MXPA97004681A - Composition for the antimictic treatment of the nails and topical use of the im - Google Patents

Abstract

The present invention relates to a method for the treatment of diseases in the nails, comprising topical administration to the nail and, if desired, also to the surrounding skin, of 1) an amino acid containing sulfhydryl or a derivative thereof, pharmaceutically acceptable salts or esters thereof or stereoisomers thereof, 2) urea, (1) and (2) administered in an amount sufficient to increase the penetration of antifungal drugs through the nail tissue, either before, or preferably concurrently with the topical administration to the nail of 3) an effective amount of antifungal drug, a bandage adapted for topical administration of medicament to the nail is also described, said bandage comprising a T-shaped adhesive backing, and a flexible pad having a waterproof backing and a nail-shaped cavity backed by said waterproof backing, wherein said nail-shaped cavity contains absorbing media having urea absorbed therein and an amino acid containing sulfhydryl or derivatives thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

Description

COMPOSITION PflRfl THE ANTIMICTIC TREATMENT OF THE NAILS AND TOPICAL USE OF THE SAME TECHNICAL FIELD The invention relates to a method for the topical treatment of diseases in the nails, and particularly to a composition and method for increasing the penetration rate of antirnicotic agents in the nails. The invention also relates to a bandage adapted for use with the method of the invention.

BACKGROUND OF THE INVENTION Although there has been a significant advance in the development of antirhnic drugs, the nail infection of the nail (eg, onychomycosis) remains a very difficult disease to treat. The target sites for the treatment of onychomycosis lies in the nail plate, the nail bed and the nail matrix (see figure 1). Topical treatment has not been effective because antifungal drugs can not easily penetrate the nail plate to reach sites of infection below the nail. The administration ofal of antirnic drugs is the only effective way to treat onychomycosis, which has limited the use of some of the most potent antifungal drugs such as intraconazole and ketoconazole due to concerns about possible side effects, however, it has been shown that if the nail barrier can be overcome or eliminated, treatment with antifungal drugs can be effective. For example, it was demonstrated that both miconazole and ketoconazole are effective in the topical treatment of onychomycosis after nail avulsion. There is a need for a methodology for the topical antifungal treatment of the nails that does not require the removal of the nail. Such topical treatment would not then allow the use of the most potent antifungal drugs in the treatment of fungal infected nails. The nail plate is too thick and too dense for the drugs to penetrate at a practical speed. Although the nail is similar to the stratum corneum of the skin in that it derives from the epidermis, it is mainly composed of hard keratin (highly disulfide bound) and has a thickness of approximately 100 times the stratum corneum. To deliver a sufficient amount of drug to the nail plate, the permeability of the nail plate to the drug needs to be increased. The properties related to the permeability of the nail differ from those observed in the stratum corneum mainly in three aspects: a) the total lipid content of the nail is much lower than the lipid content of the stratum corneum; b) the nail has a high content of asufre (cystine) in its domain of hard q? eratin while the stratum corneum does not; c) under average conditions, the nail contains much less water than the stratum corneum. The chemical composition of the nail and the experimental evidence indicate that the aqueous path plays a dominant role in the penetration of the drug into the nail. fll be hydrated, the hard plates of the nail become softer and more flexible. The hydration of the nail is influenced by many factors, such as the pH of the solution and some chemical compounds. Keratolytic agents, such as urea and salicylic acid are often used to soften the nail plates. It was reported that urea and a combination of urea and salicylic acid were used for avulsion of nail dystrophies in chemical studies before the topical treatment of onychomycosis with satisfactory results. The nail plates have a high sulfur content in the form of disulfide bonds. Some reducing agents, e.g., cysteine or a derivative thereof, can break the disulfide bond in keratin to increase the ability of the nail to hydrate. The chemical ration that occurs between the disulfide bonds in the keratin of the nail and a thiol-containing compound (in this case, cysteine) is shown in the following scheme: NH NH CHCH-SS-CHCH + 2 HS-CH-CH (NH) -COOH ========= CO CO NH NH CHCH-SH - HS-CHCH-HOOC-CH (NH) -CH-SS -CH-CH (NH) -COOH | | CO CO This invention provides assortment means for the topical treatment of nail fungus diseases that deliver drug doses to: a) the infected nail plate (and consequently, the underlying bed of the nail), whose hydration capacity has been increased to improve the penetration of the drug (nail path); and b) the surrounding skin tissues, including the nail bed and matrix through the eponychium and hyponychium (skin pathway - see figure 1).

BRIEF DESCRIPTION OF THE INVENTION The invention provides a method for the treatment of diseases in the nails, comprising topical administration to the nail and, if desired, also to the surrounding skin, of 1) an amino acid containing sulfhydryl or a derivative thereof, the pharmaceutically acceptable salts or esters thereof or stereoisomers thereof, 2) urea, (a) and (b) being administered in an amount sufficient to increase the penetration of antifungal drugs through the nail tissue, either before, or preferably concurrently with topical administration to the nail of 3) an effective amount of antirnic drug. The invention also provides a composition comprising (1), (2) and (3), as described above. The invention further provides a bandage adapted for topical administration of medicament to the nail, said bandage comprising a T-shaped adhesive backing, and a flexible pad having an impermeable backing and a nail-shaped cavity supported by said impermeable backing, wherein said nail-shaped cavity contains absorbing means having therein absorbed urea and an amino acid containing sulfhydryl or derivatives thereof, a pharmaceutically acceptable salt or ester thereof thereof, or a stereoisomer thereof.

PREVIOUS TECHNIQUE The reduction reaction between the disulphide bridges of keratin and the thioglycollates is used frequently in the cosmetics industry, e.g., for cold corrugation and depilation, and to increase the cosmetic appearance of the nail. Olthoff et al., In EP 440298 Al, discloses the use of sulfur-containing amino acid derivatives in topical preparations for the treatment of nail diseases such as onychomycosis. Ka ase et al. (EP 472858 A2, March 4, 1992) discloses a hair treatment composition containing siloxanes and penetration enhancers such as ammonium thioglycolate, which gives the treated hair good gloss and a reduced number of splitting. hair related. Puri (UO 8600013 fll, January 3, 1986) describes that the condition of hair, skin and nails is improved by treatment with an aqueous solution of ammonium thioglycolate, followed by treatment with protein hydrolyzate. Ro + hrnan (IO 8907930 fll, September 8, 1989) discloses a composition that has + a stable storage protein and a method for treating keratinous tissues. The protein-containing composition contains reducing agents such as ammonium ioglycolate. The composition is said to be useful for conditioning horny keratinous tissues of mammals such as human hair and nails, and hooves and animal hair, to improve its strength and appearance and to promote hair and nail growth. Increased intravenous drug penetration for theophylline has been reported in CK rats. Kushida et al., Chem. Pharm. Bull., 32, 1 (1984) 268-274] and insulin CY. Sun and others, Ann. New York Acade and of Sciences, 1990, 596; Y. Sun and others, Proceed. Intern. Sy. Control. I laughed Bioactive Mat., - 1990) 202; and 3.C. Liu et al., In Drug Permeation Enhancement: Theory and Applications, p. 247-272 (D.S. Hsied, Ed.) Marcel Dekker, Inc., 19943 causing the skin to be penetrated by an aqueous solution of calcium thioglycolate. On the other hand, the direct addition of calcium thioglycolate in an ointment containing the indornetacin calcium salt drastically reduces the absorption of the CT drug. Ogiso and others, 3. Phar acobio-Dyn. , 9 (1986) 517-5251. Konno et al. (EP 152281 02 21 flug 1985) describes a transdermal formulation of nicardipine hydrochloride containing urea and thioglycol.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the target sites of treatment of a fungal infected nail. Figure 2 is a graph showing the effect of urea on the inflammation of the nail using aqueous solutions of urea of various concentrations at a pH of 4.5. Figure 3a is a graph showing comparisons of the improvement in nail inflammation between various thiol-containing amino acids and analogues after immersing nail fragments in the formulation at 32 ° C for 48 hours. Figure 3b is a graph showing comparisons of the division of itraconazole into various thiol-containing amino acids and analogues after immersing nail fragments in the formulation at 32 ° C for 48 hours. Figures 4a, 5a and 6a are graphs showing the effect of N-acetyl-1-cietein and urea on the inflammation of the nail in different formulations; Figures 4b, 5b and 6b are graphs showing the effect of N-acetyl-1-cysteine and urea on the penetration of itraconazole into the nail in different formulations. Figure 7 is a graph showing the swelling of the nail and the penetration of miconazole nitrate into the nail in a miconazole nitrate cream formulation. Figure 8 is a graph showing the swelling of the nail-pH profile with nail fragments immersed in a formulation containing urea, propylene carbonate, propylene glycol, N-acetyl-1-cysteine and water, at different pH values . Figure 9 is a graph showing the penetration profiles of itraconazole from the formulations with various compositions: Figure 10 is a graph showing the amount of .itraconazole penetrated through the nail plate, as well as the amount retained in the nail plate, for three different formulations; Figure 11 is a graph showing the penetration profile of miconazole through the nail plate for three different formulations; Figure 12 is a graph showing the amount of miconazole nitrate penetrated through the nail plate, as well as the amount retained in the nail plate, for three different formulations; and Figure 13 shows three views of a device designed for topical assortment of drug to the nails.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to a method for the treatment of diseases (nicotics in the nails, comprising topical administration to the nail of 1) an amino acid or derivative thereof containing sulfhydryl, pharmaceutically acceptable salts or esters thereof, or stereoisomers thereof, 2) urea, (1) and (2) administering in an amount sufficient to increase the penetration of antifungal drugs through the nail tissue, either before, or preferably concurrently with topical administration to the nail of 3) an effective amount of antirnic drug. By the term "nail" is meant the corneal skin plate on the dorsal surface of the distal end of the fingers and toes. Figure 1 is a schematic diagram showing the basic anatomical structure of the human nail and its surrounding tissues. The topical antifungal treatment with drugs for diseases of the nails caused by fungi (onychomycosis) contemplated by this invention is intended to supply antifungal drug to the nail plate 1 (the stratum corneum layer) and the nail bed 2 (the area modified epidermis below the nail, over which the nail plate 1 slides as it grows) through the nail plate 1. Desirably, the antirnicotic drug is also administered concurrently to the matrix of the nail. the nail 3 (the proximal portion of the nail bed 2 from which the growth mainly proceeds) and the nail bed 2 through the skin of the eponychium 4 (commonly called cuticle) and the hyponychium 5 (the epidermis thickened by below the free distal end of the nail). The topical treatment of the invention can be used in combination with systemic treatment with an antifungal drug such as griseofulvin or another antifungal drug that can be given orally for prolonged periods., either concurrently throughout the systemic treatment regimen, or concurrently during a portion (usually the last phase) of the systemic treatment regimen, or after said systemic treatment. Lae diseases of the nail caused by fungi that can be treated according to the invention are those that are called "onychomycosis", which is usually an infection caused by Epiderum ophyton floccosum, several species of Trichophon or Candida albicans. Antifungal drugs that can be used in the invention include miconazole nitrate, ketoconazole, itraconazole, fluconazole, econazole, teraconazole, saperconazole, arnorolphin, cyclopirox, oxiconazole, clotrimazole, terbinafine, naftifine and other antifungal drugs that are available in a topical formulation. Preferred antifungal drugs for use in the method of the invention are itraconazole, ketoconazole and miconazole nitrate. If desired, the topical formulation containing the antirnicotico drug may include an agent such as hydroxypropyl-β-cyclodextrin which increases the water solubility of the antimicrobial drug, to better utilize the aqueous passage through. nail, as described before. Antimicrobial drugs are used in anotically effective amounts. For example, antimotentially effective amounts are generally from about 0.5% to about 10%, by weight, and preferably from about 1% to about 5%, by weight, of the formulation that is applied to the nail or that surrounds the dermal tissue. Urea is used in the invention. It is believed that the major contribution of urea to the effectiveness of the formulation used in the invention is to prevent the nail from returning to its densely packed original entangled state (said return to the densely packed original interlaced state). it would be caused by oxidation of oxygen in the atmosphere), so that the nail remains more permeable to the an- + irnicotic drug than for a prolonged period. (The ability of urea to prevent the keratin of the nail from returning to its original dense + packed interlaced state probably derives from the ability of urea to alter non-covalent interactions in the keratum of the nail). A beneficial effect of the use of urea is that the amino acid or derivative thereof containing sulfhydryl can be used in a lower concentration, thereby reducing (although probably not eliminating) the potential of the amino acid or derivative thereof for skin irritation. The invention employs an amino acid or derivative thereof containing sulfhydryl, pharmaceutically acceptable salts or ethers thereof or stereoisomers thereof. Said compounds can be represented by the formula (I): HS- (CH) CH-R (I) the pharmaceutically acceptable salts or esters thereof, and stereoisomers thereof, wherein: R = H, C0NHCHC00H, NH or COOR wherein R is H or alkyl C; R = H, COCH, CONH, or COCH) CH (NH) (COOH) where rn is 1 or 2; and n = a number having a value of 1 to 4. Illustrative examples of compounds of Formula (I) include those shown in the following table: TABLE I Cysteine (1-cysteine, d-cysteine, dl-cysteine) HS-CH-CH-COOH N-flceti1-1-cysteine HS-CH ~ CH-COOH C IOCH dl-Homocysteine HS-CH-CH-CH-COOH 1-cysteine methyl ester (methylcysteine) HS-CH-CH-COOCH | NH Ethyl ester of l-cysteine (ethylcysteine) HS-CH-CH-COOCHCH N-Carbamoylcysteine HS-CH-CH-COOH NH CO-NH Glutathione CH-CH-COOCH HCI-CONHCHCOOH N IHCOCHCHNH C IOOH Cistearnine HS-CH-CH-NH Preferred compounds for use in the invention are N-Acetyl-1-cysteine and cysteine The urea and the amino acid or derivative thereof containing sulfhydryl are used in sufficient amounts to increase drug penetration antifungal through the tissue of the nail. Therefore, the topical composition that is applied to the nail ordinarily will contain from about 1% to about 50%, and preferably from about 5% to about 20% (by weight) of urea, and about 0.1% by weight. about 40%, and preferably from about 3% to about 20% (by weight) of the amino acid or sulfhydryl-containing derivative thereof, the percentages based on the total weight of the formulation being applied to the nail. The pH scale of the formulation is generally around a pH of 2 at a pH of 10, and preferably of a pH of 3 at a pH of 8.

EXPERIMENTAL SECTION to. Effect of nail penetration c ommeters on nail inflammation and distribution of the drug on the nail The ability of a drug in a formulation to penetrate the nail plate 1 should be reflected by the speed and degree of absorption of the formulation by the nail (ie, inflammation in the formulation), as well as by the amount of the migration of the drug towards the nail (distribution of the drug in the nail). In vitro experiments were conducted to examine the effect of the drug formulation containing nail penetration enhancer on nail inflammation and drug distribution. The experimental procedure was as follows: fragments of clean human fingernails were equilibrated to a constant weight by placing them in a desiccator over the saturated CaCl.DHO solution (relative humidity of 29% at room temperature) for at least 48 hours before use. Approximately 30 mg of human nail fragments were weighed in a glass jar. Four grams of the test formulation (preheated to 32 ° C) were added to the flask and kept at 32 ° C under stirring in a heating / stirring module (Reacti-Therm III, Pierce). Changes in nail weights were monitored at predetermined intervals for 48 hours. At the end of the inflammation experiment, the nail sample was rinsed with a mixture of N, N-dimethylformamide and methanol (1: 1) to remove drug bound to the surface. The fingernail sample was then digested, and the concentration in the nail was determined by high pressure liquid chromatography as described in Badcock and Davies, flssay of itraconazole in nail clippings by reversed phase, high performance liquid chroma -tography, Ann. Clin. Biochem, 27 (1990), 506-508. Several terms were used to describe the data. Swelling of the nail was expressed by the percentage "I read the initial weight of the nail (that is, 100% of the initial weight of the nail means there is no swelling, and 200% means that the swelling of the nail doubles its original weight, etc.) An increase factor is used to show the increase in swelling of the nail due to the presence of nail penetration enhancer compared to the control, which were calculated according to the formula: increment factor = (% weight gain of the test nail sample) / (% weight gain of the control nail sample, ie, without increment or urea in the formulation). Similarly, the increase factor for the increased penetration of itraconazole into the nail is defined as: increase factor = (concentration of drug in the fingernail sample) / (concentration of drug in the fingernail sample of control) ). The concentration of drug in the nail was calculated by dividing the amount of drug in the nail (mg) by the weight of the initial fragment of the nail (that is, the weight of the dry nail in grams). This expression of drug concentration in the nail is used unless specified otherwise. The effect of urea on swelling was investigated, using aqueous solutions of urea of various concentrations at a pH of 4.5. The graph shown in figure 2 shows that as the urea concentration increased from 20% to 40%, the hydration of the nail increased from 30% to 50%. For this reason, it is believed that the use of urea alone does not produce a sigmfical increase in the penetration of drug through the nail. Table 1, above, shows the names and structures of the thiol-containing amino acids or derivatives thereof that were investigated. To examine the effects of these nail penetration enhancers on the ("nail lynching and penetration of the drug, several formulations of itraconazole and rniconazole nitrate were prepared with an incrementer in each formulation (Table 2, below, deplete the formulations.) In the control experiment, there was no penetration of the incrementing agent ("E") or urea ("U"? in the formulation.) In the experiments described below, the following abbreviations and compounds were used. Cyst = N-acetyl-l-cysteine Cysteine = 1-cysteine Ho ocyst = dl-furnace system MethylCyst = methyl ester of 1-cysteine EthylCyst = ethyl ester of 1-cysteine Intra = .itraconazole Repl: nd = refilled every n days Sfl = salicylic acid (keratolytic agent; pH control) PG = propylene glycol (solvent) PC = propylene carbonate (solvent) EDTfl = ethylenediaminetetraacetic acid (disodium salt - chelating agent) KLUCEL = hydroxypropylcellulose (thickener) BHT = butylated hydroxytoluene (antioxidant) Mic.Nit. = miconazole nitrate BHA = butylated hydroxyanisole Labrifil M 1944 CS = unsaturated polyglycolized glycerides obtained by partial alcoholysis of apricot kernel oil, consisting of glycerides and polyethylene glycol esters - an amphiphilic, solvent and / or emulsifying oil. TEFOSE 63 = Ethylene glycol palmito-stearate and polyoxyethylene glycol; the name adopted by the CTFA is stearate of PEG 6 (and) stearate of PEG-32 (and) glycol stearate - a nonionic self-eusable base for emulsified oil / water preparations. the .1 • i of .i ^ c orb to 0.1 Figure 3a shows a comparison of the incrrnento effect on the inflammation of the nail and Figure 3b shows a comparison of the effect of increase of itraconazole distribution of the thiol-containing amino acids and derivatives thereof of nail fragments after immersion in the test formulations at 32 ° C for 48 hours. The results in Figure 3a show that all thiol-containing amino acids and derivatives thereof increased nail inflammation in .itraconazole formulations, in which the increase factors vary from 1.82 to 4.57. The highest nail inflammation increase was found with 1-cysteine, followed by N-acetyl-1-cysteine and cysteine ina. As shown in Figure 3b, the same category order was observed among penetration enhancers because of their ability to increase the distribution of itraconazole to the nail. The drastic increase in the migration of traconazole to the nail (approximately 100 times) indicates that the incorporation of the penetration enhancer into a topical formulation of itraconazole will deepen the antirnic drug by reaching its target sites on the nail plate 1 and the nail plate. Nail bed 2. The graphs shown in Figures 4a-6a and 4b-6b show the effect of N-acetyl-1-cysteine as a penetration enhancer, and urea as an adjuvant synergist on nail inflammation and distribution of itraconazole. The compositions of the formulations are tabulated in Table 3 below. All three formulations of itraconazole contain 1% .itraconazole, 5% N-acetyl-cysteine and a different concentration of urea and other components. The pH of these formulations was adjusted to 3.0. As you can see from these figures, by adjusting the composition of a formulation, you can obtain the desired performance from the formulation, as reflected by the inflammation of the nail and the distribution of itraconazole. The benefit of incorporation of urea into the formulations has been demonstrated by a clear tendency shown in 4a ~ 6a and 4b-6b. As can be seen, the increase in the distribution of itraconazole to the nail due to the presence of urea is greater than the increase in inflammation of the nail in the three formulations. r-? s- NJ - yes The fingernail and drug penetration experiment was conducted for rniconazole nitrate using procedures. The graphical results shown in figure 7 show that, similarly to the itraconazole data, the significant swelling of the nail coincided with the substantial penetration. of the miconazole in the nail towards the nail, using the following formulation. 1% rniconazole nitrate, 0.005% BHfi, 1.5% heavy mineral oil, 1.5% hazard oleate (LOBRAFIL M 1944 CS), 10% pegoxol stearate 7 (TEFOSE 63), 0.05% EDT, 20% urea, 10% N-acetylcysteine and 55.9% water, with pH adjusted to 9.0 with NaOH, as required. It should be noted that, unlike the itraconazole formulations described above, which were tested at pH 3, the pH value of the miconazole nitrate formulation was set at pH 9. The significant swelling of the nail and the high penetration in the nail of the coincidental rniconazole has a wide pH scale. This was confirmed by the swelling profile-pH shown in Figure 8, using the following formulation. 20% urea, 35% propylene carbonate, 10% propylene glycol, 10% N-acetylcysteine and 25% water, pH adjusted with HCl or NaOH, as required, at pH 3.2, 4.0, 5.0 , 6.0 and 7.0. The experimental temperature was 32 ° C. b. Effect of i nail penetration enhancers on the penetration of the drug through the nail and retention and distribution of drug in the nail plate To test the increase effect of the itraconazole formulation containing N-acet lc steine, Itraconazole penetration experiments were conducted using human cadaver nails. In brief, a nail plate was mounted on a diffusion cell (exposed area of the nail = 0.1202 crn) in which the nail separated a donor chamber from a receiving chamber. The donor chamber was then loaded with an itraconazole formulation of 100-200 mg. To simulate the clinical situation, the formulation of the drug in the donor chamber was removed, and filled with a fresh drug formulation according to a predetermined schedule of time. The solution in the receiving chamber was 20% hydroxypropyl-β-cyclodextrm (5 ml, pH 4) to ensure sinking conditions. T "Sinking condition" is defined as a condition in which the concentration of the penetrator (in this case itraconazole) in the receiving solution is less than 10% of its solubility in the receiving solution - the idea is to boost the balance of such so that penetration of the penetrator to the receiving solution is favored !. The experiments were conducted under occlusive conditions (ie, the donor compartment was covered with a PVC film to minimize evaporation and exclude atmospheric oxygen) and at 32 ° C. With a predetermined sampling program, an aliquot of the receiving solution was removed for the CLfiP test of itraconazole, and replaced by an equal volume of fresh receptor medium. A typical nail penetration experiment was carried out for approximately 4 weeks. At the end of the penetration experiment, the content of itraconazole in the nail plate 1 was also determined by CLRP after the aforementioned extraction procedure (Badcock and Davies). Similar experiments were also carried out for the penetration of rniconazole nitrate into the nail. As shown in Figure 9, the penetration profiles of itraconazole in the nail, of the formulations # 41 and # 136 shows that itraconazole began to penetrate the nail plates to reach the recipient in approximately 12 days. Formulation # 136 has a nail penetration rate of itraconazole that is double that of formulation # 41, probably due to its itraconazole content (1.0% itraconazole in # 136 and 0.5% itraconazole in # 4.1), Despite the fact that formulation # 41 has twice as much acetylcysteine (10% acetylcysteine) as formulation # 136 (5% acetylcysteine). Formulation # 137 has a composition almost identical to formulation # 136, except that it has a lower acetylcysteine content (only 1.0% acetylcysteine in # 137, as opposed to 5.0% in # 136). Figure 9 shows that formulation # 137 does not deliver itraconazole through the nail plate 1. Rather, the acetylcysteine concentration in formulation # 137 was too low to exert the cysteine penetration enhancing effect. Figure 10 shows the total amount of itraconazole in the nail, including itraconazole that penetrates through the nail plate 1, and the drug retained by the nail. The substantial amount of the drug retained in the nail reflects the highly keratinophilic nature of itraconazole. It is interesting to see that the total amount of itraconzaol that the nail penetrates from formulation # 137 is about 185 of formulation # 136 (the same ratio as the aceti lcysteine contents of the two formulations). It should be noted that in the experiments vi vi tro, the amount of itraconazole that penetrates into and through the nail plate 1 greatly exceeded the terepéuticative dose required. For example (table 3), formulation # 2138-41 achieved a concentration of íttraconazole in the nail of 1096 μg / nl, and formulation # 2138-136 achieved a concentration of 692 μg / rnl. Itraconazole is a potent antifungal drug with a very broad spectrum of activity. The minimum inhibitory concentration (MIC) of itraconazole against dermatophytes and yeast is as low as 100 ng / ml. Figure 11 shows the penetration profile of miconazole nitrate. As you can see, starting on day 5 (delay time = 5 days), miconazole nitrate penetrated through the nail plates with a constant speed. With the same formulation, that is, formulation # 70, the frequency of filling the formulation (every 3 days or every 7 days) did not lead to much difference in penetration of miconazole nitrate through the nail (Figure 12). On the other hand, when the concentration of N-acetylcysteine was increased from 5% (formulation # 70) to 10% (formulation # 69), both the penetration of miconazole nitrate and the drug retention in the nail doubled. This result indicates that the penetration performance of the nail of a drug formulation can be easily adjusted by choosing an appropriate level of penetration enhancer. Figure 12 shows the amount of rniconazole nitrate penetrating through the nail plate 1, as well as the amount retained in the nail plate 1. The substantial amount of the drug retained in the nail reflects the kerati nature of. micicazole ilica. c- Formulation stability of itraconazole containing N-acetyl-1-cysteine as a penetration enhancer of the nail and urea as a penetration synergist An accelerated stability test on formulation # 41 shows that at 99.46% of initial itraconazole in the formulation remained intact after 13 weeks at 50 ° CX, indicating that the itraconazole in the formulation is sufficiently adequate to meet the storage life requirement 2 years at room temperature. d. Primary dermal irritation test The primary dermal irritation tests conducted in guinea pigs using two formulations of itraconazole at 1% (formulations # 97 and # 98) containing 1% and 5% acetylcysteine, respectively. The results show that these formulations satisfy the requirement co or topical therapeutic formulation. and. A specially designed nail medication assortment device and a two-stage regimen for topical antifungal therapy.

The sulfhydryl compounds are highly oxidizable by oxygen in the air, the stability of a nail penetration enhancer made of sulfhydryl during storage represents a problem. For this reason, an antifungal formulation containing the sulfhydryl penetration enhancer is preferably applied to the nail in a nail medication assortment device specially designed to maintain the potency of the nail. penetration enhancer of the nail. The device is designed to: (a) inhibit the sulfhydryl penetration enhancer from oxidation by oxygen in the air; (b) provide an occlusive environment for swelling of the nail to occur; (c) avoid direct skin contact of the sensitive eponychium with the sulfhydryl penetration enhancer; (d) adheres firmly to the nail and the surrounding skin with desired contour and flexibility; and (e) it is convenient for patients to use it. Urea tends to undergo a biuret reaction during storage, which could lead to a change in pH in the formulation. Since the solubility of some antifungal drugs such as itraconazole decreases as the pH of the formulation increases, the pH change would significantly reduce the dissolved form of itraconazole available for penetration, thus redicing its therapeutic efficacy. The problem of stability of the sulfhydryl nail penetration enhancer during storage and application, and the problem of pH variation due to urea, can be solved by using a nail medication assortment device designed as described below. . The nail medication assortment device comprises a bandage adapted for topical administration of medicament to the nail, said bandage comprising a T-shaped adhesive backing, and a flexible pad having a waterproof backing and a cavity in the form of nail, wherein said nail-shaped cavity contains absorbing means which have absorbed therein urea and sulfhydryl penetration enhancer, said compounds being a condition without water.

That is, the absorbing means is sufficiently free of water that the urea and the sulfhydryl penetration enhancer remain stable under ordinary storage conditions (at 25 ° C) for a reasonable storage life period, e.g., of at least six to twelve months. This device of assortment of medication for the nail includes penetration enhancer of sulfhydryl and urea dehydrated in its structure, separated from the antifungal drug formulation, thus greatly reducing the problem of instability. Figure 13 shows the assortment device 10 of medicament for the nail. The device includes a polyethylene flexible closed cell foam pad 14 (the pad is preferably coated with adhesive on the surface that will be in contact with the finger or toes whose nail is being treated) which includes a nail-shaped depression cavity defined by walls 12a-d and a backrest 16 (which can be a portion of the backrest adhesive 18). The depression contains a non-woven pad or a lyophilized porous layer 22 containing a predetermined amount of both nail penetration enhancer made of sulfhydryl and urea. (In view of the pad or layer 22, other conventional absorption means for storing the urea and the nail penetration enhancer made of sulfhydryl can be used). This pad or layer 22 serves as a drug reservoir. The waterproof backing 16 helps keep moisture in and oxygen out. The adhesive backing 18 is arranged to form a T-shaped bandage 10, which secures the nail medication assortment device 10 containing the drug formulation on the tip of the finger 20. The medication assortment device 10 is preferably stored in a metallic laminate bubble pack (not shown), which can be filled with an inert gas such as N or argon, to help ensure the storage life of the nail penetration enhancer made of sulfhydryl as well as urea. During a clinical application, a stable itraconazole formulation that did not contain as much cremonate nail penetration made of sulfhydryl as of urea, and packaged in a conventional tube, is loaded to the drug reservoir 22 of the device by application to the surface of the non-woven pad or lyophilized porous layer (or other means of absorption). The N-acetyl-i-cysteine Cu other compound of Formula (1) 1 and urea immediately dissolve in the drug formulation, and exert their penetration enhancing effect on the nail 20, when applied to the nail during the treatment. Another advantage of the device for the nail containing the enhancer is its universal utility for any antifungal drug formulation. Since the combination of both the nail penetration increment made of sulfhydryl and urea has a prolonged effect on the nail treatment regimen for the antifungal drug, a two-step antifungal treatment regimen can be employed. The first stage consists of an initial treatment period (e.g., 1-3 weeks) with a topical antifungal formulation and a nail drug assortment device, which contains both a nail penetration enhancer made of sulfhydryl and urea. As described above, the nail drug assortment device is designed in such a way as to provide occlusive conditions, i.e., exclusion of oxygen to increase the stability of the nail penetration enhancer, and moisture retention to maximize the water content of the nail, to promote the high penetration of the drug. By the end of the first stage of treatment, the permeability of the nail to the amtimycotic drug has increased significantly, and a sufficient amount of antifungal drug has reached the target sites (ie, nail plate 1, nail bed). 2 and matrix of the nail 3) to exert the antifungal action. The strong binding between some antirnicotic drugs (eg, itraconazole and rniconazole) and the nail keratin will likely result in a concentration of drug in the nail significantly above its therapeutic level for a prolonged time. The second stage of the treatment is a maintenance therapy that involves periodic applications of antifungal formulation without the penetration enhancer and urea. (This is possible because the urea acts to prevent the keratin from returning to its densely packed original interlaced state, thus maintaining the permeability of the nail to the antifungal drug formulation). The simplified procedure of the maintenance stage is well accepted by the patient, so it will help patients to apply it in the long term. The following representative formulations of antifungal, penetration enhancer and urea drug which are suitable for use in the invention: FORMULATION 0 (% p / p) Rniconazole nitrate. 2.0% Propylene carbonate 35.0% Propylene glycol 10.0% EDTR 0.1% Urea 20.0% 1-cysteine • 10.0% Purified water 22.9% Adjusting the pH to 8.00 with NaOH aq. 50% Note: formulations containing rniconazole nitrate can have pH values of about 3 to about 9.

FORMULATION B (H 8) (% p / p) Miconazole Nitrate 1.0% Propylene Carbonate 20.0% Propylene glycol 10.0% EDTA 0.1% Urea 20.0% 1-cysteine 10.0% Isopropyl alcohol 10.0% Adjust the pH to 8.00 with NaOH aq. 50% CS with distilled water at 100% (approx 28%) FORMULATION C (pH 9) (% w / w) Miconazole Nitrate 1.0% Propylene carbonate 20.0% Propylene glycol 10.0% EDTA 0.1% Urea 20.0% 1-cysteine 10.0% .isopropyl alcohol 10.0% Adjustment of pH to 9.00 with NaOH aq. 50% CS with distilled water at 100% (approx 28%) FORMULATION D (pH 8) (% w / w) Miconazole Nitrate 1.0% Propylene carbonate 20.0% Propylene glycol 10.0% EDTA 0.1% Urea 20.0% N-acetyl-1-cysteine 10.0% Isopropyl alcohol 10.0% Adjust the pH to 8.00 with NaOH aq. 50% CS with distilled water at 100% (approx 28%) FORMULATION E (H 9) (% p / p) Miconazole Nitrate 1.0% Propylene carbonate 20.0% Propylene glycol 10.0% EDTA 0.1% Urea 20.0% N-acetyl-1-cysteine 10.0% Isopropyl alcohol 10.0% PH adjustment at 9.00 with NaOH aq. 50% CS with distilled water at 100% (approx 28%) FORMULATION F (CREAM) (% p / p) BHA, NF 1.0 Miconazole Nitrate, USP 2.0% Mineral Oil, USP (heavy) 3.0% Oleate of peglicol 5 (LABRAFIL M 1944 CS) 3.0% Stearate of pegoxol 7 (TEFOSE 63) 20.0% EDTA 0.1% Urea 20.0% N-acetyl-1-cysteine 10.0% Adjust the pH to 8.00 with NaOH aq. 50% CS with purified water (USP) at 100% (approx 28%) FORMULATION G (CREAM) (% w / w) Benzoic acid, USP 0.2000% BHA, NF 0.0052% Miconazole Nitrate USP 2.0000% Mineral oil, USP (heavy) 3.0000% oleate polyglycol 5 (Labrafil M 1944 CS) 3.0000% Pegoxol stearate 7 (TEFOSE 63) 20.0000% Purified water, USP 71.7948% pH 3-4 The following are formulations containing itraconazole: FORMULATION H (H 3) (% p / p) Itraconazole 1.0% Propylene carbonate 35.0% Propylene glycol 16.5% EDTA 0.1% Urea 10.0% N-Acetyl-1-cysteine 5.0% Salicylic acid 5.0% BHT 0.05% pH adjustment to 3.0 with NaOH at 0.1N CS with distilled water at 100% (approx 25%) Note: formulations containing i traconazole. preferably they have a relatively low pH, such as about 2 to 4, to increase the solubility of itraconazole in the formulation.

FORMULATION I (pH 3) (% w / w) Itraconazole 1.0% Propylene carbonate 35.0% Propylene glycol 14.0% EDTA 0.1% Urea 10.0% N-Acetyl-1-cysteine 5.0% Salicylic acid 5.0% BHT 0.05% Adjust the pH to 3.0 with NaOH at 0.1N C? with distilled water at 100% (approximately 27.5%) FORMULATION 3 (pH 3) (% w / w) Itraconazole 1.0% Propylene carbonate 35.0% Propylene glycol 10.0% Urea 10.0% Acetylcysteine 5.0% EDTA 0.1% dietary BHT 0.1% Klucel 2.0% PH adjustment to 3 with HC.1 to 0.1N Water C.S. 100.0% FORMULATION K (pH B) (% w / w) Itraconazole 1.0% Propylene carbonate 35.0% Propylene glycol 10.0% Urea 10.0% Acetylcysteine 5.0% Disodium EDTA 0.1% BHT or .1% Klucel 2.0% Adjustment of pH to 3 with HCl to 0.1N Water C.S. 100.0% FORMULATION L Weight Itraconazole 50 rng Propylene carbonate 350 rn Propylene glycol 100 g Urea 200 rng N-Acetyl-l-cysteine 50 rng Hydroxypropylcellulose 20 rng EDTA (Na salt 1 mg BHT 0.5 mg conc. HCl for pH 3 Purified water C.S. 1000 ing Formulations containing about 10 to 50% (by weight) propylene carbonate (4-methyl-l, 3-dioxolan-2-one) and about 5 to 30% of propylene glycol are desirable because itraconazole and other Anti -nicnic compounds which have low solubility in water are soluble in said formulations. These compounds also help to increase the penetration of the an irnicotic drug to the nail.

Tips for treatment with volunteers: 1: A 57-year-old woman had onychomycosis of her left thumb nail for approximately 20 years. The plate of the affected nail 1 had a characteristic grooved irregular surface. A topical formulation containing 1% itraconazole, 5% cysteine and 10% urea and other pharmacological excipients (similar to Formulaci, -on H) was applied to the nail, under clogged conditions, daily for seven days. At the same time, a similar formulation was applied, but without acetylcysteine, to the skin surrounding the nail. A follow-up of six months showed that the nail was clinically cured. The newly grown nail had a normal healthy appearance. 2: A 32-year-old woman had onychomycosis of the toenails of both toes for approximately 8 years. The affected nails had significantly thickened nail plates and a dark gray color. A topical formulation containing 1% itraconazole, 5% cysteine and 10% urea and other pharmacological excipients (similar to Formulation 3) was applied to the nail, under clogged conditions, daily for seven days. After the initial treatment, a similar formulation was applied, but without acetylcysteine, to the nail under obstruction for two more weeks. A follow-up of six months showed that the nails improved clinically. The newly grown nails returned to their normal thickness, and the gray area of the nails was significantly reduced.

Claims (37)

1. NOVELTY OF THE INVENTION
3. A method for treating nail disease in the nails, comprising topical administration to the affected nail, or to the affected nail and the surrounding skin, of: 1) a compound represented by the formula (I):
4. HS- (CH) CH-R (I) pharmaceutically acceptable salts or esters thereof, and stereoisomers thereof, wherein: R = H, CONHCHCOOH, NH or COOR wherein R is H or C alkyl; R • - H, COCH, CONH, or CO (CH) CHINH) (COOH) where rn is 1 or 2; and n • --- a number that has a value of 1 to 4; and 2) urea; and 3) an effective amount of an antifungal drug, (1) and (2) administered in an amount sufficient to increase the penetration of antifungal drugs through the nail tissue, and (1) and (2) administered either before or concurrently with topical administration to the nail of said antifungal drug. 2. The method according to claim 1, further characterized in that the compound represented by the formula (I) is selected from the group consisting of 1-cysteine, cysteine, d-cysteine, dl-cysteine, N-acetyl-1 ~ cysteine, di-ho or cysteine, 1-cysteine methyl ester, 1-cysteine ethyl ester, N-carbamoylcysteine, glutathione and cysteamine. 3. The method according to claim 2, further characterized in that the compound represented by the formula (I) is N-acetyl-1-cysteine or cieteine. 4. The method according to claim 1, further characterized in that the antifungal drug is selected from the group consisting of miconazole, ketoconazole, itraconazole, fluconazole, econazole, cyclopirox, oxiconazole, clotri azole, terbinafine, naftifine, pharmaceutically acceptable salts of the same and stereoisomers thereof.
5. 5. The method according to claim 2, further characterized in that the antifungal drug is selected from the group consisting of miconazole, ketoconazole, itraconazole, fluconazole, econazole, ciclopirox, oxiconazole, clotrimazole, terbinafine, naftifine, pharmaceutically acceptable salts of the same and stereoisomers thereof.
6. 6. The method according to claim 3, further characterized in that the antifungal drug is selected from the group consisting of miconazole, ketoconazole, itraconazole, fluconazole, econazole, ciclopirox, oxiconazole, clotrirnazole, terbinafine, naftifine, pharmaceutically acceptable salts of the same and stereoisomers thereof.
7. 7. The method according to claim 4, further characterized in that the antifungal drug is selected from the group consisting of miconazole, ketoconazole, .itraconazole, pharmaceutically acceptable salts thereof and stereoisomers thereof.
8. 8. The method according to claim 5, further characterized in that the antifungal drug is selected from the group consisting of miconazole, ketoconazole, itraconazole, pharmaceutically acceptable salts thereof and stereoisomers thereof.
9. 9. The method according to claim 6, further characterized in that the antifungal drug is selected from the group consisting of rniconazole, ketoconazole, itraconazole, pharmaceutically acceptable salts thereof and stereoisomers thereof.
10. 10. The method according to claim 1, further characterized in that the compound of the formula (I) is N-acetyl-1-cysteine or cysteine and the antifungal drug is itraconazole.
11. 11.- The method according to the claim 1, further characterized in that the compound of the formula (I), the urea and the antifungal drug are administered to the nail under occlusive conditions.
12. 12. The method according to the claim 2, further characterized in that the compound of the formula (I), the urea and the antifungal drug are administered to the nail under occlusive conditions.
13. 13.- The method according to the claim 3, further characterized in that the compound of the formula (I), the urea and the antifungal drug are administered to the nail under occlusive conditions.
14. 14. The method according to the claim 4, further characterized in that the compound of the formula (I), the urea and the antifungal drug are administered to the nail under occlusive conditions.
15. 15.- The method according to the claim 5, further characterized in that the compound of the formula (I), the urea and the antifungal drug are administered to the nail under occlusive conditions.
16. 16. The method according to the claim 6, further characterized in that the compound of the formula (I), the urea and the antifungal drug are administered to the nail under occlusive conditions.
17. 17.- The method according to the claim 7, further characterized in that the compound of the formula (I), the urea and the antifungal drug are administered to the nail under occlusive conditions.
18. 18. The method according to claim 8, further characterized in that the compound of the formula (I), the urea and the antifungal drug are administered to the nail under occlusive conditions.
19. 19. The method according to claim 9, further characterized in that the compound of the formula (I), the urea and the antifungal drug are administered to the nail under occlusive conditions.
20. 20. - The method according to claim 10, further characterized in that the compound of the formula (I), the urea and the antifungal drug are administered to the nail under occlusive conditions.
21. 21. A bandage adapted for topical administration of the medicament to the nail, said bandage comprising a backing of T-shaped adhesive, and a flexible pad backed by said impermeable backing, wherein said nail-shaped cavity contains absorbing means that they have absorbed in them urea and a compound of formula (I) H? - (CI-I) CH-R (I) NHR pharmaceutically acceptable salts or esters thereof, and stereoisomers thereof, wherein: R • - H, C0NHCHC00H, NH or COOR wherein R is H or C alkyl; R = H, COCH, CONH, or C0 (CH) CH (NH) (COOH) wherein m is 1 or 2; and n = a number having a value from 1 to 4.
22. 22. The compliance bandage of claim 21, further characterized in that the urea and the compound of the formula (I) contained in said absorbing means are anhydrous.
23. 23. A composition comprising (1) a compound represented by the formula (I): HS- (CH) CH-R (I) NHR pharmaceutically acceptable salts or esters thereof, and stereoisomers thereof, wherein: R = H, C0NHCHC0OH, NH or COOR wherein R is H or C alkyl; R = H, COCH, CONH, or CO (CH) CH (NH) (COOH) where is 1 or 2; and n = a number that has a value of 1 to 4; and 2) urea; and 3) an effective amount of an antifungal drug, (1) and (2) administered in an amount sufficient to increase the penetration of antirnic drugs through the nail tissue.
24. 24. The composition according to claim 23, further characterized in that the compound represented by the formula (I) is selected from the group consisting of 1-cysteine, cysteine, d-cysteine, dl-cysteine, N-acetyl-1 -cysteine, di -hornocietein, 1-cysteine methyl ester, 1-cysteine ethyl ester, N-carbamoylcysteine, glutathione and cysteamine.
25. 25. The composition according to claim 24, further characterized in that the compound represented by the formula (I) is N-acetyl-cysteine or cysteine.
26. 26. The composition according to claim 23, further characterized in that the antifungal drug is selected from the group consisting of miconazole, ketoconazole, itraconazole, fl? Conazole, econazole, teraconazole, saperconazole, arnorolfma, ciclopirox, oxiconazole, clotpomazole. , terbmafine, naftifine, pharmaceutically acceptable salts thereof and stereoisomers thereof.
27. 27. The composition according to claim 24, further characterized in that the antirnic drug is selected from the group consisting of niconazole, ketoconazole, itraconazole, fluconazole, econazole, teraconazole, saperconazole, orolfin, ciclopirox, oxiconazole., clot prnazol, terbmafme, naftifine, pharmaceutically acceptable salts thereof and stereoisomers thereof.
28. 28. The composition according to claim 25, further characterized in that the antifungal drug is selected from the group consisting of miconazole, ketoconazole, itraconazole, fluconazole, econazole, teraconazole, saperconazole, arnorolfine, ciclopirox, oxycodone, clotrirnazoi, terbmafine, naftifine , pharmaceutically acceptable salts thereof and stereoisomers thereof.
29. 29. The composition according to claim 26, further characterized in that the antifungal drug is selected from the group consisting of rniconazole, ketoconazole, itraconazole, pharmaceutically acceptable salts thereof and stereoisomers thereof.
30. 30. The composition according to claim 27, further characterized in that the antifungal drug is selected from the group consisting of miconazole, ketoconazole, itraconazole, pharmaceutically acceptable salts thereof and stereoisomers thereof.
31. 31. The composition according to claim 28, further characterized in that the antifungal drug is selected from the group consisting of niconazole, ketoconazole, itraconazole, pharmaceutically acceptable salts thereof and stereoisomers thereof.
32. 32. The composition according to claim 23, further characterized in that the compound of the formula (I) is N-acetyl-cysti.i.na or cysteine and the antifungal drug is itraconazole.
33. 33. The composition according to claim 23, further characterized in that said composition contains propylene carbonate and propylene glycol.
34. 34. The composition according to claim 33, further characterized in that the antifungal compound is itraconazole.
35. 35.- The composition comprising propylene carbonate, propylene glycol and an antifungal drug.
36. 36. The composition according to claim 35, further characterized in that the antifungal drug is selected from the group consisting of miconazole, ketoconazole, itraconazole, pharmaceutically acceptable salts thereof and stereoisomers thereof.
37. 37. The composition according to claim 35, further characterized in that the antifungal compound is itraconazole.