ES2976036A1 - Enhancement of intraungual accumulation of active ingredients - Google Patents

Abstract

Enhancement of the intraungual accumulation of active ingredients. The main current problem for the treatment of nail infections is the limited effectiveness of the medications available on the market due to low absorption rates, which require very long treatments over time, with a large number of applications and there is, in addition, a high percentage of recurrences. A pharmaceutical composition and a kit are described to enhance the absorption of an active ingredient through the nail and inside it, which combines the inclusion of a transungual absorption promoter with micro-perforation of the nail, in order to to facilitate the absorption of the active ingredient through it and into the nail structure. The invention is useful in the treatment of fungal diseases, due to fungi and yeast, as well as bacterial infections and inflammatory processes of the nail unit. (Machine-translation by Google Translate, not legally binding)

Description

DESCRIPTION

Enhancement of intraungual accumulation of active ingredients

Technical sector

The present invention relates to a method for improving the absorption of an active ingredient at the nail level from a pharmaceutical composition. More specifically, it relates to the combination of a micro-perforation technique together with the application of a pharmaceutical composition for transungual application.

Background of the invention

The main problem that exists today for the treatment of nail infections, the main cause of which is fungus, is the low effectiveness of the medications available on the market, since the active ingredients they contain have very low absorption rates, which means that the treatments must be very long in time, implying a large amount of application of the formulation and, in addition, there is a high percentage of recurrences. This means that the elimination of all infectious agents is not guaranteed, which remain in the nail plate or bed, continuing the infection of the same.

In order to solve this problem of drug absorption through the nail, strategies have been developed to enhance such absorption of active ingredients into the nail. There are several strategies currently available to improve the passage of substances through the nail plate (Kreutz T. et al. “Recent Patents on Permeation Enhancers for Drug Delivery Through Nails”. Recent Pat Drug Deliv Formul. 2019; 13(3):203-218). One way to classify them is to distinguish between physical/mechanical methods (such as the use of files, occlusion, micro-perforation, iontophoresis, lasers, fractional, CO<2>) or chemical methods (solvents, keratolytic agents, compounds that break sulfide bonds, enzymes, or combinations of them).

Physical methods include etching and the use of microneedles, which result in the formation of pores and perforations that allow the penetration of the active ingredient. Thus, the transungual release of Ciclopirox has been studied, evaluating the effect of perforating the nail on the permeability of topical solutions of Ciclopirox at 8% w/v (Córdoba, D. et al. “Transungual Delivery of Ciclopirox Is Increased 3-4-Fold by Mechanical Fenestration of Human Nail Plate in an in Vitro Model. Pharmaceuticals, 2019 Jan 14:11 (1): 29).

Among the chemical compounds that have been used to enhance the absorption of active ingredients into the nail tissue is thioglycolic acid (Chouhan, P. et al. “Designing a Test for Nail Safety Evaluation to Select Nail-friendly Permeation Enhacers”. Indian Journal of Pharmaceutical Sciences 2018 July 80(4):694; Brown, M.B. et al. “Overcoming the nail barrier: A systematic investigation of ungual chemical penetration enhancement” . International Journal of Pharmaceutics 2008 November 370(1-2):61-7).

There are different mechanical techniques to improve the penetration of active substances topically, such as micro-perforation of nails creating channels that act as reservoirs (Gupta, A. K. et al. “Utility of devices for onychomycosis: a review”. J Dermatolog Treat. 2023 Dec.

34(1):2265658).

Despite the methods already described, the problem of recurrence of infections and inflammatory problems of the nail after treatment with commercial active ingredients still exists. Therefore, this invention proposes a new method of enhancing the absorption of an active ingredient through the human nail, and increasing the accumulation of the drug inside it, useful in the treatment of fungal, yeast and fungal diseases, as well as bacterial infections and inflammatory processes of the nail tissue.

Explanation of the invention

The present invention describes a method that combines the inclusion of a transungual absorption promoter based on a commercial lacquer containing an active ingredient, with prior treatment by micro-perforation of the nail, in order to facilitate the absorption of the active ingredient through it, allowing a greater accumulation of the active ingredient inside the nail structure.

A method of applying medicated lacquer is developed from a conventional medicated lacquer for the treatment of both infections of the nail tissue and the nail bed, caused by fungi or bacteria, as well as inflammatory processes in the nail unit, through the inclusion of an absorption enhancer.

This strategy is also combined with micro-perforation of the nail plate along the entire surface using equipment specially designed for this purpose (micro-drill), which avoids causing injury to the structure of the patient's nail plate. This equipment, which is authorised for use in clinical practice, makes perforations with a very precise diameter (less than 1 mm) and depth (not reaching the lowest layer of the nail layer, called the ventral layer).

Therefore, another aspect of the invention relates to a kit comprising a nail microperforator device, a pharmaceutical composition containing an anti-infective active ingredient and a compound that enhances transungual penetration and accumulation. These last two, the active ingredient and the enhancing compound, can be combined in a single pharmaceutical composition, or separated.

More specifically, the pharmaceutical composition is a conventional medicated lacquer containing Ciclopirox as the active ingredient and the absorption-enhancing agent is thioglycolic acid. The purpose of this combination is to facilitate the permeability of the nail plate, thereby increasing the capacity to introduce active ingredients between the complex keratin networks that compose it, thereby increasing the concentration of active ingredient within the target tissue (the nail plate).

The combination of the two absorption enhancement methods can be carried out in two different ways:

- After micro-perforation of the nail, it is pre-treated with thioglycolic acid, administering it through the pierced nail and, subsequently, the conventional medicated lacquer containing Ciclopirox is administered.

- After micro-perforation of the nail, a mixture of conventional medicated lacquer containing Ciclopirox and thioglycolic acid is administered.

When comparing the results obtained with these methods and applying conventional lacquer on a micro-perforated nail, contrary to what was expected, the absorption of the active ingredient is significantly faster with the lacquer in the absence of thioglycolic acid. However, the accumulation of active ingredient inside the nail tissue is greater when using thioglycolic acid. This suggests that the use of thioglycolic acid on a micro-perforated nail causes the disorganization of the keratin network of the entire transungual tissue, altering the absorption mechanism of the active ingredient that diffuses not only through the nail, but from the walls of the micro-pores to the internal structures of the nail and this effect represents a therapeutic advantage compared to other strategies where the active ingredient is retained for less time.

The method described not only eliminates the infectious agent that is colonizing the nail plate (since the active ingredient manages to reach the target tissue where the infection is located, reaching values higher than the minimum inhibitory concentration to eradicate the fungus) but also creates a pharmacological barrier against the advance of the infectious agent (since the active ingredient manages to migrate through the plate and is retained throughout the entire length of the nail plate), thus preventing the proliferation and dissemination of the infection. This accumulation of active ingredient can also act as a drug reservoir, so that, in addition to acting as a pharmacological barrier, it can also reduce the duration of topical treatment, overcoming the current drawback of long-term treatments and a high rate of reinfection.

Brief description of the drawings

To complement the description being made and in order to help better understand the characteristics of the invention, a set of drawings is included as an integral part of said description, in which the following has been presented for illustrative and non-limiting purposes:

Figure 1. Average amount of Ciclopirox accumulated (in pg) as a function of time comparing: (a) the commercial lacquer applied directly on a previously micro-perforated nail, (b) the lacquer on a previously micro-perforated nail pre-treated with enhancer; and (c) the lacquer with enhancer on a previously micro-perforated nail.

Figure 2. Transungual absorption rate, comparing: (a) commercial lacquer applied on a micro-perforated nail, (b) lacquer on a micro-perforated nail pre-treated with absorption enhancer, (c) lacquer with absorption enhancer on a previously micro-perforated nail. Figure 3. Average amount of active ingredient retained in the nail comparing: (a) commercial lacquer applied directly on a previously micro-perforated nail, (b) lacquer on a previously micro-perforated nail pre-treated with enhancer; and (c) lacquer with enhancer on a previously micro-perforated nail.

Preferred embodiment of the invention

The present invention is illustrated by the following examples, which are not intended to be limiting of its scope.

These examples describe and compare three different cases:

(a) Application of commercial formulation of Ciclopirox on micro-perforated nails

(b) Application of commercial formulation of Ciclopirox on micro-perforated nails previously treated with a 5% thioglycolic acid solution.

(c) Application of the commercial formulation of Ciclopirox combined with thioglycolic acid on micro-perforated nails.

Test (a) is performed to subsequently compare the results obtained by combining only micro-perforation with commercial lacquer with the results obtained by using thioglycolic acid as an absorption enhancer, either on the pre-treated nail (b) or directly on the non-pre-treated nail (c).

The tests were carried out imitating the administration guidelines indicated in the technical data sheet for the commercial lacquer with Ciclopirox (CICLOCHEM® Nails): 100 pl on the first day, followed by 50 pl each day for the rest of the administrations until completing 73 days.

Pretreatment with thioglycolic acid is performed at a concentration of 5% since it is the most commonly used concentration (Hao, J. et al. "Chemical method to enhance transungual transport and iontophoresis efficiency”. International Journal of Pharmaceutics, 2008, 357 (1-2), 61-69; Palliyil, B. et al. "A preformulation strategy for the selection of penetration enhancers for a transungual formulation”, AAPS PharmSciTech, 2013, 14, 682-691). Concentrations of 2.5% and 10% have also been tested, but the former gave worse results and the latter can cause problems of discomfort and pain to the patient, since such a high concentration of thioglycolic acid softens the nail plate too much (Joshi, M. et al. "Matrix based system of isotretinoin as nail lacquer to enhance transungual delivery across human nail plate”International Journal of Pharmaceutics,2015, 478(1), 268-277).

Example 1

This example concerns the preparation of micro-perforated nails and the absorption enhancer.

Eighteen human nails are selected, placed in a Petri dish and covered with MiliQ water. The plate is sealed with Parafilm and left to rest for approximately 23 hours. To make the perforations, the nails are removed, excess liquid is removed and micro-perforated with a Clearnail perforator, holding the drill perpendicular to the nail. In each sample, 16 perforations of less than 1 mm in diameter are made, ensuring that they are equidistant.

Example 2

Application of commercial formulation of Ciclopirox on micro-perforated nails.

On micro-perforated nails, according to example 1, 100 pl of commercial CICLOCHEM® Nail lacquer were administered (the first day) followed by 50 pl (the remaining administrations) until reaching 73 days and the average amount (in pg) of accumulated Ciclopirox released over time (in days) was measured. The results are shown in Figure 1 and, by means of a linear regression analysis, the following kinetic parameters were obtained:

Release constant: 234.59 ± 10.26 pg/day

Latency time: 6.733 ± 1.1998 days

The mean amount of Ciclopirox retained in the nail samples at the end of the study was 1,114.10 ± 292.53 pg.

Example 3

This example shows the pretreatment of micro-perforated nails with thioglycolic acid.

A 5% thioglycolic acid solution is prepared in a 80:20 water/ethanol mixture. To do this, 10 ml of this solution is prepared by adding 0.5 ml of thioglycolic acid, 7.6 ml of MilliQ water (to make up to 10 ml) and 1.9 ml of ethanol.

To pre-treat micro-perforated nails with thioglycolic acid (case b), the micro-perforated nails are incubated for 20 h, washed with water and dried with paper before administering the prepared thioglycolic acid solution.

Example 4

Application of commercial formulation of Ciclopirox on micro-perforated nails previously treated with a 5% thioglycolic acid solution.

On micro-perforated and pre-treated nails, according to example 3, 100 pl of commercial CICLOCHEM® Nail lacquer were administered (the first day), followed by 50 pl (the remaining administrations) until reaching 64 days and the average amount (in pg) of accumulated Ciclopirox released over time (in days) was measured. The results are shown in Figure 1 and, by means of a linear regression analysis, the following kinetic parameters were obtained:

Release constant: 51.69 ± 5.70 pg/day

Latency time: 2.30 ± 2.41 days

The mean amount of Ciclopirox retained in the nail samples at the end of the study was 2,211.82 ± 712.92 pg.

Example 5

Application of the commercial formulation of Ciclopirox combined with thioglycolic acid on micro-perforated nails.

On micro-perforated nails, according to example 1, on the first day 100 pl of lacquer composed of 95 pl of commercial lacquerClCLOCHEM®Nails and 5 pl of thioglycolic acid were administered; on subsequent days, until reaching 73 days of study, 50 pl of lacquer composed of 47.5 pl of commercial lacquerClCLOCHEM®Nails and 5 pl of thioglycolic acid were administered. The average amount (in pg) of accumulated Ciclopirox released over time (in days) was measured. The results are shown in Figure 1 and, by means of a linear regression analysis, the following kinetic parameters were obtained:

Release constants: 65.85 ± 5.08 pg/day

Latency time: 6,708 ± 3,681 days

The mean amount of Ciclopirox retained in the nail samples at the end of the study was 3,222.25 ± 872.29 pg.

Example 6

In this example, the results obtained in Examples 2, 4 and 5 are compared in order to demonstrate the surprising effect resulting from combining micro-perforation with thioglycolic acid.

In relation to diffusion, Figure 1 represents the average accumulated amount of Ciclopirox that is released to the micro-perforated nail over time for the three types of application tested: (a) Application of the commercial formulation of Ciclopirox on micro-perforated nails; (b) Application of the commercial formulation of Ciclopirox on micro-perforated nails previously treated with a 5% thioglycolic acid solution; and (c) Application of the commercial formulation of Ciclopirox combined with thioglycolic acid on micro-perforated nails. At first glance, it can be observed that there are significant differences between the study of samples treated only with the commercial lacquer (a) and the studies of samples treated with thioglycolic acid, either as a pretreatment (b) or incorporated into the commercial lacquer (c). Contrary to expectations, absorption is significantly faster without thioglycolic acid.

Figure 2 compares the average release constants (and their standard deviations) obtained for the three cases and it can be observed that the release rate of the active ingredient is much higher in the study where only the commercial lacquer (a) is used on microperforated nails.

Finally, analyses are carried out on the micro-perforated nails to determine the amount of active ingredient that remains accumulated in them at the end of the days of the tests. The results are shown in Figure 3, where it can be observed that the amounts of active ingredient accumulated inside the nail tissue are significantly higher in the cases where thioglycolic acid is incorporated, both in the case where it is used to pre-treat the micro-perforated nail (b) and in the case where it is combined with the commercial lacquer (c). Therefore, although with the commercial formulation in the absence of thioglycolic acid the transungual transfer is faster, the accumulation in the tissue is significantly lower. Taking into account the average quantities and their corresponding standard deviations, the intervals of the cases in which thioglycolic acid is incorporated (either as a pretreatment or incorporated into the commercial lacquer) overlap, which implies that there are no statistically significant differences between these two cases.

All of the above indicates that combining micro-perforations with thioglycolic acid promotes the accumulation of Ciclopirox in the nail plate, without necessarily improving the passage through the nail (from the dorsal layer to the ventral layer), which is an advantage compared to other current strategies by avoiding possible new infections in the short term.

Claims (11)

1. Pharmaceutical composition for nail application on micro-perforated nails comprising an anti-infectious active ingredient and a transungual penetration and accumulation enhancer. 2. Pharmaceutical composition for nail application on micro-perforated nails, according to claim 1, wherein the active ingredient characterized in that the enhancer compound is thioglycolic acid, the active ingredient is Ciclopirox. 3. Use of the pharmaceutical composition in the treatment of fungal and bacterial nail infections. 4. Use, according to claim 3, in the treatment of inflammatory processes of the nail unit. 5. A kit comprising: - a nail micro-piercing device - a pharmaceutical composition containing an anti-infectious active ingredient - a compound that enhances penetration and transungual accumulation. 6. Kit, according to claim 1 and 5, wherein the enhancer compound is incorporated into the pharmaceutical composition. 7. Kit, according to claims 5 and 6, where the active ingredient is Ciclopirox and the enhancer is thioglycolic acid. 8. Method of using the kit, according to claim 5, which comprises applying the compound enhanced by transungual penetration onto the micro-perforated nail and, subsequently, applying the pharmaceutical composition containing the active ingredient. 9. Method of using the kit, according to claim 6, which comprises applying the pharmaceutical composition containing the penetration-enhancing compound together with the active ingredient. 10. Use of the claimed kit in the treatment of fungal and bacterial nail infections. 11. Use of the kit, according to claim 10, in the treatment of inflammatory processes in the nail unit.