenic acid, eicosapentaenoic acid (EPA), etc. Ryu; Labrafac PG, Lauroglycol 90, propylene glycol dicaprylate/dicaprate, glyceryl stearate, glyceryl monooleate, captylic/capric triglyceride (captylic/capric triglyceride), cetyl octanoleate, isopropyl myristate, 2-ethylene isopelagonate, di-C _12-13 alkyl maleate (di -C _12-13 alkyl malate), ceteatyl octanoate, butylene glycol dicaptylate/dicaprate, propylene glycol monocapreate, propylene glycol Monolaurate (propylene glycol monolaurate), isononyl isostearate, isostearyl isostearate, coco-captylate/caprate, cetyl octanoate (cetyl octanoate), octyldodecyl myristate, cetyl esters, C _10-30 cholesterol/ _lanosterol ester, hydrogenated castor oil esters such as oil), mono-glycerides, diglycerides, and triglycerides; Beeswax, carnauba wax, suctose distearate, propylene glycol-8 beeswax (PEG-8 beeswax), candelilla (euphorbia cerifera) wax, etc. of hydrocarbons; etc. are examples of this.

Also, as an example, propyleneglycol dicaprylate/dicaprate may be commercially available from Labrafac ^TM PG (Gattefosse). The meaning of "/" means a mixture of propylene glycol dicaprylate and propylene glycol decaprate. Propylene glycol monolaurate (propyleneglycol monolaurate), commercially available Lauroglycol ^TM 90 (Gattefosse) can be used.

Preferably, the fat-soluble permeation enhancer is one selected from the group consisting of Labrafac PG, Lauroglycol 90, isopropyl myristate, and ethyl oleate. may be more than

In the pharmaceutical composition, these fat-soluble permeation enhancers may be included or present in an amount of 5 to 30% by weight based on the total weight of the composition. preferably 10 to 20% by weight, 15 to 30% by weight, 5 to 15% by weight, 8 to 28% by weight, 10 to 25% by weight, 8 to 28% by weight, about 10% by weight, about 15% by weight, or It may be included in about 20% by weight. When included in less than the weight %, the effect of improving nail permeability is reduced, and when included in more than the weight %, there may be a problem in that physical stability such as phase separation is deteriorated.

The pharmaceutical composition is more preferably used in combination with a water-soluble permeation enhancer as a water-soluble permeation enhancer together with a fat-soluble permeation enhancer. The water-soluble permeation enhancer interacts with aromatic amino acids among the components constituting the nail plate to maintain the unfolding state of the protein structure, and to maintain a structure with an increased pore volume in the nail plate. In addition, the water-soluble permeation enhancer is a solubilizing agent, and may help to maintain a drug dissolution state after evaporation of the volatile solvent.

The water-soluble permeation enhancer, cyclodextrin, polyol fatty acid ester, polyoxyalkylene polyol fatty acid ester, Cremophor, Labrasol, surfactants and co-solvents at least one selected from the group consisting of;

said alkylene is methylene, ethylene, propylene or butylene;

The polyol is one or more selected from the group consisting of polyethylene glycol (polyethyleneglycol, PEG), glycerol, sorbitol and sorbitan; and

The fatty acid ester may be a saturated or unsaturated fatty acid ester of C _6-30 .

In this case, the unsaturated fatty acid ester means containing one or more double bonds. Cyclodextrins may be cyclodextrins in which C _1-5 alkyl is substituted _in a hydroxyl group. The cyclodextrins may be α-cyclodextrins, β-cyclodextrins or γ-cyclodextrins. The fatty acid ester may be a mono (mono-), di (di-) or tri (tri-) fatty acid ester.

For example, the water-soluble permeation enhancer may include one or more surfactants, cosolvents, cyclodextrins, and the like. Pharmaceutically acceptable anionic, cationic, nonionic or amphoteric surfactants include Labrasol, Cremophor EL, tween 80, Polysorbate 80). caprylocaproyl macrogolglyceride, Polysorbate 80 (Polyoxyethylene (20) sorbitan monooleate), polyoxyethylene sorbitan fatty acid ester (tween), sorbitan fatty acid ester acid ester), span, polyoxyethylene fatty acid ester, Myrj, polyoxyethylene polyoxypropylene block copolymer, poloxamer, poly Polyoxyethylene polyoxypropylene copolymer, pluronic, reactant of natural or hydrogenated vegetable oil and ethylene glycol, cremophor , dioctylsulfosuccinic acid sodium salt, lauryl sulfonic acid sodium salt, phospholipid, propylene glycol mono or di fatty acid ester, Miglyol ), trans-esterification reactant of natural vegetable oil triglyceride and polyalkylene polyol, labrafil M, mono, di or triglycerides with polyethylene of mono- or di-fatty acid esters of glycols mixture of mono-, di- or triglycerides and mono- or di-fatty esters of polyethylene glycol, labrasol, mono-, di- or mono/di glycerides (mono-, di- or mono) /di glyceride), imbitol, a mixture of mono- or di-fatty acid esters of propylene glycol and mono-, di- or mono-, di- or glycerides) and derivatives thereof may be selected and used. In addition, a cosolvent may be included to increase the solubility of the active ingredient and improve the transmittance through hydration, and the cosolvent is propylene carbonate, propylene glycol, glycofurol, polyethylene One selected from the group consisting of glycol, dimethyl isosorbide and N-methyl pyrrolidone is used. The cyclodextrins that can be used include α-cyclodextrins, β-cyclodextrins including hydroxypropyl-beta-cyclodextrin (HP-β-CD), γ-cyclodextrin and derivatives thereof. include More preferably, β-cyclodextrins or derivatives thereof having a pupil diameter of 6.0 to 6.5 Å are suitable. More preferably, by combining hydroxypropyl beta cyclodextrin (HP-β), it is possible to significantly increase the skin and nail permeability of efinaconazole. HP-β preferably has a molecular substitution number of 0.2 to 1.0, more preferably 0.4 to 1.0. If the number of molecular substitutions is too low, the solubility decreases, and if the number of molecular substitutions is too high, the viscosity increases, which is difficult to handle.

For caprylocaproyl macrogolglyceride, commercially available Labrasol ^® can be used. Cremophor EL may be prepared by reacting, for example, oxirane; propane-1,2,3-triol.

Preferably, the water-soluble permeation enhancer is, hydroxypropyl-beta-cyclodextrin (HP-β-CD), Labrasol (Labrasol), Cremophor EL (Cremophor EL) and polysorbate (Polysorbate) 80, tween 80) may be at least one selected from the group consisting of.

In the pharmaceutical composition, these water-soluble permeation enhancers may be included or present in an amount of 0.1 to 20% by weight based on the total weight of the composition. Preferably 0.1 to 10% by weight, 0.1 to 5% by weight, 1 to 10% by weight, 2 to 8% by weight, 0.1 to 15% by weight, 0.1 to 13% by weight, 1 to 13% by weight, 3 to 6% by weight , 4 to 12 wt%, 5 to 10 wt%, about 5 wt%, about 1 wt%, about 2 wt%, about 4 wt%, or about 10 wt%. When included in less than the weight %, the effect of improving nail permeability is reduced, and when included in more than the weight %, there may be a problem in that physical stability such as phase separation is deteriorated.

As a preferred example, propylene glycol dicaprylate / decaprate, propylene glycol monocapreate, ethyl oleate, and isopropyl myristate as a fat-soluble permeation enhancer hydroxypropyl-beta-cyclodextrin (HP-β-CD), caprylocaproyl macrogolglyceride, oxirane; propane-1,2, 3-triol (oxirane; propane-1,2,3-triol), Polysorbate 80 (Polyoxyethylene (20) sorbitan monooleate) can be used. As the most preferred example, propylene glycol dicaprylate/decaprate, which is a fat-soluble permeation enhancer, and hydroxypropyl-beta-cyclodextrin, HP-β-CD, which is a water-soluble permeation enhancer, are used together. can

The pharmaceutical composition may further include a non-volatile solvent. Preferably, water may be further included as the non-volatile solvent.

In this case, water may be included in an amount of 2 to 20% by weight, 5 to 15% by weight, 6 to 13% by weight, 8 to 12% by weight, 9 to 11% by weight, or about 10% by weight based on the total weight of the composition. there is. When used in a ratio out of this, storage stability is reduced due to compatibility with other solvents and components, for example, problems such as phase separation and precipitation of active ingredients may occur.

The composition according to the present invention may contain water as a water-soluble solvent in order to facilitate drug penetration by hydration of the nail and to dissolve the water-soluble permeation enhancer.

A pharmaceutical composition containing efinaconazole according to the prior invention Korean Patent No. 10-2060546, and a commercially available topical solution formulation JUBLIA ^TM used for the treatment of onychomycosis (Related literature published by Kaken: Efinaconazole Topical Solution, 10 %: Formulation Development Program of a New Topical Treatment of Toenail Onychomycosis. J Pharm Sci 2015, 104, 7, 2177-2182) contains cyclomethicone as a wetting agent. According to the related literature published by Kaken, the cyclomethicone refers to the role of lowering the surface tension between the nail plate and the formulation, and also has excellent drug solubility, so that the dissolved state of the drug after ethanol volatilization is evaluated. It is believed that it can play a role in maintaining However, cyclomethicone is an oil with a dielectric constant value of only 2.39, and is characterized by poor compatibility with aqueous media such as water. Therefore, in Kakensa and Prior Registration Patent No. 10-2060546, ethanol is designed to contain 50% or more of the entire composition, and 'if necessary, a small amount (for example, about 1.0% by weight or less) of water is used for the content of water. It may contain additionally', limiting the amount of water. This is because phase separation will occur when the amount of water is increased in the composition comprising cyclomethicone. In addition, in the case of combining the hydrophilic permeation enhancer and cyclomethicone, if an aqueous medium corresponding to the corresponding amount is included for the combination, phase separation of the oily cyclomethicone occurs, making it difficult to secure the uniformity of the formulation.

On the other hand, since the pharmaceutical composition according to the present invention necessarily contains the hydrophilic permeation enhancer, an aqueous medium such as water is necessarily required to contain the hydrophilic permeation enhancer, and unlike the existing technology, cyclomethicone is excluded. There is a difference in the composition of the pharmaceutical composition of the present invention and the prior invention. In addition, the present invention was able to increase the water content by greatly increasing the content of an aqueous medium such as water.

The pharmaceutical composition may further comprise one or more film formers. A film former refers to a component that forms a film, such as a thin film or cover. The film former is not limited in use as long as it is a film former that can be used by those skilled in the art, but for example, hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose (HPMC) ) containing hydroxypropyl cellulose (hydroxyalkyl cellulose), polyvinyl pyrrolidone (polyvinyl pyrrolidone), vinyl pyrrolidone-vinyl acetate copolymer (vinylpyrrolidonevinylacetate copolymer), methyl cellulose (methyl cellulose) or ethyl cellulose (ethyl cellulose) Alkylcellulose, cellulose acetate phthalate (CAP), polyethylene glycol (PEG), or a plasticizer containing may be used.

The pharmaceutical composition may further include one or more antioxidants. The type of antioxidant is not limited as long as it is an antioxidant commonly used in the art. For example, butylhydroxyanisole (BHA) or butylhydroxytoluene (BHT) may be used.

The pharmaceutical composition may further comprise one or more acids. The type of acid is not limited as long as it is an acid commonly used in the art, but, for example, sorbic acid or citric acid may be used.

In addition, in some cases, the pharmaceutical composition may contain antibiotics, anti-inflammatory agents, preservatives and/or local anesthetics, and other conventional additives commonly formulated in cosmetics or therapeutic nail lacquers, such as a precipitation delaying agent, a chelating agent. , antioxidants, silicates, aroma components, wetting agents, lanolin derivatives, photostabilizers or antibacterial components and the like.

The volatile solvent is physiologically acceptable and is not limited as long as it is an organic solvent that is compatible with other components of the composition including drugs, and is not limited as long as it is an acid commonly used in the art, for example, ethanol, isopropanol, acetone, isododecane , decamethylcyclopentasiloxane, octamethyltrisiloxane decamethyltetrasiloxane, or mixtures thereof. The nonvolatile solvent may be present in the composition in an amount sufficient to dissolve the components to be liquefied, such as a solid active ingredient, a permeation enhancer and other additives, and is 30 to 85% by weight, more preferably 40 to 75% by weight, based on the total weight of the composition. It can be used in a proportion by weight.

For example, the pharmaceutical composition is

Efinaconazole 8 to 12 wt%

Fat-soluble permeation enhancer 8 to 20 wt%

Water-soluble permeation enhancer 1 ~ 15% by weight

40 to 65% by weight of a volatile solvent and

5 to 20% by weight of a non-volatile solvent,

or,

Efinaconazole 8 to 12 wt%

Fat-soluble permeation enhancer 8 to 20 wt%

Water-soluble permeation enhancer 1 to 10 wt%

40 to 65% by weight of a volatile solvent and

5 to 15% by weight of a non-volatile solvent,

or,

Efinaconazole 9-11 wt%

Fat-soluble permeation enhancer 10 ~ 18 wt%

2 to 8 wt% of water-soluble permeation enhancer

50 to 65% by weight of a volatile solvent and

8 to 11% by weight of a non-volatile solvent.

Example 1 was prepared with efinaconazole 10 g, Lauoglycol 90 15 g, HP-β-CD 5 g, ethanol 59.8 g, purified water 10 g, citric acid 0.1 g, BHT 0.1 g, HPC 0.2 g, Example 2 10 g of efinaconazole, 15 g of Labrafac PG, 5 g of HP-β-CD, 59.8 g of ethanol, 10 g of purified water, 0.1 g of citric acid, 0.1 g of BHT, and 0.2 g of HPC were prepared in Example 3, efinaconazole 10 g, ispropyl myristate 15 g, HP-β-CD 5 g, ethanol 59.8 g, purified water 10 g, citric acid 0.1 g, BHT 0.1 g, was prepared from HPC 0.2 g, Example 4 is efinaconazole 10 g, 15 g of ethyl oleic acid, 5 g of HP-β-CD, 59.8 g of ethanol, 10 g of purified water, 0.1 g of citric acid, 0.1 g of BHT, and 0.2 g of HPC were prepared in Example 5, efinaconazole 10 g, Labrafac PG 15 g , Labrasol 5 g, ethanol 59.8 g, purified water 10 g, citric acid 0.1 g, BHT 0.1 g, HPC 0.2 g, Example 6 is efinaconazole 10 g, ispropyl myristate 15 g, abrasol 5 g, ethanol 59.8 g, purified water 10 g, citric acid 0.1 g, BHT 0.1 g, HPC 0.2 g, Example 7 is efinaconazole 10 g, Lauoglycol 90 15 g, Polysorbate 80 5 g, ethanol 59.8 g, purified water 10 g, It was prepared with citric acid 0.1 g, BHT 0.1 g, HPC 0.2 g, Example 8 is efinaconazole 10 g, ethyloleic acid 15 g, Cremophor EL 5 g, ethanol 59.8 g, purified water 10 g, citric acid 0.1 g, BHT 0.1 g , was prepared with 0.2 g of HPC.

The composition for topical administration in the form of a solution containing efinaconazole can be prepared by a manufacturing method comprising the following steps.

adding and dissolving efinaconazole and a fat-soluble permeation enhancer in a volatile solvent (step 1);

dissolving a water-soluble permeation enhancer in an aqueous solvent (step 2); and

A step of mixing the solvent dissolved in steps 1 and 2 to form a transparent single phase and then purifying (step 3);

The water-soluble solvent may be, for example, water.

Looking at specific examples and experimental examples, the azole-based antifungal composition of the present invention, which includes both a fat-soluble permeation enhancer and a water-soluble permeation enhancer, is significantly different from the composition comprising the oil-soluble permeation enhancer alone or the water-soluble permeation enhancer alone. It showed increased permeability.

-CD, Labrasol, Polysorbate 80, Cremophor EL을 사용하였으며, 이들 모두가 지용성 투과촉진제를 단독으로 포함하거나 수용성 투과촉진제를 단독으로 포함하는 조성물과 비교하여 현저히 증가된 투과성을 나타내었다.Specifically, in Examples, Lauroglycol 90, Labrafac PG, isopropyl myristate, and ethyl oleic acid were used as fat-soluble permeation enhancers, and as water-soluble permeation enhancers, HP-

-CD, Labrasol, Polysorbate 80, and Cremophor EL were used, and all of them showed significantly increased permeability compared to the composition containing the fat-soluble permeation enhancer alone or the water-soluble permeation enhancer alone.

-CD를 조합군 군은 2.92-3.34 mg/cm²에 이르는 높은 20시간째 투과도를 나타내었다. 실시예 2의 경우 비교예 1, 2 및 3에 비해 약 149%, 219%, 151%에 이르는 높은 투과도를 나타내는 우수한 결과를 확인할 수 있었다.More specifically, Comparative Example 1 (manufactured by Jublia) showed the transmittance per unit area of 1.33 and 2.24 mg/cm ² at 8 hours and 20 hours, and the nail permeability described in Comparative Example 2 patent (No. 10-2060546) Examples 10 and 16, which are excellent compositions, are 0.91 and 1.52 mg/cm ² at 8 hours and 20 hours, and Comparative Example 3 (Example 16, which is a composition having excellent nail permeability described in No. 10-2060546) is 1.27 and transmittance per unit area of 2.21 mg/cm ² . On the other hand, in the case of Examples 1 to 13, the transmittance reached 2.38-3.34 mg/cm ² at 20 hours. Especially Labrafac PG and HP-

-CD combination group showed a high transmittance at 20 hours, reaching 2.92-3.34 mg/cm ² . In the case of Example 2, it was confirmed that excellent results showing high transmittance of about 149%, 219%, and 151% compared to Comparative Examples 1, 2 and 3.

In addition, when using a combination of a fat-soluble permeation enhancer and a water-soluble permeation enhancer than when the fat-soluble permeation enhancer is used alone (Comparative Examples 4 to 7) or when the water-soluble permeation enhancer is used alone (Comparative Examples 8 to 11) It was confirmed that the nail permeability of nasol significantly increased.

The azole antifungal composition of the present invention comprising both a fat-soluble permeation enhancer and a water-soluble permeation enhancer is stored under accelerated storage conditions (temperature 40 ° C., relative humidity 75%) and long-term storage conditions (temperature 25 ° C., relative humidity 60%) for 3 months. As a result of evaluating the properties and content of active substances at the time of storage for 3 months, it was confirmed that the properties and content of active substances were maintained almost the same. In other words, it can be seen that it is suitable as an antifungal nail lacquer because it maintains stable not only the appearance but also the active substances that show efficacy in the long term.

Hereinafter, Examples and Experimental Examples of the present invention will be specifically illustrated and described below. However, the Examples and Experimental Examples to be described below are only illustrative of a part of the present invention, and are not limited thereto.

< Example 1 to 13> efinaconazole Preparation of compositions for topical administration

Example 1 to 8: combination of water-soluble permeation enhancer and fat-soluble permeation enhancer

In order to prepare a composition according to a combination of various water-soluble permeation enhancers and fat-soluble permeation enhancers, compositions for topical administration of efinaconazole of Examples 1 to 8 were prepared with the compositions and contents shown in Table 1 below, and the specific preparation method is as follows. Add 40 mL to 70 mL of ethanol to a beaker, add efinaconazole and a fat-soluble permeation enhancer (Labrafac ^TM PG (Gattefosse), Lauroglycol ^TM 90 (Gattefosse), isopropyl myristate, ethyl oleic acid) while stirring with a magnetic stirrer, and dissolve at room temperature made it Separately, a water-soluble permeation enhancer (HP-β-CD (hydroxypropyl beta cyclodextrin), Labrasol ^® , Polysorbate 80, Cremophor ^® EL) was added to about 4 mL to 15 mL of distilled water, and stirred for 15 minutes. dissolved. Ethanol was added to adjust the final volume to 100 mL.

combination
purpose matter
(g) Example 1 Example 2 Example 3 Example 4 Example
5 Example 6 Example 7 Example 8 chief ingredient efinaconazole 10 10 10 10 10 10 10 10 Fat-soluble permeation enhancer Lauroglycol 90 15 - - - - - 15 - Labrafac PG - 15 - - 15 - - - Isopropyl Myristate - - 15 - - 15 - - ethyl oleic acid - - - 15 - - - 15 Water-soluble permeation enhancer HP-β-CD 5 5 5 5 - - - - Labrasol - - - - 5 5 - - Polysorbate 80 - - - - - - 5 - Cremophor EL - - - - - - - 5 volatile solvent ethanol 59.8 59.8 59.8 59.8 59.8 59.8 59.8 59.8 non-volatile solvent Purified water 10 10 10 10 10 10 10 10 pH adjuster citric acid 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 antioxidant BHT 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 film former HPC 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 total amount 100.2 100.2 100.2 100.2 100.2 100.2 100.2 100.2

Example 9 to Example 13: water-soluble permeation enhancer HP-β-CD, fat-soluble permeation enhancer Labrafac PG's Combination

Using HP-β-CD as a water-soluble permeation enhancer, Labrafac PG as an oil-soluble permeation enhancer, and using the composition and content of Examples 9 to 13 in Table 2 below to prepare a composition according to the combination ratio for permeation promotion A composition for topical administration of efinaconazole was prepared. Specific methods were the same as those of Examples 1 to 8, except that HP-β-CD was used as a water-soluble permeation enhancer, and Labrafac PG was used as a fat-soluble permeation enhancer.

combination
purpose matter
(g) Example
9 Example
10 Example
11 Example
12 Example
13 chief ingredient efinaconazole 10 10 10 10 10 Fat-soluble permeation enhancer Labrafac PG 10 20 10 15 20 Water-soluble permeation enhancer HP-β-CD 10 One 2 4 10 volatile solvent ethanol 55 64 73.9 58.3 44.8 non-volatile solvent Purified water 15 5 4 12 15 pH adjuster citric acid 0.1 0.1 0.1 - - antioxidant BHT 0.1 0.1 - 0.1 - film former HPC - - - 0.5 - total amount 100.2 100.2 100 99.9 99.8

< comparative example 1> Preparation of commercially available topical solution formulations

A commercially available topical solution formulation JUBLIA ^TM (Kaken Pharmaceutical Co., Ltd.) (containing 10% efinaconazole, topical solution formulation) used for the treatment of onychomycosis was prepared.

< comparative example 2 and 3> Preparation of composition according to Korean Patent No. 10-2060546

Examples 10 and 16, which are compositions with excellent nail permeability described in Korean Patent No. 10-2060546, were respectively prepared in Comparative Examples 2 and 3 based on the manufacturing method described in Korean Patent No. 10-2060546. prepared. Compositions and contents of Comparative Examples 2 and 3 are shown in Table 3 below.

Substance (g) Comparative Example 2 Comparative Example 3 efinaconazole 10 10 ethanol 52.75 52.29 cyclomethicone 15 15 Transcutol P 12 12 Isopropyl Myristate 10 10 TED 0.05 - DTPA - 0.000285 BHT 0.1 0.1 Purified water - 0.5 citric acid 0.1 0.1 total amount 100 99.990285

< comparative example 4 to 7> Preparation of a composition comprising a fat-soluble permeation enhancer alone

Compositions of Comparative Examples 4 to 7 were prepared with the compositions and contents shown in Table 4 below to prepare a composition containing the oil-soluble permeation enhancer alone and not including the water-soluble permeation enhancer. Specific methods were the same as those of Examples 1 to 8, except that only the fat-soluble permeation enhancer was used, and the water-soluble permeation enhancer was not added.

Substance (g) Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 efinaconazole 10 10 10 10 Lauroglycol 90 22 - - - Labrafac PG - 22 - - Isopropyl Myristate - - 22 - ethyl oleic acid - - - 22 cyclomethicone 13 13 13 13 EDTA 2Na 0.00025 0.00025 0.00025 0.00025 ethanol 53.8 53.8 53.8 53.8 Purified water 1.0 1.0 1.0 1.0 citric acid 0.1 0.1 0.1 0.1 BHT 0.1 0.1 0.1 0.1 total amount 100.00025 100.00025 100.00025 100.00025

< comparative example 8 to 11> Preparation of a composition comprising a water-soluble permeation enhancer alone

Compositions of Comparative Examples 8 to 11 were prepared with the compositions and contents shown in Table 5 below in order to prepare a composition containing the water-soluble permeation enhancer alone and not including the oil-soluble permeation enhancer. Specific methods were the same as those prepared in Examples 1 to 8, except that only the water-soluble permeation enhancer was used, and the fat-soluble permeation enhancer was not added.

Substance (g) Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 efinaconazole 10 10 10 10 HP-β-CD 5 - - - Labrasol - 5 - - Polysorbate 80 - - 5 - Cremophor EL - - - 5 ethanol 74.8 74.8 74.8 74.8 Purified water 10 10 10 10 citric acid 0.1 0.1 0.1 0.1 BHT 0.1 0.1 0.1 0.1 HPC 0.2 0.2 0.2 0.2 total amount 100.2 100.2 100.2 100.2

< Experimental example 1> cow's hoof used fingernails Permeability evaluation

In order to evaluate the transmittance of the compositions according to Examples 1 to 13 and Comparative Examples 1 to 11, the composition according to Examples 1 to 13 and Comparative Examples 1 to 11 was performed in a Franz diffusion cell using a cow hoof. The nail permeability of the composition was evaluated. The cow hoof was cut to have a thickness of 150 μm to 250 μm using a microtome, and all hoof membranes used had a density of 1.0 g/cm ³ or more. After fixing each hoof membrane in a Franz diffusion cell, 30 μL of each sample was added dropwise to the donor compartment. The bovine hoof permeability test was performed 4 times each (n=4), and the permeability test protocol using a Franz diffusion cell is as follows.

Diffusion area: 0.28 cm ²

Sample loading: 30 μL each of the solutions prepared in Examples 1 to 13 and Comparative Examples 1 to 11

Receiver compartment: phosphate buffered saline (PBS) containing 0.2% (w/v) sodium lauryl sulfate and 0.02% (w/v) sodium azide (pH) 7.4) 12 mL

Agitation speed of the receiver compartment 600 rpm

Temperature: 32℃

Sample collection: After collecting 200 μL from each receiver compartment 24 hours later, the concentration of the drug was analyzed by HPLC.

HPLC analysis conditions

item Condition column Capcell pak C18 UG120 (5 μm, 4.6 mm x 250 mm) mobile phase Acetonitrile: D.W. = 8 : 2 temperature 30℃ flow rate 1 mL/min detector 210 nm analysis time 10 min injection volume 20 μL sampler temperature 4℃

The experimental cow hoof permeability results under the above conditions are shown in Table 7 and FIG. 1 below.

Permeation amount at 8 hours (mg/cm ² ) Permeation at 20 hours (mg/cm ² ) Example 1 1.54 2.84 Example 2 2.17 3.34 Example 3 1.25 2.88 Example 4 1.17 2.60 Example 5 1.29 2.82 Example 6 1.42 2.56 Example 7 1.37 2.38 Example 8 1.75 2.75 Example 9 2.04 3.02 Example 10 1.89 3.32 Example 11 1.78 2.92 Example 12 1.71 2.64 Example 13 2.10 3.34 Comparative Example 1 1.33 2.24 Comparative Example 2 0.91 1.52 Comparative Example 3 1.27 2.21 Comparative Example 4 0.92 1.46 Comparative Example 5 0.87 1.41 Comparative Example 6 0.57 1.21 Comparative Example 7 0.66 1.30 Comparative Example 8 1.14 1.66 Comparative Example 9 0.31 0.50 Comparative Example 10 0.84 1.59 Comparative Example 11 1.00 1.42

As can be seen from the results of Table 7, the compositions prepared in Examples 1 to 13 all showed significantly increased permeability compared to Comparative Examples 1 to 3, which are prior art. Specifically, Comparative Example 1 has transmittances per unit area of 1.33 and 2.24 mg/cm ² at 8 and 20 hours, Comparative Example 2 is 0.91 and 1.52 mg/cm ² at 8 and 20 hours, and Comparative Example 3 is 1.27 and 2.21 The transmittance per unit area of mg/cm ² was shown. On the other hand, in the case of Examples 1 to 13, the transmittance reached 2.38-3.34 mg/cm ² at 20 hours. In particular, the Labrafac PG and HP-β-CD combination group showed a high transmittance at 20 hours, reaching 2.92-3.34 mg/cm ² . In the case of Example 2, it was confirmed that excellent results showing high transmittance of about 149%, 219%, and 151% compared to Comparative Examples 1, 2 and 3.

In addition, when using a combination of a fat-soluble permeation enhancer and a water-soluble permeation enhancer than when the fat-soluble permeation enhancer is used alone (Comparative Examples 4 to 7), or when the water-soluble permeation enhancer is used alone (Comparative Examples 8 to 11), Epinako It was confirmed that the nail permeability of nasol significantly increased.

< Experimental example 2> Characteristics and stability test (stability test)

In order to evaluate the properties and content stability of the composition according to Example 2, which was confirmed to have very excellent nail permeability through Experimental Example 1, the composition according to Example 2 was stored under accelerated storage conditions (temperature 40° C., relative humidity 75%). ) and long-term storage conditions (temperature of 25°C, relative humidity of 60%) for up to 3 months, and changes in appearance and main component content were evaluated through visual evaluation and HPLC analysis, respectively. The results of evaluation of the properties and the content of the active material at 3 months of storage are shown in FIG. 2 and Table 8 below. In Example 2, it was confirmed that even after storage for 3 months under all storage conditions, the properties and content of the active material were maintained almost the same as before storage and long-term storage conditions. That is, it can be seen that the composition of Example 2 is suitable as an antifungal nail lacquer because it is stably maintained not only in appearance, but also in the active material exhibiting efficacy in the long term.

at start Accelerated storage conditions
3 months storage Long-term storage conditions
3 months storage appearance Transparent liquid without phase separation Transparent liquid without phase separation Transparent liquid without phase separation content (%) 98.8 97.5 98.6

As mentioned above, although the present invention has been described in detail through preferred preparation examples, examples and experimental examples, the scope of the present invention is not limited to the characteristic examples, and should be interpreted by the appended claims. In addition, those skilled in the art will understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (17)

A pharmaceutical composition for topical administration in the form of a solution comprising efinaconazole or a pharmaceutically acceptable salt thereof, a volatile solvent, a fat-soluble permeation enhancer and a water-soluble permeation enhancer,
In this case, the efinaconazole is included in an amount of 8 to 12% by weight based on the total weight of the composition;
The volatile solvent is ethanol, and is included in an amount of 40 to 65% by weight,
While the fat-soluble permeation enhancer is included in an amount of 8 to 20% by weight,
A mixture of propyleneglycol dicaprylate and dicaprate (Labrafac™ PG), propyleneglycol monolaurate (Lauroglycol™ 90), isopropyl myristate and ethyl oleic acid (ethyl oleate) is at least one selected from the group consisting of; and
As the water-soluble permeation enhancer is included in an amount of 1 to 15% by weight,
hydroxypropyl-beta-cyclodextrin (HP-β-CD), caprylocaproyl macrogolglyceride (Labrasol ^® ), polyethoxylated castor oil (Cremophor EL ^® ) ) and at least one selected from the group consisting of polysorbate,
pharmaceutical composition.
delete delete delete delete delete delete According to claim 1,
The pharmaceutical composition further comprises water;
The water, characterized in that contained in 5 to 15% by weight based on the total weight of the composition, the pharmaceutical composition.
According to claim 1,
The pharmaceutical composition, the pharmaceutical composition, characterized in that it further comprises one or more additives selected from the group consisting of film formers, antioxidants and acids.
10. The method of claim 9,
The film forming agent, hydroxypropyl cellulose (hydroxypropyl cellulose, HPC), hydroxypropyl methyl cellulose (hydroxypropyl methyl cellulose, HPMC), polyvinyl pyrrolidone (polyvinyl pyrrolidone), vinyl pyrrolidone-vinyl acetate copolymer ( Vinylpyrrolidonevinylacetate copolymer), methyl cellulose (methyl cellulose), ethyl cellulose (ethyl cellulose), cellulose acetate phthalate (cellulose acetate phthalate, CAP) and polyethylene glycol (polyethylene glycol, PEG) characterized in that at least one selected from the group consisting of , pharmaceutical composition.
10. The method of claim 9,
The antioxidant is butylhydroxyanisole (butylhydroxyanisole, BHA) or butylhydroxytoluene (butylhydroxytoluene, BHT), characterized in that the pharmaceutical composition.
10. The method of claim 9,
The acid is sorbic acid or citric acid, characterized in that the pharmaceutical composition.
delete According to claim 1,
The pharmaceutical composition is characterized in that for the prevention or treatment of onychomycosis, a pharmaceutical composition.
delete According to claim 1,
The content of the water-soluble permeation enhancer is 1 to 10% by weight,
pharmaceutical composition.
adding and dissolving efinaconazole and a fat-soluble permeation enhancer in a volatile solvent (step 1);
dissolving the water-soluble permeation enhancer in water (step 2); and
Including; mixing the solvent dissolved in step 1 and step 2 and purifying (step 3);
In this case, the efinaconazole is included in an amount of 8 to 12% by weight based on the total weight of the composition;
The volatile solvent is ethanol, and is included in an amount of 40 to 65% by weight;
While the fat-soluble permeation enhancer is included in an amount of 8 to 20% by weight,
A mixture of propyleneglycol dicaprylate and dicaprate (Labrafac™ PG), propyleneglycol monolaurate (Lauroglycol™ 90), isopropyl myristate and ethyl oleic acid (ethyl oleate) is at least one selected from the group consisting of; and
As the water-soluble permeation enhancer is included in an amount of 1 to 15% by weight,
hydroxypropyl-beta-cyclodextrin (HP-β-CD), caprylocaproyl macrogolglyceride (Labrasol ^® ), polyethoxylated castor oil (Cremophor EL ^® ) ) and at least one selected from the group consisting of polysorbate,
The method for preparing the pharmaceutical composition of claim 1.

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