JP2012519669A - Method for dissolving an antifungal agent and a composition comprising a high concentration of an antifungal agent suitable for application to the nail - Google Patents

Abstract

  The invention relates to an antifungal agent derived from the class of allylamine or morpholine, at a concentration of at least 5%, water, at least one branched or straight chain C2-C8 alkanol, a ternary solvent comprising at least one glycol A pharmaceutical composition comprising a system is provided wherein the total amount of water represents more than 30% (w / w) of the composition. This composition is intended for application to the nail to treat onychomycosis.

Description

  The present invention relates to the development of a ternary solvent system comprising water, which makes it possible to dissolve antifungal agents from a substantial amount of allylamine class or morpholine class. This invention makes it possible to prepare a composition specifically adapted for application to the nail, which is optionally chemically or physically perforated or pretreated.

  This type of pharmaceutical or skin composition is particularly useful for the treatment of onychomycosis, particularly onychomycosis caused by dermatophytes or Candida in humans and animals.

  Antifungal agents from the allylamine class, in particular terbinafine or naphthifine, and antifungal agents from the morpholine class, in particular amorolfine, are promising compounds in antifungal control. Their putative or proven mode of action involves, in particular, inhibition at the level of ergosterol, a specific component of the fungal cell wall, through inhibition of squalene epoxidase ("Terbinafine: Mode of action and properties of the squalene epoxidase inhibition, British Journal of Dermatology, Vol. 126, s39, pp. 2-69 (February 1992); `` Preclinical data and mode of action of amorolfine '', Dermatology, 1992, 184, SUP1 (10 ref.), Pages 3-7).

  Traditionally, antifungal agents have been administered either topically or orally.

  By the oral route, terbinafine administered at a level of 250 mg / day over 6 months has been found to be effective and low toxic in the treatment of onychomycosis caused by Trichophyton rubrum. However, this type of treatment raises time and cost issues and may have side effects affecting the digestive area, taste disorders, or transient skin rashes (GUPTA A, LYNDE C, LAUZON G Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature. Br J Dermatol, 1998, 138: 529-532).

  Depending on the topical route, transungual administration represents an alternative solution to oral administration to treat onychomycosis. However, the challenge that arises when administered to the nail is to ensure penetration and diffusion of the antifungal agent in the nail and to obtain a therapeutically effective concentration in and under the nail, in other words, in the nail bed. Is to make it possible.

  The nail itself is essentially made of keratin, a fibrous protein that is actually insoluble but has an affinity for water. Thus, the nails are considered to be hydrophilic in nature, that is, the nails behave like a hydrogel. As a result, it may seem essential to formulate an antifungal agent in water for trans-nail application. However, water itself exhibits little ability to diffuse into the nails, and furthermore has difficulty in compatibility with the above-mentioned antifungal agents, particularly terbinafine, which are intended to be almost insoluble in water.

  Among all the technical solutions proposed for antifungal trans-nail formulations in the prior art, the solution used was an aqueous-alcoholic mixture solution by addition of polymers.

  As an alternative, the document EP 0 503 988 describes an aqueous-alcoholic medium, a hydrophilic penetrant previously known and used to promote the transdermal penetration of active agents through the stratum corneum of the skin. Proposed to be mixed with. This stratum corneum is oleophilic and acts as a water barrier.

  However, even in the presence of such hydrophilic penetrants, the proportion of water in the composition described in document EP 0 503 988 never exceeds 30% of the total weight of the composition.

EP 0 503 988

`` Terbinafine: Mode of action and properties of the squalene epoxidase inhibition '' British Journal of Dermatology, Vol. 126, s39, pp. 2-69 (February 1992) `` Preclinical data and mode of action of amorolfine '', Dermatology, 1992, 184, SUP1 (10 ref.), 3-7 GUPTA A, LYNDE C, LAUZON G et al. Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature.Br J Dermatol, 1998, 138: 529-532.

  Accordingly, there is a need to find new formulations for antifungal agents that allow improved diffusion of effective amounts of active ingredients through the nails.

  The present invention includes the ability to dissolve significant amounts of antifungal agents, including water, the potential for large amounts of water, and effectiveness in and through keratinized ungual tablets of nails Proof of a ternary solvent system that combines the ability for effective diffusion and effective penetration.

  “Large amount of water” means the total amount of water in the composition that is greater than 30% by weight relative to the total weight of the composition.

More specifically, the present invention takes the form of a solution,
-First, an effective amount of at least one antifungal agent;
-A nail comprising a solvent medium for said antifungal agent composed of a mixture of water, at least one branched or straight chain C2-C8 alkanol, and at least one glycol having a free hydroxyl function Skin compositions intended for the treatment of mycosis are provided.

  Such a composition has a total water (w / w) of more than 30% by weight, advantageously more than 33%, or even more than 35%, based on the total weight of the composition, or In fact, it is characterized by over 40%.

  In the context of the present invention, an “effective amount” of at least one antifungal agent is a substantial amount of said agent in the composition. It is clear that solubility problems in solvent media, and more particularly in water, arise for a considerable amount of this species.

  In practice, a substantial amount of antifungal agent, as defined below, is greater than 5% of the total composition, or even at least 8%, or indeed at least 10% (w / It corresponds to w). Thus, it is possible to envision up to 15% or 20% of this drug in the composition.

  Of course, it is of course possible to envisage a mixture of antifungal agents from different classes.

  As already mentioned, the antifungal agents of interest which are the target of the present invention in more detail are antifungal agents derived from the allylamine class and the morpholine class, the allylamine class being preferred.

  Within the class of allylamines, mention may be made in particular of terbinafine and its acid salts and naphthifine and its acid salts. Among the acid salts, terbinafine hydrochloride and naphthifine hydrochloride are selected, and their respective formulas are as follows:

  Of the molecules from this class, terbinafine is selected.

  As an alternative, antifungal agents may belong to the morpholine class, in particular amorolfine and its acid salts, in which case the same problem of solubility in water arises.

  As indicated above, the present invention is based on the proof of a ternary solvent system that contains water and shows a synergistic effect in dissolving the antifungal agent of interest.

This system is
Water known to be a very poor solvent for antifungal agents derived from the allylamine class or the morpholine class;
-Single chain alcohols, and more particularly at least one branched or straight chain C2-C8 alkanol (these alcohols may be solvents for antifungal agents derived from the allylamine class or the morpholine class. Are known);
-Contain at least one glycol.

  A very poor solvent is a solvent that allows dissolution of 1% (w / w) or less of an antifungal agent derived from the allylamine class or the morpholine class.

  Notably, therefore, the inventors have shown that this combination of three solvents, including water, shows a synergistic effect in dissolving the antifungal agent of interest, thereby dissolving a significant amount of the antifungal agent. It proved to be possible to increase the amount of water in the mixture, while making it possible at the same time.

  As already mentioned, it should be noted that the total amount of water is greater than 30% by weight, advantageously greater than 33%, or even greater than 35%, based on the total weight of the composition (w / w). Or actually more than 40%. As a result, the total water amount advantageously corresponds to more than one third of the ternary solvent mixture.

  The total amount of water means the amount of water that is itself introduced into the composition plus the amount of water from various solvents and / or excipients in the composition containing water.

  On the other hand, the total water amount advantageously corresponds to less than 60% or even less than 50% of the total composition amount.

  The second entity in this ternary system is a short chain alcohol, more specifically at least one branched or straight chain C2-C8 alkanol, preferably ethanol, isopropanol and n-butanol. Ethanol is particularly preferred. Mixtures of different alcohols may also be contemplated.

  Finally, the ternary solvent system contains at least one glycol. The glycol here is a compound having at least two hydroxyl functions. The present invention relates more particularly to glycols whose two hydroxyl functions are free, ie not involved in ether and ester linkages. Such glycols include, for example, propylene glycol, butylene glycol, hexylene glycol, ethylene glycol and polyethylene glycol. Propylene glycol is preferred. Mixtures of different glycols may also be contemplated.

  Advantageously, the ternary solvent system represents at least 60%, or even 70%, 80%, or indeed 90% (w / w) of the total composition amount.

  Furthermore, advantageously the proportion of alcohol is greater than or equal to the proportion of glycol.

  Even more advantageously, the total proportion of water is greater than the total proportion of glycol.

  Generally speaking, the pharmaceutical composition or skin composition according to the invention takes the form of a solution. It can be equally formulated as a lotion, spray, emulsion, foam or gel, advantageously a fluid.

The composition according to the invention comprises:
Preservatives such as phenylethyl alcohol, benzyl alcohol and phenoxyethanol, parabens and derivatives;
-Antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), palmityl ascorbate, α-tocopherol and / or its esters;
-Dyes, fillers or pigments such as titanium mica commonly used in the cosmetics field to produce nail polish;
-Polymers capable of preventing the flow of the composition prior to penetration, such as, for example, alkylcellulose derivatives, in particular hydroxy-alkylcellulose such as methylcellulose, ethylcellulose and those sold under the name `` KLUCEL '';
-Chelating agents such as disodium edetate (EDTA);
-Softeners such as cyclomethicone;
-Disinfectants, in particular at least one additive selected from the group consisting of acetic acid or chlorhexidine may be included.

  The amount of each of these additives is readily determined by those skilled in the art.

  As already mentioned, the composition according to the invention is particularly adapted for the treatment of onychomycosis trans-nails. Therefore, application to the surface of the nail is intended.

The solubility of terbinafine HCl is shown.

(Example)
The invention and its attendant advantages will emerge more clearly from the working examples that follow. However, in any case, these examples are not limiting.

In these examples, the following compounds were tested:
-Antifungal agent = terbinafine hydrochloride (terbinafine HCl);
-Water = purified water;
-Alcohol = ethanol;
-Glycol = propylene glycol.

1 / Demonstration of synergy of ternary solvent system for dissolution of antifungal agent:
Different solubility tests for terbinafine HCl were performed with different solvent systems. Solubility was both estimated visually by Method 1 below and then quantified by HPLC assay according to Method 2 below.

Method 1: Dissolution of terbinafine HCl Terbinafine HCl is accurately weighed into a 20 ml flask and then the solvent is added. Subsequently, the flask is placed in a chamber thermostatted at 20 ° C. for 16 hours with magnetic stirring. If some of the active ingredient does not dissolve, additional solvent is added. The flask is then re-entered with magnetic stirring into the auto-controlled chamber for 16 hours until dissolution is complete. If not, repeat the previous step.

Method 2: Preparation of terbinafine quantification solution by HPLC:
Diluted solution:

Stock solution A (300 μg / ml)
Precisely weigh approximately 15 mg of terbinafine HCl into a 50 ml volumetric flask. Dissolve in diluent and make up to volume with the same solvent. Prepare solutions in duplicate (A1, A2)
Daughter solution (60 μg / ml)
Dilute solution A 1/5 in diluent. Dilution A1 => STD1, Dilution A2 => STD2
Standard range A standard range is created by varying the injection volume of solution A at an equivalent concentration of 4 μg / ml to 120 μg / ml.

Sample solution
Two tests are prepared per sample at concentrations from 40 μg / ml to 100 μg / ml.

Operating conditions Eluent phase

Chromatographic system parameter column: Sun Fire C18 with precolumn attached 4.6 x 100 mm 3.5 μm
Column temperature: 30 ° C
Flow rate: 1.5 ml / min Injection volume: 30 μl for sample solution
Analysis time: 10 minutes
Detection gradient at 285 nm:

Chromatographic compatibility test Six injections of the control solution STD and measure the following parameters at the peak of the active ingredient being assayed:

-Inject an empty sample (diluent) and check that the peak of the empty sample does not interfere with terbinafine HCl.
-Inject solutions STD1 and STD2 and check that the% deviation between the two controls is <2%.

A / Binary solvent system:
A-1 / Ethanol / Propylene glycol
-In ethanol, the visual solubility of terbinafine HCl is 19.7% w / w, confirmed by HPLC assay to be 18.09% w / w;
-In propylene glycol, the visual solubility of terbinafine HCl is 8.9% w / w, confirmed by HPLC assay to be 10.3% w / w;
In a -50/50 ethanol / propylene glycol mixture, the visual solubility of terbinafine HCl is 23.3% w / w, which is confirmed by HPLC assay to be 20.4% w / w.

  In conclusion, propylene glycol is not as good a solvent for terbinafine HCl as ethanol, but the solubility obtained in the binary mixture is slightly greater than that obtained in ethanol. According to the additive effect, the expected solubility of terbinafine HCl would have been around 14%. The fact that a solubility of around 20% was measured demonstrates the existence of a synergistic effect in the dissolution of terbinafine HCl between propylene glycol and ethanol.

A-2 / water / ethanol The visual solubility of terbinafine HCl in water is 0.6% w / w.

  In the case of a binary water / ethanol mixture (50/50), the visual solubility of terbinafine HCl is 16.7% w / w, in other words, less than that obtained with ethanol alone.

In the case of A-3 / water / propylene glycol binary water / propylene glycol mixture (50/50), the visual solubility of terbinafine HCl drops to 2.2% w / w, i.e. slightly less than the solubility obtained with propylene glycol alone. Low.

  In conclusion, in binary water / propylene glycol and water / ethanol mixtures, water reduces the solubility of terbinafine HCl compared to the solubility obtained in propylene glycol and ethanol, respectively.

B / Ternary solvent system:
Surprisingly, when 15% water was introduced into a mixture composed of 70% propylene glycol and either 15% ethanol or 70% ethanol and 15% epropylene glycol, the visual solubility of terbinafine HCl increased. Reach 25.0% w / w and 25.2% w / w respectively.

  In conclusion, unlike any expectation, the introduction of water (appropriate amount up to 100%) into a binary propylene glycol / ethanol mixture (70/15 or 15/70) is that water is a poor solvent for terbinafine HCl. Despite this, surprisingly, the solubility of terbinafine HCl was increased. Therefore, there is a synergistic effect on the solubility of terbinafine HCl in the ternary mixture of propylene glycol / ethanol / water.

  In order to approach the optimal conditions for nail application, i.e., a large amount of water and at least 10% terbinafine HCl in the pharmaceutical composition, then the amount of water is then reduced to an equivalent amount of propylene glycol 35% and ethanol 35%. Increased to 30% in presence.

  Under these conditions, the visual solubility of terbinafine HCl is 18.5% w / w, i.e. well above 10%, which is the concentration deemed optimal with respect to the biological activity of the active ingredient.

  When the amount of water was increased to 33% in the presence of equivalent amounts of propylene glycol (33%) and ethanol (33%), the visual solubility of terbinafine HCl was 15.5% w / w, i.e. 10% Still above.

  In conclusion, the water that is desirable to provide moisture to the nail in the intended application and thus promote improved diffusion of the antifungal agent within the nail matrix is also due to its insufficient solubility in this antifungal agent. Regardless, it appears to be possible to increase the solubility of terbinafine HCl. This increase in solubility depends on the combination of propylene glycol and ethanol.

  As already seen above, in binary water / propylene glycol or water / ethanol mixtures, water reduces the solubility of terbinafine HCl. Thus, only the water / propylene glycol / ethanol ternary mixture combination makes it possible to increase the solubility of terbinafine HCl. Thus, the solubility of terbinafine HCl was found to be greater than 10% in a water / propylene glycol / ethanol ternary mixture containing at least 30% water (Graph 1).

  The solubility of terbinafine remains greater than 10% at 40% water, provided that the amount of ethanol is at least greater than the amount of propylene glycol.

  In this way it is possible to dissolve at least 10% terbinafine HCl, in which the total amount of water is at least the amount of water required to obtain an improved diffusion of terbinafine in the nail matrix It became possible to define the ratio of ternary mixture of propylene glycol / ethanol / water which is 30%.

2 / Composition based on ternary solvent system:
The ternary solvent system as defined made it possible to produce a variety of formulations containing significant amounts of terbinafine HCl without solubility problems. The examples below are given for illustration and are in no way limiting.

  For each example, the recipe is expressed as a function of the percentage of each ingredient used in the sales state (first column).

  The formulation is also expressed by taking into account the water present in each component. In this case, the% corresponding to the ingredient is considered to be added up to 100% (second column).

The formulation is prepared by the following procedure:
Step 1: Dissolve hydroxytoluene in ethanol.
Step 2: Once the butylated hydroxytoluene is completely dissolved,
Propylene glycol purified water
EDTA
In order,
Stir until complete solubilization of EDTA.
Step 3: Add terbinafine HCl to the mixture obtained in step 2.
Stir until complete solubilization.

(Example 1)

Physical and chemical stability was measured over 3 months at room temperature and 40 ° C.
Physical stability:
Specification at T0 Macroscopic appearance: Clear, colorless liquid Microscopic appearance: No terbinafine HCl crystals

Chemical stability:

(Example 2)

Physical and chemical stability was measured over 3 months at room temperature and 40 ° C.
Physical stability:
Specification at T0 Macroscopic appearance: clear, colorless, slightly viscous solution Microscopic appearance: no terbinafine HCl crystals

Chemical stability:

Example 3

Example 4

(Example 5)

  By using a ternary mixture of propylene glycol / ethanol / water at certain ratios, we can obtain terbinafine HCl solubility much greater than that obtained using each solvent separately. certified.

  This propylene glycol / ethanol / water ternary mixture thus shows a synergistic effect in dissolving terbinafine HCl at the ratio used.

  Based on this ternary mixture of propylene glycol / ethanol / water, it is possible to produce a stable composition containing at least 30% total water while allowing solubilization of terbinafine HCl content of 10% w / w. It was possible.

Claims (9)

An antifungal agent derived from the class of allylamine or morpholine at a concentration of at least 5%;
A ternary solvent system, including: water;
At least one branched or straight chain C2-C8 alkanol;
Contains at least one glycol,
A pharmaceutical composition, wherein the total amount of water represents more than 30% of the composition.   The pharmaceutical composition according to claim 1, characterized in that the antifungal agent is terbinafine or one of its acid salts.   3. The pharmaceutical composition according to claim 2, wherein the terbinafine acid salt is terbinafine hydrochloride.   4. The pharmaceutical composition according to claim 1, wherein the concentration of the antifungal agent is 8% or more, preferably 10% or more.   The pharmaceutical composition according to any one of claims 1 to 4, wherein the alkanol is ethanol.   The pharmaceutical composition according to any one of claims 1 to 5, wherein the glycol is propylene glycol.   7. A pharmaceutical composition according to any one of claims 1 to 6, characterized in that it takes the form of a lotion, spray, emulsion, foam or gel.   The medicament according to any one of claims 1 to 7, characterized in that it further comprises at least one compound selected from the following list: chelating agents, antioxidants, polymers, disinfectants, softeners. Composition.   Use of a pharmaceutical composition according to any one of claims 1 to 8 for the preparation of a medicament intended for application to the nail to treat onychomycosis.