KR101799008B1

KR101799008B1 - Pharmaceutical composition for treating fungal infections of keratinous tissue

Info

Publication number: KR101799008B1
Application number: KR1020160028730A
Authority: KR
Inventors: 손미원; 전준호; 박형근; 한상덕; 최성락
Original assignee: 동아제약 주식회사
Priority date: 2015-03-12
Filing date: 2016-03-10
Publication date: 2017-11-17
Also published as: KR20160110209A

Abstract

The present invention relates to a pharmaceutical composition for improving drug permeation for treating keratoconjunctive fungal infections, a method for preparing the same, and a method for administering the composition. Specifically, the present invention provides a pharmaceutical composition comprising: a) at least one antifungal active substance; b) an alkalizing agent which can be adjusted to pH 7 to pH 13; And c) an organic solvent containing an antifungal active ingredient dissolving or promoting absorption to increase absorption of keratin tissue to prevent and treat fungal infectious diseases.

Description

[0001] The present invention relates to a pharmaceutical composition for treating keratinous tissue of keratinous tissue,

The present invention relates to a pharmaceutical composition for treating fungal infections capable of improving drug permeation into keratin tissues.

Keratin is a protein that forms the basis of the epithelial structure. It is made up of various amino acids such as glutamic acid and arginine. The content of cysteine is high, and typical tissues include hair, claws, and skin.

Trichophtosis is caused by infection of hair, hands and toenails by dermatophyte. Dermatophyte has keratinase which can dissolve keratin. Therefore, it is important that keratinous tissue It can easily invade, live the horny nutrients, and cause various lesions. These dermatophytes are known to be various species, but Trichophyton rubrum and Trichophyton mentagrophytes are representative.

Onychomycosis, a kind of ringworm, is a common disease that affects about 20% of the whole population, especially on the thumb nail and thumb nail, and mainly occurs on the nail bed of the dermatophagus. And penetrate through the nail. The occurrence of nail fungus in smokers, peripheral vascular disease patients and diabetic patients is well developed, especially in the elderly. Patients with nail fungus feel a sense of cosmetic discomfort such as thickening of the hands and nails and becoming opaque, and functional disorders such as breakage of hands and toenails and breakage occur. Treatment may also be necessary due to possible contact with other parts of the body or other persons through contact.

There are five clinically significant types of nail fungus. The lesions were divided into two groups: distal nail parotypes (DSO), white superficial nail fungus (WSO), proximal nail paraplegia (PSO), nail paraplegia (EO) Distal nail-to-shoulder fungus (DSO) is a case in which the foot and tines are transferred to the nail. The dermatophytes infiltrate the inside of the nail plate through the stratum corneum of the distal nail and the nail of the nail, It is the most common form of toenail fungus that progresses to the proximal part in the opposite direction. The superficial nail fungus (WSO) is a case of the causative bacteria invading the surface of the nail plate, which is called white superficial nail fungus with small white spots with clear boundaries on the nail plate. Proximal nail paraplegia (PSO) is transmitted through the lower stratum corneum of the proximal paraplegia of the nail. Because the fungi are present in the lower part of the nail plate, the inflammation reaction is less and the surface of the nail plate looks normal but the nail palate is accompanied by the fact that it does not invade the nail plate. This is because most of the causative bacteria of the nail fungus are not only distributed in the nail plate but also penetrate into the lower nail of the nail plate, so that the core of the nail fungus treatment must eradicate the causative bacteria .

The treatment of nail fungus is most commonly used as first-line treatment of terbinafine, which has good antibacterial activity against dermatophytes and fungi, and daily 250 mg of terbinafine hydrochloride is taken daily for 12 weeks. Complete cure, in which both mycological cure and clinical cure occurs, is reported to be approximately 38%. Oral administration of azole-based antifungal agents such as itraconazole and fluconazole, which have a lower clinical cure rate than terbinafine, is often used. However, the above-mentioned oral antifungal agents have side effects such as gastrointestinal diseases, headache, and rash, and occasionally, fatal side effects such as hepatotoxicity may occur. Therefore, monitoring of liver function such as blood test is necessary. There are restrictions.

The other methods for treating nail fungus include the administration of a local solvent such as cyclopirox, amoropine and thioconazole directly to the hands and toenails, thereby minimizing side effects and inconveniences of such oral solutions. However, the hands and toenails are about 100 times thicker than the stratum corneum of the skin, and the tissues forming the hand and toenails are tightly bound through the sulfide linkage with a protein called α-keratin, making it difficult to penetrate the drug. Therefore, topical medicines administered directly on the hands and toenails, such as cyclopirox (Penrox, ropurox and sanofi-aventis), show a low complete cure rate of only 5.5 to 8.5% at 12 months cure.

Therefore, it is a big task in the art to remove the side effects such as hepatotoxicity by topical administration and to develop a therapeutic agent for the nail fungus which is more effective than the conventional commercialized therapeutic agent. For this purpose, it is essential to improve the permeability of the drug through the hand and toenails which are difficult to penetrate the drug, and various attempts have been made heretofore.

Korean Patent Laid-Open Publication No. 2012-38444, Korean Patent Laid-Open Publication No. 2014-25341, and Korean Laid-Open Patent Publication No. 2012-15319 disclose an antifungal active substance, a solvent at least capable of dissolving an antifungal agent, and an organic acid as a permeation enhancer Compositions are disclosed.

International Patent Publication No. WO 2010-010470 and U.S. Patent No. 7,740,875 disclose a composition having a pH of 7.0 or less which enhances the hand, claw or skin permeability of an active substance by using a phospholipid and a surfactant in the active substance.

European Patent Publication No. 0777457 and U.S. Patent No. 5,346,692 are readily applicable on the nails and form a film after the volatile solvent is dried to form a hydrophobic film on the antifungal active substance and the volatile solvent so that the antifungal substance can be continuously released A composition comprising the same is disclosed. However, since the water-insoluble film covers the fingernail before the re-administration, the above-described composition has a disadvantage in that it is necessary to remove the film before use in order to prevent the absorption of the re-administered drug.

In order to solve the above inconvenience, a composition for permeating drug penetration of the hand and toenails using a water-soluble polymer is also disclosed. For example, in International Patent Publication No. WO 2002-007683, US Patent No. 8,697,753, British Journal of Dermatology, 2010 162 p311-317, Journal of the European Academy of Dermatology and Venereology 2009 23 p773-781, [Drug Development and Industrial Pharmacy, 31: 11-17, 2005] discloses a composition containing an antifungal agent and using hydroxypropylchitosan and carboxymethylchitosan as water-soluble polymers to increase penetration of the active ingredient. The composition exhibited about twice the improvement in permeability compared to the existing commercial products. However, even after 48 weeks of treatment, the complete cure rate is only 5.7%, which is still very low.

U.S. Patent No. 6,846,837 discloses a composition for treating a lacrimal fungus comprising an antifungal agent and an inorganic alkaline agent such as sodium hydroxide or potassium hydroxide at pH 7.5 to 13.0. However, since the above-mentioned composition, which is simply adjusted to have a pH, is mostly an aqueous solution, it is impossible to dissolve the antifungal agent and penetrate into the fingernail, so that there is a technical limitation that a large amount of the antifungal agent can not penetrate into the fingernail.

As described above, numerous attempts have been made to overcome the disadvantages of oral antifungal agents such as hepatotoxicity in the field of the treatment of the nail fungus and infiltrate the drug into the hands and toenails in order to increase the clinical complete cure rate. However, There is no clinically satisfactory penetration technique for the hands and toenails. Since the age of the palsy is rapidly increasing in the aging society, the age of the palsy is high in the population of the elderly, and it is very inconvenient to taste or function. Therefore, a new excellent treatment method is needed to solve this problem.

While analyzing prior art for studies to improve nasal permeation of antifungal agents, the inventors of the present invention disclosed in Korean Patent Publication No. 2012-38444, Korean Patent Publication No. 2014-25341 and Korean Patent Publication No. 2012-15319 The prior art described in the prior art uses an organic acid such as lactic acid as a permeation enhancer for nasal permeation of the antifungal active substance. The prior art contains an organic acid and the solution becomes acidic, so that the nasal permeation of the antifungal active substance is easy One, however, was found to be less stable in chemical reaction and degradation, and that the solid state was stable.

In addition, the prior art described in U.S. Patent No. 6,846,837 uses an inorganic alkaline agent such as sodium hydroxide and potassium hydroxide dissolved in an aqueous solvent for nasal permeation of an antifungal active substance, and since various antifungal active substances are poorly soluble It was impossible to dissolve in an aqueous solvent and the permeation of drug from the hand and toenails was insufficient.

Surprisingly, the present inventors have found that a composition in which an active ingredient of an antifungal compound is dissolved in an organic solvent and a solution in which the active ingredient of the antifungal compound is dissolved is adjusted to pH 7 to pH 13 is significantly superior in nasal permeability to active ingredient The present inventors have also confirmed that the nasal permeability increases remarkably when the ion introducing apparatus is used in combination with the composition. Based on these results, the present invention has been completed.

It is an object of the present invention to provide a composition capable of significantly increasing the permeation of the antifungal active substance into the nail and thereby increasing the clinical treatment rate or reducing the treatment period.

In order to achieve the above object, the present invention provides a composition capable of maximizing the nasal permeability by locally administering an antifungal active substance.

Hereinafter, the present invention will be described in detail.

The present invention

a) at least one antifungal active substance;

b) an organic solvent capable of enhancing dissolution or permeation of the active ingredient; And

c) an alkalizing agent which can be adjusted to pH 7 to pH 13;

To a pharmaceutical composition for preventing and treating fungal infectious diseases by increasing absorption of keratinous tissue.

The pharmaceutical composition according to the present invention comprises at least one antifungal active substance. In the present invention, the antifungal active substance may be selected from any known antifungal agent of synthetic or natural origin. The following components are examples and may be free acids or bases in their own right, or in the form of their salts.

Examples of the antifungal active substance according to the present invention include 1-hydroxy-2-pyridone compounds and their salts such as cyclopirox, cyclopioxolamine and lilopirox, examples of imidazole derivatives Which is at least one selected from the group consisting of clotrimazole, econazole, isoconazole, ketoconazole, miconazole, thioconazole, butonazole, penticonazole, oxiconazole, butoconazole, seletaconazole, sulconazole, ricinazole, Naphthalene, naphthalene, naphthalene, naphthalene, naphthalene, naphthalene, naphthalene, naphthalene, naphthalene, Salts, such as alvaconazole, epinaconazole, fluconazole, itraconazole, isobuconazole, labuconazole, posaconazole, voriconazole and terconazole, and in addition thereto, Durafunjin, Mika Fenugine, benzoic acid, haloprozin, undecylenic acid, griseofulvin, tonaphthate, and flucytosine, preferably cyclopiox, ketoconazole, amoropine, terbinafine.

The composition of the present invention comprises one or more of the antifungal active substance or substance series, and the contained amount thereof is in a range of the stability and effectiveness of which is known, and ranges from 0.1 to 10 times the concentration of each ingredient in the market desirable.

The present invention is characterized by containing at least one organic solvent. The organic solvent is an organic solvent capable of dissolving the antifungal active substance. The active substance contained in the composition can be present at a certain concentration. When applied to the topical application, the main ingredient is uniformly delivered to the lesion site. Can be increased. It also evaporates quickly after application and minimizes external contamination, making it convenient to use.

Examples of the volatile organic solvent which can be included in the present invention include organic solvents such as alkanes, alcohols, alcohols, esters, ketones, ethers and silicones, , Alcohols such as ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-poroxanol and 1-pentanol 3-methyl-1-butanol; Esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl formate, butyl acetate and the like; Ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone, and methyl isobutyl ketone; Ethers such as ethyl ether, tert-butyl methyl ether, isopropyl ether and petroleum ether; Examples of the organic solvent include heptane, pentane, isooctane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, methyltetrahydrofuran, anisole, dimethylsulfoxide, isododecane, Organic solvents are preferred. A silicone oil consisting of a siloxane having an organic side chain; Dimethicone, methyltrimethicone, and cyclic acid compounds such as cyclomethicone, dimethicone, hydrogendimethicone, and methicone, and may contain isopropyl alcohol, ethyl acetate, ethanol, acetone, dimethicone Chicone, and cyclomethicone are preferable.

The amount of the organic solvent that can be added to the composition of the present invention is sufficient to dissolve the active substance and facilitate drug delivery to the nares and should be contained in an amount to match the concentration of the appropriate active substance, 5 to 99% by weight, preferably 8 to 98% by weight, more preferably 8 to 90% by weight.

The present invention may contain additional water in addition to the organic solvent as a solvent. At this time, the amount of water that can be contained in the present invention is a sufficient amount to dissolve the antifungal active substance, and may be added at an appropriate concentration to match the effective concentration of the active substance.

The composition of the present invention is also characterized by comprising an alkalizing agent. The alkalizing agent of the present invention may include both an inorganic alkalizing agent and an organic alkalizing agent which increase the pH of the composition according to the present invention. The inorganic alkalizing agent is selected from the group consisting of ammonium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, sodium acetate, sodium borate, sodium carbonate, sodium hydrogen carbonate, sodium phosphate, potassium carbonate, Potassium, potassium phosphate, ammonium phosphate, etc., and hydrates thereof. Organic alkalizing agents may include primary amines (-NH2), one secondary substituted amine (-NHR), and two substituted tertiary amines (-NRaRb) as amines. Examples of the primary amine include 2-ethanolamine, 2-heptanolamine, 2-amino-2-methyl-1,3-propanediol, 2-amino- , 1,4-butanediamine, n-butylamine, cyclohexylamine, ethylamine, ethylenediamine, methylamine, alpha -methylbenzylamine, phenethylamine, propylamine and trishydroxymethylaminomethane. The secondary amine can be selected from the group consisting of methylaminoamine, ethylaminoamine, isopropylaminoamine, butylaminoamine, cyclopropylaminoamine, cyclohexylaminoamine, n-hexylaminoamine, phenylaminoamine, benzylaminoamine, Hydroxyethylaminoamine, diethanolamine, diethylamine, diisopropylamine, and dimethylamine. The tertiary amine can be selected from the group consisting of dibutylaminoamine, diethylaminoamine, dimethylaminoamine, diisopropylaminoamine, ethylchloroaminoamine, dimethylaminoamine, diisopropylaminoamine, methylchloroethylaminoamine, ethylcyclopropylaminoamine , Methylhexylaminoamine, methylbenzylaminoamine, N, N-diethylaniline, N, N-dimethylglycine, triethanolamine, triethylamine and trimethylamine. Amides have a structural formula of R1- (CO) -NR2-R3- and include, for example, hexamethylene acetamide, hexamethylene octamide, hexamethylene lauramide, hexamethylene palmitamide, N, N, N-dimethylacetamide, N, N-dimethyloctamide, N, N-dimethyldecamide, toluamide, dimethyl-m-toluamide, diethyl- Pyrrolidone, 1-methyl-2-pyrrolidone, 1-methyl-2-pyrrolidone, Dodecyl acacycloheptan-2-one, ethylenethiourea, hydantoin, hydroxyurea, imidanilylurea, N-octadecylmorpholine, dodecylpyridinium, N-dodecylpyrrolidide , N-dodecylpiperidine, and N-dodecylhoffepiperidine. Other basic amino acids such as lysine, arginine, meglumine and the like may be included.

The alkalizing agent according to the present invention may be varied depending on the solubility and stability of the antifungal active substance and may be an alkalizing agent capable of adjusting the pH to 7 to 13 when the composition itself or the composition is diluted with water, desirable. The amount of the alkalizing agent according to the present invention may vary depending on the strength of the base, the molecular weight, the number of the hydroxyl (OH-) ions which can be dissociated, and the kind of acid contained in the preparation. The pH is preferably 6 to 14, more preferably 7 to 13.

The present invention may further comprise a film former. In this case, when the composition of the present invention is applied to a lesion site, a film-forming agent can form a film at a lesion site so that it can be uniformly applied to a certain thickness, and an organic solvent can prevent crystallization of a viral article even after volatilization, To maintain sustained delivery of the drug to the nail. The film-forming materials that may be further included in the present invention include chitosan, chitosan derivatives or salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, carbomer, PVP / MA, HP Acrylate copolymer, an ethyl acrylate / methacrylate copolymer, an aminoalkyl methacrylate copolymer, an ammonium methacrylate copolymer, a PVP / VA copolymer, a PVA , PVA / MA butyl ester copolymers, shellac, and alkyl acrylate copolymers, hydroxypropylcellulose phthalate, hydroxypropylcellulose acetate succinate, acrylate / dimethicone copolymers, and trimethylsiloxysilicate. The amount of the film-forming agent which may be contained in the present invention is 0.1 to 20% by weight, preferably 0.2 to 15% by weight.

The composition of the present invention is an excipient that is convenient to administer, improves feeling, enhances formulation stability, and increases penetration of drugs into the nail. In addition to the above essential components, the composition of the present invention includes plasticizers, thickeners, surfactants , An auxiliary dissolving agent, a preservative, a flavoring agent and the like, examples of which are well illustrated in Handbook of Pharmaceutical Excipients 7th edition (Raymond C. Rowe).

In addition, the present invention can be formulated in units of one or more formulations. The composition of the present invention can be administered in a single dosage unit, but it is also possible to use a first agent containing an alkalizing agent and a second agent in the form of a second agent form containing the drug and the organic solvent or a combination of an alkalizing agent 1, A solvent, and a solvent.

In addition, the composition of the present invention can be applied with iontophoresis, which increases the absorption of drugs by giving a potential difference to the skin or nails during administration. Ion implantation may include any method of maintaining a constant voltage or maintaining a constant current to provide a potential difference. The composition of the present invention shows a remarkable increase in permeability by itself, but shows a remarkable increase in permeability when the ion plating method is applied together.

The present invention allows high-concentration penetration of an excellent antifungal active substance into keratin tissues and enables treatment of intractable white pneumonia in the tissues. Increase the rate of complete cure, or shorten the minimum administration period for complete treatment. In addition, the drug can be infiltrated at a high concentration by a single administration, and the concentration can be maintained at an effective concentration for a long time in the tissue, thereby increasing the administration interval and reducing the number of administrations.

Fig. 1 is a graph showing the results of a comparison between the results of Examples 1, 5, 8, 9, 10, 11, and 21 evaluated using a cow foot slice and Comparative Example 1 as a comparative example, Which represents the cumulative amount of permeation over time.
FIG. 2 is a graph showing the cumulative permeation amounts of antibacterial active materials contained in Examples 12 to 17 evaluated using cow foot slices, Comparative Example 1 as a comparative example, and Lofu Rox, a full-scale commercial product, for 48 hours.
FIG. 3 is a graph showing the cumulative permeation amounts of the antibacterial active materials in Examples 29 to 34 evaluated using the bovine cut pieces and Comparative Example 1 and Comparative Example 1 for 4 hours. 3 is an enlarged view of Example 29 and Comparative Example 1. FIG.

Hereinafter, the present invention will be described in detail with reference to examples.

However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

&Lt; Examples 1 to 4 > Preparation of a composition containing an antifungal active substance according to the present invention

A part of (about 50% equivalent) organic solvent was added to the antifungal active substance, the alkalizing agent and other substances in the composition shown in Table 1 below, and the solution was completely dissolved by using an overhead mixer. Separately, the remaining organic solvent is placed in a Homo-Agi Mixer, and then a film-forming material (polymer such as hydroxypropylcellulose) is added to dissolve or disperse the solution. Then, a solution containing the active material is added thereto and mixed thoroughly. The compositions were prepared and described in Examples 1 to 4, respectively. In order to confirm the pH of Examples 1 to 4, purified water was diluted with an amount of 10 times the total amount, and pH was measured. The results are shown in Table 1.

&Lt; Examples 5 to 11 > Preparation of compositions containing antifungal active substances, including various alkalizing agents

A pharmaceutical composition for the treatment of fungal infectious diseases comprising various alkalizing agents according to the present invention was prepared with the composition shown in Table 2 below. An antifungal active substance, an alkalizing agent and an acrylate / ammonium methacrylate copolymer were put into an organic solvent or an organic solvent and a purified water mixed solvent and completely dissolved by using an overhead mixer to prepare a solution. In order to confirm the pH, purified water was diluted to 10 times the total amount, and the pH was measured. The results are shown in Table 2.

&Lt; Examples 12 to 17 > Preparation of compositions containing antifungal active substances, including various organic solvents

In the same manner as in Examples 5 to 11, compositions for treating fungal infection were prepared using various organic solvents as shown in Table 3 below.

< Example 18 to 22> variety Organic solvent Preparation of a composition containing an antifungal active substance containing

In the same manner as in Examples 1 to 4, a composition for treating fungal infection was prepared using an organic solvent and purified water as shown in Table 4 below.

&Lt; Examples 23 and 24 > Preparation of composition for divided administration

As shown in Table 5, monoethanolamine was added to purified water, an ethanol mixed solvent or ethanol, and the mixture was dissolved in an overhead mixer and dissolved in 1 part. Then, cyclopropyl or amorphous hydrochloride was added to isopropyl alcohol, purified water or ethylacetate and mixed with an overhead mixer To prepare a second agent.

&Lt; Examples 25 to 27 > Preparation of a composition containing at least one antifungal active substance

In the same manner as in Examples 1 to 4, a composition for treating fungal infection was prepared in the same manner as the amount shown in Table 6 below. To confirm the pH, purified water was diluted to 10 times the total amount, and the pH was measured. The results are shown in Table 6.

&Lt; Examples 29 to 34 > Composition containing an antifungal active substance and an alkalizing agent and ion-applying method

As shown in Table 7 below, the active substance (cyclopirox) and the film-forming substance (hydroxypropylcellulose) were completely dissolved in an organic solvent in the same manner as in Example 1-4 using an overhead mixer (Example 29 ~ 34). The bovine hoof was cut to a certain thickness and maintained at a constant voltage of 9 V or a constant current of 0.05, 0.1, 1, or 10 mA using a Franz diffusion cell and a DC power supply as a power supply device 30-34). In order to allow the current to flow, a negative electrode is applied to the donor phase and a positive electrode is applied to the receptor phase.

&Lt; Comparative Example 1 & The preparation of the preparation described in Example 1

As shown in the following Table 8, the composition of Example 1 of U.S. Patent No. 6,846,837 was prepared so that 8% of cyclophirox was added.

<Experimental Example 1> Evaluation of keratinous tissue permeability by pH

The bovine hoof was cut to a certain thickness and the permeability of the antifungal active substance was evaluated by using Franz diffusion cell.

Examples 1, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 21 and Comparative Example 1 (Example 1 of U.S. Patent No. 6,846,837, a commercially available product pool Care ^® (Korea menari you), ropu Rocks ^® (Sanofi-German &) were used as controls. Cumulative noodle permeability at 48 hours from the start of the test is shown in Figs.

As can be seen in Figures 1 and 2, the permeability of the active material was significantly increased in the composition of the present invention compared to the comparative example.

<Experimental Example 2> Evaluation of keratinous tissue permeability upon application of the compositions and iontophoresis devices of Examples 29 to 34 according to the present invention

The keratinous tissue permeability of Comparative Example 1 and Examples 29 to 34 was evaluated. The cumulative noodle permeability at 4 hours from the start of the test is shown in Fig. As can be seen from FIG. 3, the composition of the present invention showed significantly increased transmittance compared to comparative examples and commercially available products. Surprisingly, the iontophoresis significantly increased the permeability of the active material compared to when the iontophoresis was not applied.

Claims

a) 8% by weight of cyclopirox;
b) 80 to 89.5% by weight of an organic solvent selected from ethanol, isopropyl alcohol, acetone, ethyl acetate, dimethicone or cyclomethicone;
c) from 0.5 to 5% by weight of one or two alkalizing agents selected from 2-amino-2-methyl-1-propanol, monoethanolamine, diethanolamine or triethanolamine; And
d) a film forming agent selected from hydroxypropylcellulose, acrylate / ammonium methacrylate copolymer, hydroxypropylmethylcellulose phthalate, 2 wt%
And increasing absorption in a keratinous tissue having a pH ranging from 8 to 13 to prevent and treat fungal infectious diseases.

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The pharmaceutical composition according to claim 1, wherein the keratinous tissue is characterized by hair, skin and nails.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is prepared in liquid, gel or ointment form.

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a) 8% by weight of cyclopirox;
b) 56% by weight isopropyl alcohol;
c) from 1.5 to 4% by weight of sodium hydroxide or monoethanolamine;
d) 2% by weight of hydroxypropylcellulose or acrylate / ammonium methacrylate copolymer and
e) purified water 25 to 32.5 wt%
And increasing absorption in a keratinous tissue having a pH ranging from 8 to 13, thereby preventing and treating fungal infectious diseases.

a) 8% by weight of cyclopirox;
b) 61.7% by weight of isopropyl alcohol;
c) 2.6% by weight of potassium hydroxide;
d) 0.5% by weight of hydroxypropylcellulose; And
e) Purified water 27.2 wt%
To increase the absorption in the keratin tissue by increasing the permeation of cyclophilus to flow through a current of 0.05 to 10 mA into the pharmaceutical composition.

15. The pharmaceutical composition according to claim 14, wherein an ion-introducing device is used to apply a voltage for maintaining a current of 0.05 to 10 mA.

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