Efinaconazole oral composition

Abstract

The present invention relates to an oral composition for efinaconazole, which comprises a coformulation of efinaconazole with polyethylene glycol and a pharma- ceutical acceptable excipient, and which is stable, has high bioavailability, and is excellent in administration efficacy.

Description

[Technical field]

[0001] The present invention relates to an oral composition for efinaconazole which is stable, has high bioavailability, and exhibits excellent administration efficacy. [Background technology]

[0002] Efinaconazole is a triazole compound that has demonstrated activity in the treatment of onychomycosis and exerts its antifungal effect by inhibiting the synthesis of ergosterol, the main component of fungal cell membranes.

[0003] Currently available commercial products include Jubria TM Jublia is a treatment for onychomycosis caused by dermatophytes that uses efinaconazole as its main ingredient. It received product approval from the Ministry of Food and Drug Safety in May 2017 and was fully launched on the market in Korea.

[0004] JUBLIA is a topically applied formulation, and topical antifungal agents are relatively free from the drawbacks of oral antifungal agents, such as skin rash, liver toxicity, and gastrointestinal side effects, and show high compliance and preference.

[0005] Dosage forms useful for the topical delivery of efinaconazole and other triazole antifungal drugs in the treatment of onychomycosis are described, for example, in US Pat. No. 8,486,978.

[0006] However, topical application formulations may be somewhat insufficient in suppressing fungi that have taken root deeply, since they have the property of penetrating through the cuticle and nail plate, and since they must be applied evenly to each affected area, there are limitations to their ability to suppress and prevent fungi that have spread widely over the entire body.

[0007] In fact, the reason why fungal diseases such as tinea manus, tinea pedis, and tinea unguium easily recur is also closely related to the limitations of topical application formulations mentioned above: topical application formulations may work well on fungi that are normally present on the surface, but they cannot reach deep within the skin at the desired effective concentration to completely kill the fungi.

[0008] Therefore, it is important to develop an administration method (e.g., injections, oral tablets, liquids, capsules, powders, etc.) that can deliver the antifungal components to the relevant tissues via the blood, etc., and in particular, there is a demand for the development of oral dosage forms that are easy to take and have high compliance and preference.

[0009] However, since the aqueous solubility of efinaconazole is relatively low at approximately 0.61 mg / mL, there may be problems with absorption and bioavailability when administered orally.

[0010] Furthermore, solution formulations containing efinaconazole have a stability problem, i.e., they discolor within a short storage period, resulting in a composition color ranging from yellow to deep red or brown. To solve such stability problems, U.S. Patent No. 9,662,394 discloses a liquid or semi-solid composition containing a specific chelating agent, an antioxidant, and an acid, i.e., ethylenediaminetetraacetic acid (EDTA) or its salt, butylated hydroxytoluene (BHT), and citric acid.

[0011] Therefore, there is a need to develop an oral formulation of efinaconazole that is highly bioavailable and stable.

[0012] For reference, the contents of the following prior art documents are all cited and incorporated herein as background to the present invention. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] US Patent No. 08486978 [Patent Document 2] US Patent No. 09662394 [Patent Document 3] US Patent No. 05620994 Summary of the Invention [Problem to be solved by the invention]

[0014] The present invention aims to solve the above-mentioned problems of the prior art and to provide an oral formulation of efinaconazole which is highly bioavailable and stable. [Means for solving the problem]

[0015] The present invention has been devised to solve the above-mentioned problems of the prior art, and provides an oral pharmaceutical composition comprising a coformulation of efinaconazole and polyethylene glycol, and a pharma- ceutical acceptable excipient.

[0016] The present invention also provides an oral pharmaceutical composition which is in the form of a tablet or liquid.

[0017] The present invention also provides an oral pharmaceutical composition comprising 0.6 to 2040 mg of efinaconazole.

[0018] The present invention also provides an oral pharmaceutical composition, wherein the coformulate has a weight ratio of efinaconazole:polyethylene glycol=1:1.

[0019] The present invention also provides an oral pharmaceutical composition, wherein the pharma- ceutical acceptable additive comprises at least one selected from the group consisting of an excipient, a binder, a disintegrant, a surfactant, a lubricant, and a colorant.

[0020] The present invention also provides an oral pharmaceutical composition, wherein the excipient is one or more selected from the group consisting of lactose hydrate, microcrystalline cellulose, microcrystalline cellulose-lactose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salts, other substituted and unsubstituted celluloses, corn starch, gelatinized starch, lactose, anhydrous lactose, sugar alcohols, sucrose, xylitol, acrylate polymers and copolymers, dextrates, dextrin, dextrose, maltodextrin, pectin, gelatin, and inorganic diluents.

[0021] The present invention also provides an oral pharmaceutical composition, wherein the binder is selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone vinyl acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, gelatin, propylene glycol, sodium alginate, and mixtures thereof.

[0022] The present invention also provides an oral pharmaceutical composition, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, crospovidone, carboxymethylcellulose salts, hydroxypropylcellulose, microcrystalline cellulose, gelatinized starch, sodium starch, glycolate, and sodium starch glycolate.

[0023] The present invention also provides an oral pharmaceutical composition, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, and glyceryl behenate.

[0024] The present invention also provides an oral pharmaceutical composition, the use of which is for the prevention or treatment of fungal infections.

[0025] The present invention also provides an oral pharmaceutical composition, wherein the fungal infection is onychomycosis. Effect of the Invention

[0026] The present invention has the advantage that it exhibits high stability and bioavailability and is therefore suitable for oral administration. [Brief description of the drawings]

[0027] [Figure 1] 1 is a powder XRD pattern for the cocrystal of efinaconazole and polyethylene glycol. [Diagram 2] FIG. 1 is a DSC thermal analysis diagram for a cocrystal of efinaconazole and polyethylene glycol. [Diagram 3] 1 is a powder XRD pattern for efinaconazole crystalline forms. [Figure 4] FIG. 2 is a DSC thermogram for efinaconazole crystalline forms. [Diagram 5] 1 is a graph comparing the stability of efinaconazole crystalline forms and efinaconazole polyethylene glycol co-crystal (Co-crystal). [Figure 6] 1 is a graph showing time-plasma concentration of voriconazole in a preclinical study. [Figure 7] 1 is a graph showing time-plasma concentration of efinaconazole in a preclinical experiment. BEST MODE FOR CARRYING OUT THEINVENTION

[0028] The present invention will be described in detail below.

[0029] The present invention relates to an oral pharmaceutical composition comprising a coformulation of efinaconazole and polyethylene glycol, and a pharma- ceutically acceptable excipient.

[0030] Coformates are substances in which two or more substances exhibit unique physical properties as if they were a single individual substance, and can be classified into co-amorphous, which is in an amorphous form, and co-crystal, which is in a crystalline form.

[0031] The term "cocrystal" refers to a form in which two or more different molecules form a crystal structure in a single crystal lattice at a certain stoichiometric ratio, and the bonding form between molecules in a cocrystal is different from that of a salt or a mixture.

[0032] In addition, a cocrystal means a crystalline solid that has a new crystal structure due to the abundance of functional groups capable of forming hydrogen bonds such as O, OH, N, etc., or due to the bonding with coformers in a regular ratio through hydrogen bonds.

[0033] The coformer refers to an inactive molecule among the molecules that constitute the crystal of a co-crystal drug, and in the present invention, polyethylene glycol is preferably selected.

[0034] The powder XRD pattern and DSC thermogram for the cocrystal of efinaconazole and polyethylene glycol according to the present invention are shown in FIG. 1 and FIG. 2, and the XRD pattern and DSC thermogram for the efinaconazole crystalline form are shown in FIG. 3 and FIG.

[0035] 1 to 4, it can be seen that the coformulation of efinaconazole according to the present invention shows a tendency that is completely different from that of the efinaconazole crystal form.

[0036] That is, the coformation product of efinaconazole and polyethylene glycol has a crystalline structure that characteristically exhibits diffraction angles (2θI / I0>10%) of 7.78, 11.50, 13.85, 15.49, 16.79, 18.97, 19.22, 23.57, 26.18, and 27.09 in the powder XRD pattern, and maximum endothermic peaks were observed at 61.62°C and 78.78°C in the spectrum analyzed by differential scanning calorimetry (DSC). However, such XRD pattern and DSC thermal analysis diagram are definitely different from those of the crystalline form of efinaconazole.

[0037] Therefore, it can be confirmed that the coformulated efinaconazole of the present invention is a novel substance having physicochemical properties completely different from those of existing efinaconazole crystal forms.

[0038] In addition, since efinaconazole is a somewhat unstable drug, its stability must be increased in order to be used as an active ingredient in a pharmaceutical composition, and this stability can be increased by forming a coformate.

[0039] That is, as shown in FIG. 5, the coformulation of efinaconazole according to the present invention has excellent stability.

[0040] In addition, the coformulation of efinaconazole can increase the solubility and dissolution rate of the drug, thereby altering the absorption rate and bioavailability of the drug in the human body.

[0041] That is, as shown in FIG. 6, the coformulation of efinaconazole according to the present invention has excellent bioavailability.

[0042] Based on these characteristics, the coformulation of efinaconazole according to the present invention satisfies all of the requirements for an active ingredient in a pharmaceutical composition, i.e., chemical purity of the crystals, stability to solution and temperature, and bioavailability upon oral administration.

[0043] A more detailed understanding of the stability and bioavailability of the coformulated efinaconazole of the present invention can be obtained through the examples described below.

[0044] In the oral pharmaceutical composition of the present invention, the active ingredient efinaconazole is contained in a prophylactically or therapeutically effective amount based on safety and efficacy data. In some embodiments, the therapeutically effective amount may be about 0.01 to about 30 mg / kg, and in some specific embodiments, about 0.01 to about 6 mg / kg, and the content of efinaconazole in the oral dosage form may be 0.6 to 2040 mg, or 0.6 to 410 mg, but is not necessarily limited thereto and may vary according to clinical findings.

[0045] The pharma- ceutically acceptable additive may be any pharmaceutical additive that is obvious to a person skilled in the art and is widely known, and may be used without limitation. Examples of the pharma- ceutically acceptable additive include stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, bases, adsorbents, flavorings, binders, suspending agents, hardeners, antioxidants, glossing agents, flavorings, flavorings, pigments, coating agents, wetting agents, wetting regulators, fillers, antifoaming agents, refreshing agents, chewing agents, antistatic agents, coloring agents, sugar-coating agents, isotonic agents, softeners, emulsifiers, adhesives, thickening agents, foaming agents, pH regulators, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, solubilizing agents, solvents, and fluidizing agents. More specifically, the pharma-ceutically acceptable additive may be one or more selected from the group consisting of excipients, binders, disintegrants, surfactants, lubricants, and coloring agents.

[0046] Examples of the excipient include one or more selected from the group consisting of lactose hydrate, microcrystalline cellulose, microcrystalline cellulose-lactose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salts, other substituted and unsubstituted celluloses, corn starch, gelatinized starch, lactose, anhydrous lactose, sugar alcohols, sucrose, xylitol, acrylate polymers and copolymers, dextrates, dextrin, dextrose, maltodextrin, pectin, gelatin, and inorganic diluents.

[0047] Examples of the binder include those selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone vinyl acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, gelatin, propylene glycol, sodium alginate, and mixtures thereof.

[0048] Examples of the disintegrant include one or more selected from the group consisting of croscarmellose sodium, crospovidone, carboxymethylcellulose salts, hydroxypropylcellulose, microcrystalline cellulose, gelatinized starch, sodium starch, glycolate, and sodium starch glycolate.

[0049] Examples of the surfactant include sodium dodecyl sulfonate (SDS), sodium lauryl sulfate (SLS), Pluronic F127, Pluronic F68, poly(ethylene glycol) (PEG), polyoxyethylene sorbitan monooleate (Tween 80), poloxamer (Lutrol F68), polyethylene glycol-15-hydroxystearate (Solutol HS15), hydroxypropyl methylcellulose (Hydroxypropyl methylcellulose), and the like. Examples of such materials include cellulose, HPMC, poly(N-vinyl-2-pyrrolidone, PVP), Silwet L77, poly(vinylalcohol, PVA), bovine serum albumin, and sucrose fatty acid esters.

[0050] Examples of the lubricant include those selected from the group consisting of magnesium stearate, sodium stearyl fumarate, and glyceryl behenate, but are not necessarily limited thereto, and any pharmaceutical additive that is obvious to a person skilled in the art and widely known can be used without limitation.

[0051] The composition of the present invention can be used for the prevention or treatment of fungal infection.Specific examples of indications include, but are not limited to, candidal vaginitis, tinea versicolor, tinea corporis caused by dermatophytes, tinea cruris (ringworm), tinea manus, tinea pedis, oral candidiasis, fungal keratitis, onychomycosis, aspergillosis, candidiasis, candiduria, candidemia, cryptococcosis (including cryptococcal meningitis), paracoccidioidomycosis, systemic fungal infection, seborrheic dermatitis, dandruff caused by yeast fungi, etc.

[0052] The present invention will be described in more detail below with reference to examples. However, it should be made clear that the following examples are merely for the purpose of explaining the invention in detail and are not intended to limit the scope of the invention.

[0053] <Example> Example 1 - Preparation of co-crystals of efinaconazole and polyethylene glycol (1:1 ratio) Efinaconazole (1 g) was dissolved in acetonitrile (5 mL) by stirring at room temperature. Polyethylene glycol-6000 (1 g) was added to the reaction solution and stirred for 1 hour, and then the solvent was removed by distillation under reduced pressure, and the crystalline form of the cocrystal of efinaconazole and polyethylene glycol-6000 was spontaneously formed within a short time. The crystals were collected under vacuum drying, and the yield was 95% and the purity was 99.5%. The powder X-ray diffraction spectrum and differential scanning calorimeter thermogram of the cocrystal of efinaconazole and polyethylene glycol-6000 prepared in Example 1 are attached in FIG. 1 and FIG. 2, respectively.

[0054] Example 2 - Preparation of oral liquid A homogeneous oral liquid was prepared by dispersing 0.5% methylcellulose in distilled water containing 1% surfactant and the above-prepared Example 1, and subjecting it to vortex and ultrasonic treatment. The specific ingredient composition is shown in Table 1 below.

[0055] [Table 1]

[0056] Example 3 - Preparation of oral tablets The above-prepared Example 1 was mixed with an excipient, and a disintegrant and a lubricant were added in sequence to adjust the particles, and then the mixture was compressed into tablets to prepare plain tablets. The specific ingredient composition is shown in Table 2 below.

[0057] [Table 2]

[0058] Example 4 - Preparation of oral capsules The preparation of Example 3 prepared above was put into a gelatin capsule without tableting to prepare a capsule preparation.

[0059] <Test Example> < Stability Testing> In order to confirm the stability of the cocrystal of efinaconazole of the present invention to temperature and composition solution, the following experimental method was carried out to compare the stability of efinaconazole to temperature and composition solution.

[0060] *Experimental method The efinaconazole crystalline form and Example 1 were left dissolved in the composition solution for 1 week, 2 weeks, and 4 weeks at room temperature and in an oven at 65°C, respectively, and then analyzed by high performance liquid chromatography (HPLC) to determine the purity.

[0061] The results are shown in Table 3 below and in FIG.

[0062] [Table 3]

[0063] As can be seen from Table 3 and Figure 5, the efinaconazole cocrystal of the present invention is more stable at temperature and when dissolved in a liquid composition than the existing efinaconazole crystal forms, and therefore has the advantage of being more useful in the manufacture of medicines. Moreover, the efinaconazole cocrystal of the present invention is a novel substance and satisfies all the requirements for an active ingredient in a pharmaceutical composition.

[0064] <Preclinical trials> Twenty-four male beagle dogs were used, divided into four groups, with six dogs in each group, and a single dose of the control drug (voriconazole) was administered orally and the test drug (efinaconazole) was administered intravenously and orally under fasting conditions. PK profiles were obtained for each drug, and PK parameters were calculated and pharmacokinetics was evaluated. The specific test conditions and methods are as follows:

[0065] 1. Preparation of study medication For the oral administration groups, voriconazole (oral administration G1 group), efinaconazole (oral administration G2 group), and efinaconazole cocrystal prepared in Example 1 (oral administration G3 group - Efinaconazole copolymer) were weighed using an electronic balance at the dosage calculated based on the body weight calculated at the time of preparation of the test substances, and then placed in a glass container and prepared homogeneously using an excipient (0.5% methylcellulose in 1% Tween 80 solution (distilled water) by vortexing and ultrasonic treatment.

[0066] For intravenous administration, efinaconazole (intravenous administration G1 group) calculated according to the administration dose and PEG400 as an excipient equivalent to 30% of the total formulation volume were added and completely dissolved using a vortex and ultrasonic wave. Ethanol equivalent to 20% of the total formulation volume was added and homogenized using ultrasonic wave. 0.9% saline equivalent to 50% of the total formulation volume was added and homogenized using a vortex and ultrasonic wave treatment before use.

[0067] 2. Administration -Route of administration: Intravenous (IV), oral (PO) -Administration dose: G1(Voriconazole)-6mg / 5ml / kg (PO);G2(Efinaconazole)-6mg / 5ml / kg (PO);G3(Efinaconazole-Polymer)-6mg / 5ml / kg (PO);G1(Efinaconazole)-0.5mg / 1ml / kg (IV) -Dosage frequency: Single (once daily) - (QD)

[0068] The composition of the test groups by administration is as shown in Table 4 below.

[0069] [Table 4]

[0070] 3. Test Results When conducting the test, the animals were assigned numbers 1 to 6 for the oral administration G1 group, numbers 7 to 12 for the G2 group, numbers 13 to 18 for the G3 group, and numbers 1 to 6 for the intravenous administration G1 group. The average body weight of each group on the day of the test was confirmed to be 11.5 ± 1.2 kg for the oral administration G1 group, 11.5 ± 1.3 kg for the G2 group, 11.5 ± 1.0 kg for the G3 group, and 11.6 ± 1.6 kg for the intravenous administration G1 group.

[0071] During the test, no abnormal symptoms (vomiting, salivation, diarrhea, abnormal behavior, etc.) related to the administration of the test substance were observed, no deaths occurred in any of the animals during the entire test, and the blood collection process was also carried out smoothly. The amount of blood collected was 4ml per point, and the collected blood was centrifuged, and 500μl of the plasma supernatant was dispensed into 1.5ml EP tubes, and the remaining plasma was dispensed into one set of 1.5ml EP tubes and stored in a deep freezer at -80℃. After the test was completed, the blood collection record, specimen content confirmation sheet, dispensing record, clinical symptom observation record, medication / blood collection results, and test specimen (plasma) were sent to a specialized analysis institution.

[0072] The samples were stored in a freezer until analysis. The samples were analyzed by LC / MS / MS, and pharmacokinetic parameters were calculated by noncompartmental methods using Phoenix WinNonlin (Version 8.2 or higher, Certara LP) software.

[0073] For the analysis of plasma samples, the voriconazole (6 mg / kg, PO) group was assigned to group G1 (No. 1-6), and the efinaconazole groups were assigned to group G2-0.6 mg / kg IV (No. 1-6), group G3-6 mg / kg PO (No. 7-12), and group G4-copolymer 6 mg / kg PO (No. 13-18), as shown in Table 5 below.

[0074] [Table 5]

[0075] Six animals were assigned to each group, and after a single dose, a total of 24 test samples were analyzed. The changes in the blood concentrations of voriconazole and efinaconazole are shown in Figure 6, Figure 7, and Tables 6 and 7. Among the samples in which peaks were detected, test samples below the lowest limit of quantification were treated as BLQ.

[0076] [Table 6]

[0077] [Table 7]

[0078] AUC as a bioavailability parameter t is the area under the plasma concentration-time curve from the time of administration to the last blood sampling time when measurements were possible, and was calculated using the trapezoidal rule. maxThe highest plasma concentration was obtained from the plasma drug concentration-time curve for each individual, and T max The time to reach the maximum plasma drug concentration was calculated from the plasma drug concentration-time curve for each individual. AUC ∞ was calculated as the area under the plasma concentration-time curve from the time of dosing to infinity. The calculated PK parameters for voriconazole and efinaconazole are shown in Table 8 below.

[0079] [Table 8]

[0080] As shown in the table, the PK parameters were AUC10 of the voriconazole (6 mg / kg, PO) group, the efinaconazole (0.6 mg / kg, IV) group, the efinaconazole (6 mg / kg, PO) group, and the efinaconazole copolymer (6 mg / kg, PO) group. t were 53,905.19 ± 7,138.87, 253.28 ± 74.20, 1,494.88 ± 475.14, and 987.98 ± 271.62, respectively, and the AUC ∞ were confirmed to be 109,208.24±24,516.63, 270.71±84.91, 1,610.32±540.33, and 1,114.49±323.58, respectively, and C max were confirmed to be 3,674.45±169.60, 322.20±58.61, 925.10±236.42, and 827.06±349.93, respectively.

[0081] Statistical analysis showed that the test drug efinaconazole copolymer (6 mg / kg, PO) group had a significantly higher C than the efinaconazole (6 mg / kg, PO) group. max and AUC t The indicators showed significantly lower results (Tables 9 to 12 below).

[0082] [Table 9]

[0083] [Table 10]

[0084] [Table 11]

[0085] [Table 12]

[0086] The bioavailability of the efinaconazole copolymer (6 mg / kg, PO) group and the efinaconazole (6 mg / kg, PO) group was determined to be 35.69±22.61% and 51.36±24.63%, respectively (Tables 13 and 14 below).

[0087] [Table 13]

[0088] [Table 14]

[0089] As a result, the efinaconazole copolymer (6 mg / kg, PO) group had a significantly lower AUC t It was confirmed that the value was significantly lower at the 66% level, but considering that the raw material components contained in the copolymer formulation were 50%, it was confirmed that the level was higher than this.

[0090] In addition, the bioavailability of the efinaconazole copolymer (6 mg / kg, PO) group was 35.69%, which was confirmed to reach a level of approximately 70% when compared with 51.36% for the efinaconazole (6 mg / kg, PO) group under the assumption of dose linearity. This shows that the bioexposure of the efinaconazole copolymer formulation, the test substance, in beagles was far higher than the theoretically predicted level (50%).

[0091] These test results show that oral administration of efinaconazole showed far superior bioavailability even at low doses compared to other antifungal agents such as voriconazole and itraconazole, and therefore a high therapeutic effect can be expected from oral administration.

Claims

1. An oral pharmaceutical composition comprising a co-crystal of efinaconazole and polyethylene glycol-6000, and a pharma- ceutically acceptable excipient.

2. 2. The pharmaceutical composition for oral administration according to claim 1, which is in the form of a tablet or liquid.

3. 2. The pharmaceutical composition for oral administration according to claim 1, comprising 0.6 to 2040 mg of efinaconazole.

4. The pharmaceutical composition for oral administration according to claim 1, wherein the cocrystal is composed of efinaconazole:polyethylene glycol-6000 in a weight ratio of 1:

1.

5. The pharmaceutical composition for oral administration according to claim 1 , wherein the pharma- ceutically acceptable additive comprises at least one selected from the group consisting of an excipient, a binder, a disintegrant, a surfactant, a lubricant and a colorant.

6. 6. The pharmaceutical composition for oral administration according to claim 5, wherein the excipient is one or more selected from the group consisting of lactose hydrate, microcrystalline cellulose, microcrystalline cellulose-lactose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salts, other substituted and unsubstituted celluloses, corn starch, gelatinized starch, lactose, anhydrous lactose, sugar alcohols, sucrose, xylitol, acrylate polymers and copolymers, dextrates, dextrins, dextrose, maltodextrins, pectin, gelatin, and inorganic diluents.

7. 6. The oral pharmaceutical composition of claim 5, wherein the binder is selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone vinyl acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, gelatin, propylene glycol, sodium alginate, and mixtures thereof.

8. The pharmaceutical composition for oral administration according to claim 5, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, crospovidone, carboxymethylcellulose salts, hydroxypropylcellulose, microcrystalline cellulose, gelatinized starch, sodium starch, glycolate and sodium starch glycolate.

9. 6. The oral pharmaceutical composition of claim 5, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, and glyceryl behenate.

10. The oral pharmaceutical composition according to any one of claims 1 to 9, characterized in that its use is for the prevention or treatment of fungal infections.

11. The pharmaceutical composition for oral administration according to claim 10, characterized in that the fungal infection is onychomycosis.

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