Injectable composition with prolonged duration of action for its use in the treatment of nail diseases and/or for accelerating nail growth

文档序号：538222 发布日期：2021-06-01 浏览：40次中文

阅读说明：本技术 用于其在治疗指或趾甲疾病中的使用和/或用于加速指或趾甲生长的具有延长的作用持续时间的可注射组合物 (Injectable composition with prolonged duration of action for its use in the treatment of nail diseases and/or for accelerating nail growth ) 是由 R·彻里夫-奇克 F·拉寇贝 L·拉沙普 X·J·卡普顿 A·多美施阿瓜拉 M·塞拉诺卡雷于 2019-07-31 设计创作，主要内容包括：本申请的目标在于具有延长的作用持续时间的可注射组合物,该组合物用于其在治疗指或趾甲疾病(包括任选地加速指或趾甲生长)中的使用,或者用于其用于加速指或趾甲生长的用途。(The present application is directed to injectable compositions having an extended duration of action for their use in the treatment of nail diseases, including optionally accelerating nail growth, or for their use in accelerating nail growth.)

1. Composition for its use in the treatment of nail diseases, characterized in that the composition comprises one or more biodegradable solid polymers with extended release, and optionally one or more active ingredients, and that the composition is presented in the form of a device intended to be administered by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last digit or knuckle.

2. Composition comprising one or more biodegradable solid polymers with extended release and optionally one or more active ingredients, for its use in the treatment of nail diseases, by: administration is carried out by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle.

3. A composition for its use according to claim 1 or 2, which comprises one or more active ingredients selected from the group consisting of:

-an anti-infective agent selected from:

an antifungal agent, which is a compound selected from the group consisting of,

an antibiotic, and

an antiparasitic agent;

-an anti-inflammatory agent selected from:

a steroidal anti-inflammatory drug which is a drug capable of inhibiting,

a non-steroidal anti-inflammatory drug, and

inhibitors of janus kinases (JAKs);

-cyclosporins;

-vitamin D or a derivative of vitamin D;

-an immunosuppressant;

-an amino acid, preferably arginine;

-an active ingredient accelerating nail growth, preferably selected from:

(ii) prostanoids such as prostanoids,

chitosan, hydroxypropyl chitosan, and a mixture of chitosan and hydroxypropyl chitosan,

the concentration of the valproic acid,

horsetail, hyaluronic acid, biotin, Growth Hormone (GH), minoxidil, finasteride;

-an active ingredient for promoting blood circulation selected from:

vasodilators, and

anti-platelet aggregation agents;

-local anesthetics.

4. Composition for its use in the treatment of nail diseases according to one of claims 1 or 2, characterized in that it comprises one or more active ingredients selected from the following:

-an antifungal agent,

-a steroidal anti-inflammatory drug,

nonsteroidal anti-inflammatory drugs and inhibitors of janus kinases (JAKs),

-an active ingredient accelerating the growth of nails, preferably selected from prostanoids, equisetum arvense (equisetum), chitosan, hydroxypropyl chitosan, hyaluronic acid, biotin, valproic acid, Growth Hormone (GH), minoxidil and/or finasteride,

-an amino acid, preferably arginine,

-a local anesthetic for the administration of a drug,

-a vasodilator for the treatment of a disease,

-an antibiotic agent, the antibiotic agent being selected from the group consisting of,

-antiparasitic agents.

5. Composition for its use in the treatment of nail diseases according to one of claims 1 or 2, characterized in that the nail disease is psoriasis with or without accompanying inflammatory phenomena and in that it comprises one or more active ingredients selected from:

-a steroidal anti-inflammatory drug,

-a non-steroidal anti-inflammatory drug,

inhibitors of Janus kinase (JAK),

-a group of cyclosporins, which is,

-an amino acid, preferably arginine,

-vitamin D or a derivative of vitamin D,

-an immunosuppressive agent, which is capable of inhibiting the growth of,

-a retinoid and a retinoid, which is capable of inhibiting the formation of a retinoid,

compounds, such as anthralin (or dithranol) and urea,

-one or more active ingredients accelerating nail growth, preferably selected from: prostanoids, Equisetum arvense (Equisetum arvense), chitosan, hydroxypropyl chitosan, hyaluronic acid, biotin, valproic acid, Growth Hormone (GH), minoxidil and/or finasteride,

-a vasodilator for the treatment of a disease,

-local anesthetics.

6. Use of a composition for accelerating the growth of a nail, characterized in that the composition comprises one or more biodegradable solid polymers with extended release, and optionally one or more active ingredients, and that the composition is presented in the form of a device intended to be administered by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle.

7. Use of a composition according to claim 6 for accelerating nail growth, characterized in that the composition comprises one or more biodegradable solid polymers with extended release, and one or more active ingredients selected from the group consisting of:

-cyclosporins;

-prostanoids;

-Equisetum arvense (Equisetum hiemale), chitosan, hydroxypropyl chitosan, hyaluronic acid, arginine, biotin, valproic acid, Growth Hormone (GH), minoxidil and/or finasteride,

-a vasodilator for the treatment of a disease,

-a source of valproic acid,

and optionally, one or more active ingredients selected from the group consisting of:

-an anti-infective agent selected from:

an antifungal agent, which is a compound selected from the group consisting of,

an antibiotic, and

an antiparasitic agent;

-an anti-inflammatory agent selected from:

a steroidal anti-inflammatory drug which is a drug capable of inhibiting,

a non-steroidal anti-inflammatory drug, and

inhibitors of janus kinases (JAKs);

-vitamin D or a derivative of vitamin D;

-an immunosuppressant;

-an amino acid, preferably arginine;

-an active ingredient for promoting blood circulation selected from:

vasodilators, and

anti-platelet aggregation agents;

-a local anesthetic for the administration of a drug,

and the composition is in the form of a device intended to be administered by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle or knuckle.

8. Non-therapeutic method for accelerating the growth of nails, characterized in that it comprises the administration of a composition as defined in one of claims 6 or 7 and comprising one or more biodegradable solid polymers with prolonged release, one or more active ingredients selected from the group consisting of:

-cyclosporins;

-prostanoids;

-Equisetum arvense (Equisetum hiemale), chitosan, hydroxypropyl chitosan, hyaluronic acid, arginine, biotin, valproic acid, Growth Hormone (GH), minoxidil and/or finasteride,

-a vasodilator for the treatment of a disease,

-a source of valproic acid,

and optionally, one or more active ingredients selected from the group consisting of:

-an anti-infective agent selected from:

an antifungal agent, which is a compound selected from the group consisting of,

an antibiotic, and

an antiparasitic agent;

-an anti-inflammatory agent selected from:

a steroidal anti-inflammatory drug which is a drug capable of inhibiting,

a non-steroidal anti-inflammatory drug, and

inhibitors of janus kinases (JAKs);

-vitamin D or a derivative of vitamin D;

-an immunosuppressant;

-an amino acid, preferably arginine;

-an active ingredient for promoting blood circulation selected from:

vasodilators, and

anti-platelet aggregation agents;

-a local anesthetic for the administration of a drug,

9. Composition as defined in one of the preceding claims, characterized in that it is presented in the form of an implant, optionally with a sharp tip, a cylindrical tube or a wire, and that it is administered by subcutaneous route at a distance of more than 1cm from the edge of the nail on its proximal side, preferably in the finger or toe except for the last knuckle.

10. Composition as defined in one of the preceding claims, characterized in that a biocompatible, preferably biodegradable or bioabsorbable polymer, preferably a polyester, and more preferably a lactic-glycolic acid copolymer (PLGA) or a lactic acid Polymer (PLA) with extended release and a loading of active ingredient of 0% to 99%, preferably lower than or equal to 85%, and more preferably of 20% to 70% by weight.

11. Composition as defined in one of the preceding claims, characterized in that it comprises 0.04 to 6.5mg of ciclopirox, ciclopirox olamine, terbinafine or terbinafine hydrochloride, or itraconazole, and PLGA.

12. Composition according to one of claims 1 to 5 in the form of an implant for its use in the treatment of nail mycoses, characterized in that it comprises one or more biodegradable solid polymers with prolonged release, and optionally one or more antifungal agents, and in that it is presented in the form of an implant with a maximum length of 25mm, preferably 4 to 15mm, and a diameter of 0.1 to 1mm, preferably 0.3 to 0.8mm, intended to be administered by subcutaneous route at a distance greater than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last digit.

13. Non-therapeutic method for accelerating nail growth, characterized in that it comprises the administration of a composition as defined in one of claims 6 or 7, in the form of an implant, comprising one or more biodegradable solid polymers with prolonged release, and one or more active ingredients selected from:

-cyclosporins;

-prostanoids;

-Equisetum arvense (Equisetum hiemale), chitosan, hydroxypropyl chitosan, hyaluronic acid, arginine, biotin, valproic acid, Growth Hormone (GH), minoxidil and/or finasteride,

-a vasodilator for the treatment of a disease,

-a source of valproic acid,

and optionally, one or more active ingredients selected from the group consisting of:

-an anti-infective agent selected from:

an antifungal agent, which is a compound selected from the group consisting of,

an antibiotic, and

an antiparasitic agent;

-an anti-inflammatory agent selected from:

a steroidal anti-inflammatory drug which is a drug capable of inhibiting,

a non-steroidal anti-inflammatory drug, and

inhibitors of janus kinases (JAKs);

-vitamin D or a derivative of vitamin D;

-an immunosuppressant;

-an amino acid, preferably arginine;

-an active ingredient for promoting blood circulation selected from:

vasodilators, and

anti-platelet aggregation agents;

-a local anesthetic for the administration of a drug,

and the composition is in the form of an implant having a maximum length of 25mm, preferably 4 to 15mm, and a diameter of 0.1 to 1mm, preferably 0.3 to 0.8mm, the implant being intended to be administered by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle.

14. Composition as defined in one of the preceding claims, characterized in that it is in the form of an implant, a cylindrical tube or a wire, optionally with a sharp tip; and applying the composition in the finger or toe, except in the last digit, in the first and second, preferably the second, digit of the finger or toe, and in the first digit or toe of the thumb or toe; simultaneously administering one or more compositions, preferably one to eight compositions, more preferably one to six compositions, more preferably one to four compositions, in the same finger or toe; and the treatment is continuous, preferably for a minimum duration of 48 weeks when the entire nail is affected, for a minimum duration of 24 weeks when less than half of the nail is affected, for a minimum duration of 12 weeks when less than one quarter of the nail is affected, or for a maximum duration of 6 weeks when less than 10% is affected.

15. The solid composition as defined in one of the preceding claims, comprising one or more biodegradable or non-biodegradable solid polymers with extended release, and optionally one or more active ingredients; and the composition is presented in the form of a device intended to be applied by insertion into the space between the nail bed and the nail plate; and optionally, said composition is used simultaneously or staggered in time with the administration by subcutaneous route of one or more compositions according to any one of claims 1 to 6 or 8 to 11 at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle.

16. Liquid or non-solid composition for its use according to claim 1, comprising one or more biodegradable or non-biodegradable polymers with prolonged release, and optionally one or more active ingredients, preferably one or more antifungal agents, characterized in that said composition is presented in the form of a device intended to be administered by insertion into the space between the nail bed and the nail plate; and optionally, said composition is used simultaneously or staggered in time with the administration by subcutaneous route of one or more compositions according to any one of claims 1 to 7 or 9 to 12 at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle.

17. Nail polish having antifungal effect comprising one or more antifungal agents, preferably selected from fluconazole, ketoconazole, miconazole, tioconazole, tavatoro, terbinafine hydrochloride, tolnaftate, amorolfine, ciclopirox olamine, terbinafine hydrochloride or miconazole, for its use in the treatment of nail diseases by: application on the nail simultaneously or staggered in time with the administration by subcutaneous route of one or more compositions according to any one of claims 1 to 7 or 9 to 12 in the finger or toe at a distance of more than 1cm from the edge of the nail at its proximal side, preferably except for the last knuckle, and/or simultaneously or staggered in time with the administration of one or more solid, liquid or non-solid compositions according to one of claims 15 or 16 by insertion into the space between the nail bed and the nail plate.

18. An antifungal pharmaceutical composition comprising one or more antifungal agents, preferably selected from azole derivatives such as ketoconazole, fluconazole, isaconazole, itraconazole, posaconazole or voriconazole; echinocandins such as anidulafungin, caspofungin, micafungin, flucytosine, griseofulvin, terbinafine hydrochloride and terbinafine; amphotericin B, for its use in the treatment of nail diseases, by: administration by the oral or injectable route simultaneously or staggered in time with the subcutaneous administration of one or more compositions according to any one of claims 1 to 7 and 9 to 12 in the finger or toe at a distance of more than 1cm from the edge of the nail at its proximal side, preferably except for the last knuckle, and/or simultaneously or staggered in time with the administration of one or more solid, liquid or non-solid compositions according to one of claims 15 or 16 by insertion into the space between the nail bed and the nail plate, and/or simultaneously or staggered in time with the application of the antimycotic nail varnish according to claim 17 on the nail.

19. Composition according to one of claims 1 to 7 and 9 to 12, characterized in that it is preferably in the form of an implant, optionally with a sharp tip, and is administered in the finger or toe at a distance of more than 1cm from the edge of the nail at its proximal side, preferably except for the last knuckle, for its use in the treatment of nail diseases, by administration simultaneously or staggered in time with:

-applying a solid composition comprising one or more biodegradable or non-biodegradable polymers with extended release, and optionally one or more active ingredients, preferably one or more antifungal agents, and/or

-administering a non-solid composition according to claim 16 comprising one or more biodegradable or non-biodegradable polymers with extended release, and optionally one or more active ingredients, preferably one or more antifungal agents, and/or

-applying to the nail polish having an antifungal effect according to claim 17, said nail polish comprising one or more antifungal agents, preferably selected from the group consisting of fluconazole, ketoconazole, miconazole, tioconazole, tavalarole, terbinafine hydrochloride, ciclopirox olamine, tolnaftate, amorolfine, ciclopirox, tioconazole or miconazole, and/or

-administering by oral or injectable route an antifungal pharmaceutical composition comprising one or more antifungal agents, preferably selected from azole derivatives such as ketoconazole, fluconazole, isaconazole, itraconazole, posaconazole or voriconazole; echinocandins such as anidulafungin, caspofungin, micafungin, flucytosine, griseofulvin, terbinafine hydrochloride and terbinafine; amphotericin B, and/or

Treatment with a laser that causes destruction of the fungus by a photobiological thermal effect.

Prior Art

Among the various diseases that may affect the nails or the extremities, inflammatory diseases may be mentioned, such as psoriasis, or lichen planus; tumors of the nail, such as hemangiosphere tumors, mucomatous tumors, mucoid skin cysts; infections, such as paronychia, felon, mycoses and other fungal conditions such as onychomycosis (also known as onychomycosis or onychomycosis), nail atrophy, onychomycosis, nail curvature, concave nails, black nails of the nail, under-nail hyperforization, brittle nails, paronychia, diseases of chemical, infectious, inflammatory or other traumatic origin such as alopecia areata, Darrier's (Darrier) disease, and other common diseases known to those skilled in the art, not limited to fungal mycoses.

Mycoses and other fungal infections can also affect skin, mucous membranes and hair.

Onychomycosis is the most common nail disorder, involving 6-9% of the general population. It is rare in children and its frequency increases with age, it therefore affects 50% of the population over 70 years of age. These people today are not treated properly due to their often reduced mobility and their multiple medications.

In the united states alone, the prevalence is estimated to exceed 3500 thousands of people.

There are many factors that increase the propensity to develop onychomycosis: possible genetic predisposition, minor injuries, related diseases (psoriasis, diabetes, poor blood circulation in the foot, immunosuppression, etc.), certain medications (immunosuppressants, chemotherapy, corticoids, etc.), age-related factors, and in particular environmental factors (especially heat and humidity, profuse sweating, continuous wearing of closed shoes, walking barefoot on public grounds).

Onychomycosis is a fungal infection of the nail bed, matrix or nail plate. The first clinical features of onychomycosis are distal nail detachment (separation of the nail plate from the nail bed), under-nail hyperstimulation, and discolored dystrophic nails.

Patients with onychomycosis are often embarrassed by defects in their nails and one of the well-recognized important effects of this pathological condition is a social impact and a loss of confidence.

The symptoms of the disease are initially only aesthetic (with spots appearing on the nail), but if the disease is not treated, the infection may spread and be accompanied by physical symptoms, which may sometimes limit mobility, with difficulty in walking (even loss of dexterity), and may be associated with pain. The disease may also indirectly reduce peripheral circulation and cause venous stasis, which may aggravate pathological conditions such as ulcers in diabetic patients.

Fungal infections of the nail may also spread to other parts of the body and potentially to others.

In the case of nail mycoses or onychomycosis, various pathogenic fungal species can be detected. The most common and in more than 70% of cases are dermatophytes, particularly Trichophyton rubrum (Trichophyton rubrum), Trichophyton interphalangeae (Trichophyton interphalangeae) or Trichophyton mentagrophytes (Trichophyton mentagrophytes).

The remaining 30% are yeasts of the Candida type, usually Candida parapsilosis (Candida parapsilosis), Candida quaternary (Candida guilliermondii), Candida albicans (Candida albicans), or moulds of non-dermatophytes, such as Aspergillus species (Aspergillus spp), Scopulariopsis species (Scopulariopsis spp), Brevibacterium species (Breviculis spp), Fusarium species (Fusarium spp), Acremonium species (Acremonium spp) and Neusculium species (Neostalidium spp).

Other dermatophyte pathogens may be mentioned in general, such as, for example, Epidermophyton floccosum (Epidermophyton floccosum), Trichophyton violaceum (Trichophyton violaceum), Microsporium gypseum (Microsporium gypseum), Trichophyton truncatum (Trichophyton tonsurnans), Trichophyton schoenleini (Trichophyton schoenleini) or Trichophyton sudahlon sudaense (Trichophyton soueadenense).

There are five subtypes of onychomycosis that have been cleared and associated with severity. However, distal onychomycosis (DLSO) represents the most commonly observed condition, even though patients tend to consult their physician very late when the ingressing part of onychomycosis begins to approach the area of the nail base, thereby compromising the mother's stroma itself. Until then, they rarely linked their morphological alterations to nail disease.

Although the most common pathological condition is onychomycosis, the object of the present invention enables the treatment also of all mycoses, but also of nail diseases (onychomycosis) such as those indicated above, and in particular psoriasis or pustulosis of the head, and of improving and reconstituting morphological alterations of the nail (nail dystrophies) related or not to the aforementioned pathological condition. The object of the present invention may also be to treat so-called acropathy known to the person skilled in the art in general.

In the case of these infections, the current pharmacological treatments most commonly used include, in the case of aesthetic recovery of the dermatophytosis or affected areas, daily administration of topical pharmaceutical forms and/or oral forms to eradicate the fungus for several months or even for the whole year.

It is likely and often verified that treatment is required for more than one year in order for the treatment to be definitive or to avoid any recurrence. However, this is not conceivable in practice with the current daily application or administration of the treatment.

Antifungal agents for the treatment of onychomycosis may preferably include: nystatin, amphotericin B, abafungin, benzalkonium chloride, caspofungin, cetyltrimethylammonium bromide, clioquinol, copper sulfate, haloprogin, echinocandins, flucytosine, Mycobactir, Novexatine, natamycin, cetylpyridinium chloride, benzylamine butenafine, Benzoxaboroles (Benzoxaboroles) (cyclic derivatives of boric acid), abaconazole, araconazole, bifonazole, butoconazole, clotrimazole, itraconazole, econazole, Eficonazol, fenticonazole, fluconazole, Fosravuconazole, isoconazole, itraconazole, isazoconazole (Isauconazole), ketoconazole, liazole, Lianozole, Cloconazole, miconazole, oxadiazole, oxiconazole, posaconazole, Posaconazole, Promiconazole, Rataconazole, sulticonazole, sulconazole, Thiabenzazole, thiadiazole, Thiaclonidazole, Thiazol, Amiodarone, naftifine, tavabororo (Tavaborole), butenafine, flucytosine, griseofulvin, caspofungin, micafungin, nitric oxide, sodium oxichloride, povidone iodine, tolnaftate thiocarbonate, sulbenine, zinc pyrithione, and more particularly selected from terbinafine, ciclopirox olamine, itraconazole, and amorolfine.

Treatment by the oral route may include, for example, ketoconazole, fluconazole, isaconazole, itraconazole, posaconazole or voriconazole; echinocandins such as anidulafungin, caspofungin, micafungin, flucytosine, griseofulvin, and terbinafine; amphotericin B, and in particular ketoconazole, itraconazole, terbinafine hydrochloride, fluconazole, griseofulvin, terbinafine, and in the case of hospital emergency treatment, posaconazole or posaconazole and voriconazole. These antifungal agents may also be used in the practice of the present invention. However, these oral antifungals are associated with mild (migraine, rash, loss of taste or light sensitivity) or severe (e.g. heart or liver problems) systemic effects, which strongly limit their use, especially in the most affected patient population.

Topical therapy with antifungal agents such as fluconazole, ketoconazole, miconazole, terbinafine, tolnaftate, sertaconazole, eberconazole, fenticonazole, oxiconazole, clotrimazole, bifonazole is an alternative to patients where oral antifungal therapy is contraindicated.

All of these antifungal agents may also be used in the practice of the present invention.

For the treatment of topical dermatomycoses that are theoretically accessible but difficult for most patients to apply (e.g. the limitation of their physical ability to reach the area to be treated). Pharmaceutical forms such as creams, gels, ointments, sprays, powders, aerosols and lotions are used. Oiling with one or more antifungal agents is also a frequently used treatment, although with many side effects, such as: irritation, itching, rash, inflammation, contact dermatitis, burning of the skin near the application area, and changes in the nails (discolored, fragile or brittle nails).

These pharmaceutical forms applied topically on the affected area do not allow direct access to all the fungi that are often distributed in the various keratin layers of the nail, and do not generally allow satisfactory control of the infection, not only on their surface, but also due to the fungicidal and fungicidal effect of the therapeutic agents incorporated into the preparation. When the results are satisfactory (less than 20% of cases), eradication of the fungus and reconstruction of the healthy morphological appearance of the nail are obtained after a treatment period that can last from weeks to months.

Nail mycosis remains one of the most difficult diseases to treat today due to its difficult accessibility. This is because the fungus may colonize on the nail, starting from the nail bed which is not possible to treat with the topical product, and gradually spread, affecting the keratinized structure of the nail. If the infection is not prevented in time, it may colonize the entire nail (up to the mother mass), with serious systemic consequences for the patient (e.g. for diabetic patients). In addition, onychomycosis is treated in only 5% of the population in the united states suffering from onychomycosis and 8% of the european population. The vast majority of the affected population does not attempt to resolve the infection, which can lead to late relief and thus complicate the difficulty of treatment.

The case of late stage mycoses, where the mother substrate is infected or threatened by infection due to disease progression, which is one of the primary focus of the present invention, often involves the use of oral, topical and other treatments of the laser type, which do not penetrate well up to the base of the infection and therefore cannot take care of where the particular nail is renewed.

Thus, at the level of the nail, fungi are difficult to reach by using traditional topical treatments. This is why systems have been developed for facilitating direct treatment of the nail and therapeutic agents across the nail.

One of the therapeutic solutions envisaged is a therapeutic nail varnish such as described in international application WO 2010/086723. They contain a film-forming agent and a solvent which evaporates after application to allow the active ingredient to deposit on the nail.

For example, international application WO 2007/147052 describes a composition comprising, inter alia, terbinafine for use in the treatment of onychomycosis by topical application. The composition consists of a delivery vehicle comprising a non-polymeric crystallization inhibitor, a film-forming agent, and a volatile solvent.

International application WO 2011/79234 describes antifungal topical compositions comprising an antifungal agent, a zwitterionic surfactant or a charged derivative thereof, a carboxylic acid, a low molecular weight alcohol and water.

It may also be mentioned that has been approved by the U.S. food and drug administration for mild to moderate onychomycosisOf Valerant Pharmaceuticals for topical treatment ofNail polish (8% ciclopirox solution).

These nail varnishes should be applied very regularly and typically contain up to 10% of the therapeutic agent (except for Pfizer)Besides the product, the tioconazole can reach 28 percent). These drugs propose topical treatment of nail mycoses on the surface, but do not attack the infected nest and create a barrier or active restraint to its spread. Furthermore, penetration through the nail is very weak and only a very small fraction of the dose reaches directly to the area to be treated.

It is also important to consider the influence of the environment and the use of a large amount of organic solvent. Recently, in order to compensate for this drawback, a novel film-forming composition in which the amount of organic solvent is reduced has been developed; however, they did not alter the dosage used nor the duration of treatment.

Considerable research effort has been expended in developing systems to enhance the penetration of therapeutic agents through the nail.

Recently, inspired from transdermal systems, formulations have been developed which can be administered by iontophoresis, as described for example in application WO 2008/121709.

In order to maximize the contact of the active ingredient with the infection, there are also some proposals which involve perforating the nail in multiple places by means of laser radiation and depositing a formulation containing a therapeutic agent.

Such a process is described in international patent application WO 02/11764 and more recently in application WO 2011/071137. These very invasive and painful methods are also expensive. They offer the advantage of targeting infections under the nail, but do not attack possible collateral infections such as contact infection features due to fungal infections.

Onychomycosis is also commonly associated with fungal diseases in adjacent areas such as fingers, toes, feet and hands. Furthermore, due to the size of the pores opened on the nail, this type of administration allows only an infinitely small amount of active ingredient to be provided, which does not have a long-lasting effect capable of treating the nail within weeks or months without the need to renew the product.

At the level of the matrix, it is not possible to envisage satisfactory local treatments that work effectively deep in living tissue. When there is an infection at this level, the matrix will continue to produce infected diseased nails. In these advanced cases of mycoses, orally taken drugs (which may preferably be combined with topical forms) should be considered, despite their side effects.

As noted above, physicians have heretofore had no other options than resorting to alternatives to systemic treatment via the oral route due to limitations from lack of accessibility, efficacy, frequency and duration of treatment.

Typically, these oral forms in tablet dosage form are administered daily at high doses over a duration limited to 3 months (alone or in combination with a topical form containing daily applied antifungal agents) and force regular examination of the patient.

These oral treatments cause high exposures of the whole body for long durations and have the disadvantage of inducing major side effects (especially hepatotoxicity), which limits their routine use in the case of the latest stages of the disease.

In all cases, and regardless of treatment, one should wait for the nail to completely re-grow (6 months for the hand; and 12 months for the toes) to be able to obtain complete relief; this mandatorily specifies an extreme discipline of daily monitoring throughout the duration of treatment. Remission refers to the absence of infection and return to a normal aesthetic appearance, according to the necessary criteria of remission by those skilled in the art.

Therefore, there is no easy-to-use drug for treating onychomycosis or nail diseases today. Current therapy generally does not allow a cure to be obtained because it relies on strict adherence to daily treatment or the limits of treatment with risk of side effects for the duration of a year, and also often depends on the patient's ability.

Patients often stop their treatment themselves once the aesthetic appearance that impedes daily activities appears to have disappeared or diminished, and in these cases fungal colonies often remain, which then proliferate rapidly and lead to the recurrence and recurrence of the infection (there is no mycological cure).

As noted above, one of the reasons for current treatment failure is the lack of compliance or compliance, i.e., the patient has not followed the prescription of his physician and the sanitary dietary provisions associated therewith in taking these medications. The treatment is mandatory and sometimes complex. This is because, for example, the daily use of a topical form that is difficult to apply to the toenails of infected feet (which requires special physical abilities) is very complicated for elderly patients with reduced mobility.

Adherence is a key element of the success of pharmacotherapy and more particularly in these treatments for which it is important to have the presence of antifungal products permanently at the level of the infected site.

This non-compliance is considered one of the major reasons for the failure of these treatments.

Another reason for these failures is related to the time limit of taking a single oral form that can ensure that there is no infection at the nail production at the maternal level. Furthermore, the oral form is the only systemic treatment for dermatophytosis or other skin, hair or nail infections. In addition, systemic antifungals are used when the pathogenic microorganism in question (a microscopic fungus) shows resistance or when local treatment is not possible. However, these treatments are prescribed only in extreme cases and are not suitable for all populations.

In hospital emergency treatments and in the face of serious fungal infections such as aspergillosis or mucocutaneous candidiasis, as well as mycoses in immunocompromised patients, caregivers schedule injectable antifungal treatments by the intravenous route. As examples, intravenous solutions of amphotericin B, fluconazole, voriconazole, itraconazole or posaconazole are present.

There are already known treatments which are administered by injection at the level of the tip of the finger or toe and around the nail. Treatment of psoriasis may for example result in the injection of an anti-inflammatory glucocorticoid in the lesion. For example, when triamcinolone is administered in the proximal folds of the nail, along the side folds and each side, in the matrix, or in the nail bed, local anesthesia is involved, as these areas are known to be very sensitive. This type of treatment often causes side effects such as nail atrophy or subungual bleeding.

Several patent applications have been filed which aim to treat nail diseases and in particular onychomycosis by means of biodegradable drug delivery systems formulated for implantation into the nail and its surrounding tissues to treat various pathological conditions of the nail.

One system of this type is described in application WO2006/086888 (equivalent to US application US 2008/0299165).

The system comprises compositions which can also be formulated in solid form, in particular in the case of the later international applications WO 2007/139804 and WO 2011/086723.

However, in the case of diseases and especially onychomycosis, implantation of curable or solid formulations under the nail or in the surrounding tissue has a number of disadvantages and can prove to be very painful.

This is because there is not enough room in these particular areas to administer a composition having a volume sufficient for treatment within months. Invasive injection procedures in or near the diseased or infected area are also undesirable, which can increase trauma and even promote spread of infection.

These are areas that are particularly innervated and vascularised or too close to the joint where inserting the needle and applying the curable or solid form have problems of traumatic injury and scarring, and may even trigger other pathological conditions related to, for example, arthritis, which are detrimental to the healing of the affected tissue, which is the target of treatment.

It is also not possible to increase the number of curable or solid forms injected in these areas, nor to easily repeat these injections.

This is because, in the presence of combined pathological conditions, various active ingredients and in particular various antifungal agents are often required to treat these pathological conditions, and the limited space under the nail or in the surrounding tissues does not allow the injection of these treatments in combination with a sufficient amount of several active ingredients.

This is because it is now recognized that one of the additional reasons for the failure of nail disease treatment is that they are often caused by a variety of different types of pathogens and often have associated consequences such as inflammation or other diseases.

As a non-limiting example, some fungi are sometimes resistant to terbinafine, while others are resistant to ciclopirox. However, as indicated above, there is today no means for patients to treat these mycoses simultaneously and specifically without exposing the body to high doses of therapeutically active ingredients with a certain toxicity.

Another disadvantage of the solutions proposed in these patent applications is that the upstream region of the nail matrix is not targeted, which is a preferential target for internally provided therapies (injectable or oral).

For externally provided treatments (e.g., topical treatments or nail polish), this upstream region is also not targeted.

For all the reasons mentioned, nowadays most people suffering from nail diseases do not have any treatment.

In summary, it appears that no satisfactory solution has been found to date to the treatment problems posed by the treatment of nail diseases and in particular onychomycosis, such as lack of compliance, lack of efficacy, duration and frequency of treatment.

Brief description of the invention

The present invention therefore aims at a composition for its use in the treatment of nail diseases and/or for accelerating nail growth, characterized in that the composition comprises one or more biodegradable solid polymers with prolonged release, and optionally one or more active ingredients, and that the composition is presented in the form of a device intended to be administered by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last finger or toe and also in the joint area, preferably in the penultimate finger or toe (away from the tendon and its bony insertion area).

The object of the present invention is especially a composition for its use in the treatment of nail diseases and/or for accelerating nail growth, characterized in that the composition comprises one or more biodegradable solid polymers with prolonged release, and optionally one or more active ingredients, and that the composition is presented in the form of a device intended to be administered by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, in the finger or toe, preferably in addition to the last finger or toe and also in the joint area, preferably in the penultimate finger or toe (away from the tendon and its bony insertion area).

The above-described composition according to the present invention may be administered by subcutaneous route at a distance of more than 1cm from the edge of the nail on its proximal side, preferably in the finger or toe except for the last knuckle or knuckle.

In a preferred embodiment, the composition according to the invention may be administered by subcutaneous route in the finger or toe at a distance of more than 1cm from the edge of the nail at its proximal side, preferably except for the last finger or toe.

Brief Description of Drawings

FIG. 1: in vitro release profile: comparison between various compositions prepared according to example 1.

FIG. 2: in vitro release profile: comparison between various compositions prepared according to example 18.

FIG. 3: graph of in vitro release of the compositions according to example 2 and example 6.

FIG. 4: graph of in vitro release of the composition according to example 16.

FIG. 5: photograph of halo of agar plate after planting the compound according to example 1(1) on seeds of Candida parapsilosis strain incubated at 35 ℃.

FIG. 6: photograph of halo of agar plate after planting the compound according to example 2 on seeds of Candida parapsilosis strain incubated at 35 ℃.

FIG. 7: photograph of halo of agar plate after planting compound according to example 19 on seeds of Trichophyton rubrum strain incubated at 35 ℃.

FIG. 8: halo-inhibiting activity profile of the implant according to example 1(3) on seeds of a strain of P.erythraea incubated at 35 ℃ for 75 days.

FIG. 9: halo-inhibiting activity profile of the implant according to example 2 on seeds of Candida parapsilosis strains incubated at 35 ℃ for 168 days.

FIG. 10 a: halo-inhibiting activity profile of the implant according to example 19 on seeds of Candida parapsilosis strains incubated at 27 ℃ and 35 ℃ for 115 days.

FIG. 10 b: halo-inhibiting activity profile of the implant according to example 19 on seeds of a strain of P.erythraea incubated at 35 ℃ for 135 days.

FIG. 11: photographs of implants of the composition described in example 18(3) after 84 days of in vivo implantation.

FIG. 12: amount of active ingredient released over time according to the device of example 1 (4).

FIG. 13: remaining curves over time for the apparatus according to example 18 (3).

FIG. 14: remaining curves over time for the apparatus according to example 25.

FIG. 15: graph of in vitro release of the composition according to example 26.

FIG. 16: graph of in vitro release of the composition according to example 27.

FIG. 17 a: photo-lateral view of the implant obtained according to example 1 (4).

FIG. 17 b: photo-cross-sectional views of implants obtained according to example 1 (4).

FIG. 18: photo-lateral view of the implant obtained according to example 7.

FIG. 19: photo-lateral view of the implant obtained according to example 8.

FIG. 20: photo-lateral view of an implant obtained according to example 16.

FIG. 21: photo-lateral view of the implant obtained according to example 18 (3).

FIG. 22: photo-lateral view of an implant obtained according to example 26.

FIG. 23: photo-lateral view of the implant obtained according to example 27.

FIG. 24: schematic side view of a preferred implant region.

Detailed Description

More particularly, "the edge of the nail on its proximal side" refers to the proximal region of the nail on the side of the matrix and nail arc defined by the stratum corneum.

"affected area" or "area to be treated" refers to the smallest area, extremity, such as a fingernail or toe toenail, that can extend beyond one extremity, nail, finger or toe until all of the patient's extremities, nails, fingers and toes are likely to be touched.

Application or reapplication will preferably be performed on the dorsal side on both sides of the extensor tendon and over the angio-nerve bundles in these areas.

The application area of the composition according to the invention is preferably located in the penultimate phalanx, preferably outside the joint area, and preferably said application area is remote from the tendon and its bone insertion area.

Biocompatible solid polymers or copolymers that may be used may be selected from lactic acid Polymers (PLA), glycolic acid polymers, lactic acid-glycolic acid copolymers (PLGA), Polycaprolactone (PCL), copolymers of lactic acid and caprolactone, polyglycolide-co-lactide-co-caprolactone (PLGC), polyanhydrides, copolymers between 1, 3-bis (carboxyphenoxypropane) (PCPP) and Sebacic Acid (SA), polyethylene glycols, polyorthoesters, polycarbonates, polyurethanes, polyacetals, polycyanoacrylates, polyphosphoesters, poly (oxyethylene), poly (oxypropylene), polydioxans or polydioxanones, amino acid polymers such as polyarginine, and copolymers and mixtures of these polymers.

Preferred biocompatible polymers or copolymers are biodegradable polymers, more particularly lactic acid Polymers (PLA), glycolic acid polymers, lactic-glycolic acid copolymers (PLGA).

Biodegradation of the biodegradable solid polymer, preferably comprising lactic acid and/or glycolic acid, releases lactic acid and/or glycolic acid, which is an acid that potentially generates an acidic medium that can facilitate treatment of nail diseases and/or promote nail growth.

The composition according to the invention may also comprise other injectable excipients, for example amino acids, such as histidine, lysine or arginine, preferably arginine.

In other words, the first object of the present invention is a solid composition comprising one or more biodegradable polymers with extended release, optionally other injectable excipients, and optionally one or more active ingredients, for its use in the treatment of nail diseases and/or for accelerating nail growth, by: administration is by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last digit and preferably in the penultimate digit.

Thus, the primary object of the present invention is especially a solid composition comprising one or more biodegradable polymers with extended release, optionally other injectable excipients, and optionally one or more active ingredients, for its use in the treatment of nail diseases, by: administration is by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last digit and preferably in the penultimate digit.

It is therefore an object of the present invention to facilitate the treatment of nail diseases, and in particular the treatment of topical mycoses. In particular, it is an object of the present invention to propose a local regional, internal, parenteral (i.e. injectable) treatment of nail diseases with prolonged duration.

More particularly, the invention may be used in a novel topical area of a novel pharmaceutical form which is long acting or has prolonged release, which is highly concentrated in the active ingredient, but corresponds to a lower daily dose of antifungal agent than the dose delivered by the usual systemic route or than the dose available with a topical area use of a topical form.

The invention makes it possible in particular to care for infections caused by fungi, in particular by administering antifungal agents by subcutaneous internal injection at least 1cm from the infected nail and outside the last finger or toe that carries it, or by external insertion between the nail plate and the nail bed, with excellent efficacy, in doses that are used that are unexpected and different from those conventionally used, at very low doses and very reduced frequency.

Furthermore, surprisingly, the inventors of the present application have also found that the intervention consisting in injecting subcutaneously one or more implants outside the nail site carrying onychomycosis, but in the vicinity of this site, makes it possible to effectively treat nail diseases and in particular onychomycosis, not only without the need to administer high doses of antifungal agents conventionally used in this type of treatment, but also in the complete absence of active ingredients such as antifungal agents.

Depending on the type of nail disease, one or more such implants not comprising an active ingredient (e.g. those considered in the composition according to the invention) may be administered at least 1cm from the infected nail outside the finger or toe carrying the nail, and which enable the treatment of nail diseases, in particular onychomycosis and morphological changes of the nail or nail dystrophies.

In this case, it is not necessary, but possible, to combine these medical devices in the form of implants which do not contain an active ingredient, in particular an antifungal agent (which also constitutes a composition according to the invention), with one or more antifungal agents, whether they are administered in accordance with the invention in the vicinity of the diseased nail or systemically.

However, it would be possible to incorporate one or more of these molecules in a very low total dose compared to the dose necessary for these treatments, in order to avoid contamination of the implanted medical device or the spread of mycoses. Controlled release of these very low doses will also allow protection of the nail matrix as nail infection progresses and threatens the nail matrix.

In the case where the attempted explanation of the mechanism by which a device which constitutes the composition according to the invention and which contains no or only very little active ingredient can cure onychomycosis may not constitute any limitation, it may be assumed that the implantation of such a device may cause an inflammatory process and/or a micromechanical reaction to foreign bodies, with mobilization of the usual biological factors in response, which would regenerate the implanted area and the surrounding tissues.

These processes (e.g., vasodilation, presence of macrophages) can also be initiated by the acidic environment associated with the elimination process of biodegradable and slowly absorbable implanted devices composed of biodegradable polymers (more commonly referred to as PLA or PLGA) formed, for example, from lactic and/or glycolic acid, which can result in mobilization of the body's natural defenses, elimination and/or scarring means that can cause healing of the affected nearby nail.

Furthermore, due to the microenvironment located near the area to be treated, bioabsorbable implantable devices create a barrier that also avoids superinfection, contamination or colonization recurrence by the micromechanical effect of a physical barrier that prevents the disease from spreading outside the affected area and producing a protective effect.

The inventors of the present application have therefore surprisingly and advantageously found that nail diseases, and in particular onychomycosis, can be advantageously treated by: solid depot formulations are implanted under the skin, not under the nail or in the immediately surrounding tissue, but at a distance from the diseased nail in a site that allows for easier, more comfortable and non-pathogenic injection of this type.

Furthermore, the present invention is the only solution that enables the administration of doses of active ingredients in vascularised and innervated tissues in injection or implant (i.e. by passing under the skin) compatible with the requirements of these prolonged treatments. This is also the only solution that enables access to the deep regions of the nail matrix by diffusion of the treatment into the vascular channels that ensure nutrient supply and growth of the nail.

In this way, the invention also offers the possibility of use in combination with other therapies which reach this deep region of the matrix only with great difficulty.

Surprisingly and unexpectedly, the present invention provides the possibility of releasing in a single administration a dose of active agent compatible with the requirements of the treatment in an initial amount at the start of the treatment, which may correspond, as a non-limiting example, depending on the patient, to a very low dose of less than 10% of the total dose administered in the first week after administration, followed by a release period at a lower or higher level depending on the extent of the disease and its speed of progression. Thus, it is possible according to the invention to cover various different release regimes depending on the needs of the patient.

Within the scope of this application, "treatment" includes the prevention, protection, control, management, or alleviation of disease. Also included are basal treatments at the production or deep roots of the nails composed of the matrix, reduction of the risk of recurrence, slowing of transmission, stopping of disease progression, and the fact that pain is alleviated. This is because the present invention offers the unique possibility of protecting the nail matrix as a perfect, non-flawless feature of the treatment, which may or may not be associated with eradication of infections already or not yet settled there, which is of great benefit to all people, people already under oral or topical treatment, people at high risk of infection or relapse due to their pathological condition, or people at high risk or suffering from non-fungal nail morphological aberrations due to their daily physical activity.

Within the scope of the present invention, the treatment of nail diseases also includes accelerating the growth of healthy nails, particularly in the case of onychomycosis; or to resume the growth in the event that nail disease, particularly onychomycosis, has completely or almost completely interrupted the growth. Furthermore, the reconstruction of aesthetically and morphologically healthy nails is one of two mandatory clinical criteria established by those skilled in the art for the confirmation of healing and the absence of fungal contamination and included in the recommendations of international regulatory regulations.

This is because one of the major problems of efficacy for the treatment of nail diseases is related to the slowness of nail growth, more so in the case of "diseased" nails. It is therefore an object of the present invention to make available excipients or active ingredients capable of reconstituting and/or accelerating healthy nail growth, alone or in combination with other excipients or other active ingredients.

It is also an object of the present invention to accelerate healthy nail growth, particularly in the absence of onychomycosis.

The invention according to the present application differs from the prior art by two basic features:

on one hand:

either they contain no active ingredient in particular, and in the case of the treatment of onychomycosis they contain no antifungal agent,

either they contain only a very low total dose of active ingredients, in particular antifungal agents, which is a dose intended only to avoid contamination of the implanted composition or to protect the nail matrix or to avoid the spread of mycoses, for example less than 50%, preferably less than 20%, preferably less than 5%, more preferably less than 2%, still more preferably less than 1%,

either they contain a dose which is significantly lower than the dose conventionally used for the treatment, in particular of onychomycosis with antifungal agents, for example lower than 50mg per area to be treated;

in another aspect, the invention enables care of the condition caused by the fungus, in particular by administration at least 1cm from the infected nail.

When they are present, the antifungal agents are used in dosages that are unexpected and different from the dosages conventionally used, especially in very low dosages and with excellent efficacy.

In the case of terbinafine, for example, the prescribed dose for oral forms for treatment of nail diseases is typically 250 mg/day for 6 to 12 weeks (depending on the affected area), representing a total dose of 21g of active ingredient over a treatment duration of 12 weeks, with only 38% complete recovery results at the time of clinical study.

With the same active ingredient, the composition according to the invention allows a prolonged treatment over 48 weeks and more, with a total dose of terbinafine lower than 2g (i.e. at least 10 times lower than the dose of the present oral forms), preferably lower than 200mg (i.e. 100 times lower than the dose of the present oral forms), more advantageously lower than 60mg (i.e. 350 times lower than the dose of the present oral forms), more advantageously lower than 20 mg/year (i.e. at least 1000 times lower than the dose of the present oral forms) and still more advantageously lower than 5 mg/year (i.e. at least 4000 times lower than the dose of the present oral forms).

Certain active agents, such as itraconazole, may be prescribed at 200 mg/day within 48 weeks with results for no more than 15% of patients fully cared for with 67g of systemically administered active ingredient.

In all of the aforementioned cases, the dose administered by the composition according to the invention may be added to or combined with these treatments to improve the percentage of recovery.

The present application also aims at the treatment of nail diseases with compositions comprising one or more active ingredients for the treatment of acropathy, wherein these compositions according to the invention comprising various active ingredients can be administered alternately in time and with the most suitable frequency. By way of example, it would be possible to administer a composition comprising an active ingredient such as terbinafine during a first treatment phase, followed by a second treatment phase in which the patient would receive a composition comprising a second active ingredient such as ciclopirox, which would be followed by a third treatment phase in which the patient would be re-administered to re-administer a composition comprising the first active ingredient, or a composition comprising a third active ingredient (e.g., ciclopirox olamine or itraconazole), and this until complete recovery. It is also possible to administer compositions comprising several active ingredients at once and to alternate them with compositions possibly comprising a single or several different active ingredients per treatment phase.

Likewise, it is also possible to administer one or more implants simultaneously, each implant comprising one (or more) different active ingredients; and then alternated simultaneously with one or more implants, each implant containing one (or more) active ingredients, which may or may not be different from the initial active ingredient implanted.

On the other hand, the composition according to the invention is not administered systemically under the nail or in the immediately surrounding tissue, but at a distance of more than 1cm from the edge of the nail at its proximal side and preferably outside the last finger or toe section or joint area, preferably in the penultimate finger or toe section.

The delivered dose of excipients and active ingredients is directly proportional to the total size of the injected solid formulation.

These new application areas enable higher daily doses to be delivered than those compatible with the prior art, starting from formulations that are larger, easier, more comfortable and less painful than those administered too close to or in the wounded and particularly sensitive areas of the nail.

One or more solid formulations having a diameter of greater than 0.5mm and a length of greater than 1cm will be injected, for example. For administration under the nail or in the immediately surrounding tissue, solid formulations of this size require a needle of diameter greater than 0.9 mm. It is readily understood that the needle would be incompatible with injection in these too small areas and would be extremely painful to the patient.

It is therefore easy to see that the forms and volumes considered in the composition according to the invention are never compatible with the application area of the treatment methods proposed in the prior art.

The present invention therefore aims at compositions for their use in the treatment of diseases and/or morphological changes of the nail and/or for accelerating the growth of the nail, wherein these compositions comprise one or more active ingredients. In particular, the present invention relates to compositions comprising one or more active ingredients selected from the group consisting of:

-an anti-infective agent selected from:

an antifungal agent, which is a compound selected from the group consisting of,

an antibiotic, and

an antiparasitic agent;

-an anti-inflammatory agent selected from:

a steroidal anti-inflammatory drug which is a drug capable of inhibiting,

a non-steroidal anti-inflammatory drug, and

inhibitors of janus kinases (JAKs);

-cyclosporins;

-vitamin D or a derivative of vitamin D;

-an immunosuppressant;

-an amino acid, preferably arginine;

-an active ingredient accelerating nail growth, preferably selected from:

(ii) prostanoids such as prostanoids,

chitosan, hydroxypropyl chitosan, and a mixture of chitosan and hydroxypropyl chitosan,

the concentration of the valproic acid,

horsetail (equisetum arvense), hyaluronic acid, biotin, Growth Hormone (GH), minoxidil, finasteride;

-an active ingredient for promoting blood circulation selected from:

vasodilators, and

anti-platelet aggregation agents;

-a local anesthetic for the administration of a drug,

the composition is for its use in the treatment of nail diseases by: administration is carried out by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle.

The present invention therefore aims at a composition as described above and preferably comprising one or more active ingredients selected from the group consisting of:

antifungal agents selected from nystatin, amphotericin B, abafungin, benzalkonium chloride, caspofungin, cetyltrimethylammonium bromide, clioquinol, copper sulphate, haloprogin, echinocandins, flucytosine, Mycobactovir, novexantine, natamycin, cetylpyridinium chloride, benzylamine butenafine, benzoborazole (cyclic derivative of boric acid), abaconazole, araconazole, bifonazole, butoconazole, clotrimazole, itraconazole, econazole, eficonazol, fenticonazole, fluconazole, Fosravuconazole, imidazole, isoconazole, itraconazole, isazole, isaconazole, ketoconazole, liazole, lianozoles, clenoliconazole, miconazole, oxadiazoles, oxiconazole, posaconazole, profenoconazole, rivaconazole, sulticonazole, thiazole, tioconazole (thiaconazole), mercaptoconazole, sulconazole, Voriconazole, arginine, amiodarone, naftifine, tavabororo, butenafine, flucytosine, Viabecline, griseofulvin, caspofungin, micafungin, nitric oxide, oxichlorocin, povidone iodine, piroctone olamine, climbazole, tolnaftate thiocarbonate, sulbenine, zinc pyrithione, and more particularly selected from terbinafine, ciclopirox olamine, itraconazole, miconazole and amorolfine.

Preferably, the antifungal agent is selected from terbinafine (optionally in the form of a hydrochloride salt), ciclopirox olamine, amorolfine and miconazole.

Especially for the treatment of infections caused by pseudomonas, the composition according to the invention may comprise antibiotics, preferably fluoquinols (Fluoroquinoles) and tetracyclines.

The composition of the invention may also comprise an antiparasitic agent, which may be selected from: emamectin (emamectin), selamectin, imidacloprid, moxidectin, Milbemycin oxime (Milbemycin oxime), lufenuron, fumagillin, anti-amoebic: rifampin, amphotericin B; anthelmintic agents: fenbendazole, triclabendazole, flubendazole, abamectin, suramin, levamisole, niclosamide, nitrozalone, hydroxychlorozamide, aminoacetonitrile derivatives, spiroindoles, punicalagine sulfate, and artemisinin.

For the treatment of mycoses and in particular onychomycosis, it may be advantageous to administer an anti-inflammatory agent simultaneously with one or more of the above-mentioned antifungal products by using the composition of the invention.

Steroidal anti-inflammatory drugs that can be administered concurrently with the antifungal agent can be selected from the following: hydrocortisone, metrafenone, prednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, halcinonide, beclomethasone, betamethasone, fluocortolone, halomethasone, mometasone, alclomethasone dipropionate, betamethasone dipropionate and betamethasone valerate, clobetasol propionate and clobetasol butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone in the form of ethylester, acetate, butyrate and valerate, prednisonate, and ticortisone pivalate, preferably dexamethasone or triamcinolone.

The non-steroidal anti-inflammatory drugs that can be administered simultaneously with the antifungal agent can be selected from the following: acetylsalicylic and lysine acetylsalicylic acid, methyl salicylate, diflunisal, arylalkanoic Acids, rofenes, indole derivatives, Oxicams (Oxicams), CINODs, Sulfonanilides (Sulfonanilides), Coxibs group, phenylbutazone, niflumic acid and fenamic Acids (Phenamic Acids).

Another type of anti-inflammatory drug that may be administered is an inhibitor of janus kinase (JAK).

For the treatment of inflammatory diseases and in particular psoriasis with or without inflammatory phenomena, it is also possible to use the anti-inflammatory agents mentioned above.

In addition to one or more anti-inflammatory agents, the treatment of nail diseases and in particular the treatment of inflammatory diseases such as psoriasis may be carried out with the aid of the compositions of the present invention comprising one or more cyclosporins, preferably cyclosporin a, vitamin D or a derivative of vitamin D, preferably calcipotriol or paricalcitol.

The compositions of the invention may also comprise immunosuppressive agents, preferably methotrexate, retinoids, preferably tazarotene, or compounds such as anthralin (or dithranol) and urea.

The composition according to the invention may also comprise one or more amino acids, preferably arginine.

The composition according to the invention may also comprise one or more active ingredients accelerating nail growth, preferably selected from prostanoids. Prostanoids which may be used may preferably be selected from derivatives of prostaglandin F2 α or prodrugs of PGF2 α, and especially latanoprost, travoprost or bimatoprost, more preferably latanoprost or bimatoprost.

To promote nail growth, chitosan, hydroxypropyl chitosan, valproic acid, equisetum arvense (equisetum), hyaluronic acid, biotin, Growth Hormone (GH), minoxidil and/or finasteride may also be used.

The composition of the present invention may further comprise one or more active ingredients for promoting blood circulation such as vasodilators and anti-platelet aggregation agents. The vasodilator may be selected from amlodipine (benzene sulfonic acid, methane sulfonic acid or maleic acid), nifedipine, diltiazemVerapamil, Ginkgo biloba (Ginkgo biloba), iloprost, endothelin, Nacitentan, bosentan, nicotinic acid (niacin), arginine, nitric oxide, nitroglycerin, isosorbide dinitrate, prostacyclin (PGI2) and other prostaglandins, histamine, bradykinin.

In particular, for the treatment of diabetic foot complications, buerger's disease, raynaud's disease, lower limb arteritis, antiplatelet aggregation agents such as clopidogrel may be used.

The compositions of the present invention may also comprise a local anesthetic, which may be selected from lidocaine, articaine, bupivacaine, levobupivacaine, mepivacaine, procaine, and ropivacaine.

Preferably, a composition comprising valproic acid, a substance commonly known and used in the treatment of diseases caused by keratin deficiency, such as androgenic alopecia, is used.

In particular, the present invention is directed to the above-described composition for its use in the treatment of nail diseases, characterized in that the nail disease is onychomycosis and in that it comprises one or more of the above-mentioned active ingredients selected from the following:

an antifungal agent, preferably selected from terbinafine (optionally in the form of a hydrochloride salt), ciclopirox olamine, amorolfine, miconazole and itraconazole,

-steroidal or non-steroidal anti-inflammatory drugs, preferably selected from dexamethasone and triamcinolone,

-a group of cyclosporins, which is,

-an amino acid, preferably arginine,

-an active ingredient which accelerates the growth of the nail, in particular chitosan, hydroxypropyl chitosan,

-a vasodilator for the treatment of a disease,

-a local anaesthetic drug,

-an antibiotic agent, the antibiotic agent being selected from the group consisting of,

antiparasitics, in particular emamectin, ivermectin and selamectin.

The composition according to the invention to be used for the treatment of the above-indicated inflammatory diseases and in particular psoriasis may advantageously comprise one or more cyclosporins such as cyclosporin a or G, preferably cyclosporin a.

The object of the present invention is therefore also a composition for its use in the treatment of nail diseases, as described above, characterized in that said nail disease is psoriasis, with or without accompanying inflammatory phenomena, and in that it comprises one or more active ingredients, preferably selected from the following:

-a steroidal anti-inflammatory drug selected from: hydrocortisone, metrafenone, prednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, halcinonide, beclomethasone, betamethasone, fluocortolone, halomethasone, mometasone, alclomethasone dipropionate, betamethasone dipropionate and betamethasone valerate, clobetasol propionate and clobetasol butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone in the form of ethylester, acetate, butyrate and valerate, prednisonate, and ticortisone pivalate, preferably dexamethasone or triamcinolone,

-a non-steroidal anti-inflammatory drug selected from: acetylsalicylic and lysine acetylsalicylic acid, methyl salicylate, diflunisal, arylalkanoic acids, profen, indole derivatives, oxicams, CINODs, sulfonanilides, Coxibs, phenylbutazone, niflumic acid and fenamic acid,

inhibitors of Janus kinase (JAK),

-one or more cyclosporins, preferably cyclosporin A,

vitamin D or a derivative of vitamin D, preferably calcipotriol or paricalcitol,

-a vasodilator for the treatment of a disease,

-an immunosuppressive agent, preferably methotrexate,

retinoids, preferably tazarotene,

compounds, such as anthralin (or dithranol) and urea,

-an active principle accelerating the growth of the nail, selected from prostanoids, preferably latanoprost or bimatoprost,

-chitosan, hydroxypropyl chitosan,

-a source of valproic acid,

-a vasodilator for the treatment of a disease,

-a local anaesthetic agent,

-arginine.

For the treatment of diabetic foot complications, Burger's disease, Raynaud's disease, lower limb arteritis, an antiplatelet agent such as clopidogrel, and a vasodilator selected from (benzenesulfonic, methanesulfonic or maleic) amlodipine, arginine, nifedipine, diltiazem may be added to the composition according to the inventionVerapamil, ginkgo biloba, iloprost, endothelin, Nacitentan, bosentan, nicotinic acid (niacin), nitric oxide, arginine, nitroglycerin, isosorbide dinitrate, prostacyclin (PGI2), and other prostaglandins, or for example histamine and bradykinin.

When only nail growth is sought, the composition according to the invention may comprise one or more active ingredients selected from cyclosporins, prostaglandins, preferably the above mentioned cyclosporins and prostaglandins, chitosan, hydroxypropyl chitosan, and/or valproic acid.

In particular, the present invention also aims at the composition described above for its use for accelerating nail growth, characterized in that it comprises one or more active ingredients selected from the following:

-a cyclosporin, preferably cyclosporin A,

prostanoids, preferably selected from latanoprost or bimatoprost,

-Equisetum arvense (Equisetum hiemale), chitosan, hydroxypropyl chitosan, hyaluronic acid, biotin, valproic acid, Growth Hormone (GH), minoxidil and/or finasteride,

-an amino acid, preferably arginine,

vasodilators selected, for example, from ginkgo biloba, nitric oxide and arginine,

-valproic acid.

In particular, the present invention also aims at a non-therapeutic method of accelerating nail growth, characterized in that it comprises the administration of a composition as defined above and comprising one or more biodegradable fixing polymers with extended release, one or more active ingredients selected from:

-cyclosporins;

-prostanoids;

-Equisetum arvense (Equisetum hiemale), chitosan, hydroxypropyl chitosan, hyaluronic acid, arginine, biotin, valproic acid, Growth Hormone (GH), minoxidil and/or finasteride,

-a vasodilator for the treatment of a disease,

-a source of valproic acid,

and optionally, one or more active ingredients selected from the group consisting of:

-an anti-infective agent selected from:

an antifungal agent, which is a compound selected from the group consisting of,

an antibiotic, and

an antiparasitic agent;

-an anti-inflammatory agent selected from:

a steroidal anti-inflammatory drug which is a drug capable of inhibiting,

a non-steroidal anti-inflammatory drug, and

inhibitors of janus kinases (JAKs);

-vitamin D or a derivative of vitamin D;

-an immunosuppressant;

-an amino acid, preferably arginine;

-an active ingredient for promoting blood circulation selected from:

vasodilators, and

anti-platelet aggregation agents;

-a local anesthetic for the administration of a drug,

In particular, the present invention also aims at the use of a composition as defined above for accelerating the growth of the nail.

In summary, for the treatment of mycoses and in particular onychomycosis, it may be advantageous to administer an anti-inflammatory drug, preferably a steroidal anti-inflammatory drug, simultaneously with one or more of the above-mentioned antifungal products, by using the composition of the invention.

The composition according to the invention may preferably comprise:

one or more antifungal products selected from the group consisting of: ciclopirox olamine, amorolfine, imidazoles, tolnaftate, bifonazole, butenafine, tioconazole, terbinafine, itraconazole, fluconazole, griseofulvin, ketoconazole, ciclopirox olamine, ciclopirox, miconazole, and more particularly selected from terbinafine, ciclopirox olamine, itraconazole, and amorolfine;

one or more anti-inflammatory agents which can be administered simultaneously with the antifungal agent, preferably selected from:

-inhibitors of janus kinases (JAKs);

one or more vasodilators selected from amlodipine (benzenesulfonic acid, methanesulfonic acid or maleic acid), nifedipine, arginine, diltiazemVerapamil, ginkgo biloba, iloprost, endothelin, Nacitentan, bosentan, nicotinic acid (niacin), nitric oxide, nitroglycerin, isosorbide dinitrate, prostacyclin (PGI2) and other prostaglandins, histamine, bradykinin;

local anesthetics, such as lidocaine.

The composition according to the invention may be of any shape or size compatible with the new specific area of application and with the initiation of a local reaction with the body, capable of treating nail diseases in the absence of an active ingredient, such as an antifungal agent, or capable of delivering a sufficient amount of an active ingredient to be therapeutically effective in treating nail diseases and/or accelerating or re-establishing nail growth or regrowth.

The composition may be presented in the form of an implant, optionally with sharp ends, or a cylindrical tube, rod or wire. They may also be in the form of granules, discs or flakes.

The composition of the invention can be administered, for example, by means of a needle or by means of a device which avoids the use of a needle altogether and with which the composition is injected directly under the skin of the patient. Devices of this type, compositions which can be administered in this way and processes for their preparation are described, for example, in international application WO 96/08289.

The composition according to the invention may for example be a monofilament or multifilament suture of equivalent PLA and PLGA, preferably having a length of at least 10mm and up to 25 mm. These flexible threads can be placed by means of needles and have the advantage of being able to conform to the shape of the fingers.

The composition according to the invention can take various different forms (implants, wires), it being possible to implant two or more implants or wires, for example on each side of the finger or toe, optionally symmetrically and preferably on the outer dorsal part of the penultimate digit or toe.

In the form of a thread, the compositions of the invention may have a greater length, greater than 25mm, and for example 10cm, so as to be able to be implanted starting from the same needle by cutting them to the desired length, for example on each side of the finger or toe to be treated or one after the other in the same finger or toe.

Another advantageous manifestation of the composition according to the invention in the form of a thread directly fixed to a needle with curvature may enable its introduction under the skin and its re-extraction after placement of a length that may vary according to the needs of the treatment and according to the morphology of the fingers or toes.

According to this advantageous application method, at the time of application, it is sufficient to perform the implantation until the end of the thread opposite the needle disappears under the skin and then to cut off the thread at the surface of the skin. The implantation of these line segments starting from the same thread and the same needle can be performed anew. Another advantage of this device is that it allows implantation with a needle diameter comparable to that of the wire, rather than larger as in the case where the wire is previously contained inside the needle. This reduces pain, improves the comfort of the treatment and its in situ retention in the tissue in direct contact with the thread.

Advantageously, the composition may comprise a tip having the shape of a toothpick and having sufficient hardness to allow it to penetrate through the skin into the subcutaneous layer.

In particular, the present invention also aims at the above-described composition for its use in the treatment of nail diseases and/or for accelerating nail growth, characterized in that said composition is in the form of an implant, a cylindrical tube or a wire, optionally with a sharp tip; and applying the composition in the finger or toe except for the last digit. According to the present invention, "accelerating nail growth" or "acceleration of nail growth" refers to the fact that the rate of nail growth is reestablished, allowed and/or increased.

According to a preferred embodiment of the invention, the composition according to the invention is presented in the form of an implant comprising one or more active ingredients and one or more biocompatible, biodegradable or bioabsorbable polymers.

"biocompatible" refers to a polymer that does not cause irritation of surrounding tissue.

"biodegradable" polymers that degrade over time under the action of enzymes or hydrolysis.

By "bioabsorbable" is meant that the polymers that make up the composition are metabolized and absorbed by the surrounding tissue.

In a preferred embodiment of the invention, a copolymer of lactic acid and glycolic acid (PLGA) is used. The percentage of each monomer can vary from 0 to 100%. For example, it may be about 50/50, but may also be about 100-0%, 85-15%, 75-25%, 65-35%, and 55-45% or less.

The polymers and copolymers may be capped at their ends by acidic or ester functional groups.

Preferred solid polymers with extended release are polymers of L-lactic acid, D-lactic acid, DL-lactic acid, L-lactide, D-lactide, DL-lactide, glycolide, glycolic acid, caprolactone, polydioxanone and all corresponding copolymers.

Preferred PLA polymers are poly (D, L-lactide) having a viscosity of 0.16 to 2dL/g, preferably 0.20 to 1.8dL/g, and preferably 0.5 to 1.2 dL/g.

Preferred PLGA copolymers are 85:15 copolymers having a viscosity on the order of 0.15 to 7dL/g, preferably 0.25 to 3dL/g, and preferably 0.50 to 1.8 dL/g.

The loading of active ingredient may vary between 0% and 99%, in particular below 85%, preferably below 75%, preferably it is between 20% and 70%. In particular, it may be 20%, 30%, 35%, 40%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69% or 70%.

As indicated above, the composition according to the invention may not comprise any active ingredient ("placebo" composition). They may also contain very low doses of active ingredients such as antifungal agents to avoid contamination of the implanted composition, to protect areas, or to avoid the spread of mycoses. In the last case, the concentration may be around 0.01%.

The amount of active ingredient (preferably terbinafine hydrochloride, ciclopirox olamine or ciclopirox, itraconazole) per implant (which is a preferred form of the composition of the invention) may be from 0 to 6.5mg, more particularly from 0.01 to 2.5mg of product. The amount of the active ingredient may be, for example, 0.01, 0.02, 0.04, 0.16, 0.20, 0.30, 0.5, 0.78, 1.00, 1.10, 1.20, 1.30, 1.40, 1.50, 1.60, 1.70, 1.80, 1.90, 2.00, 2.10, 2.20, 2.30, 2.40, 2.50, 2.60, 2.70, 2.80, 2.90, 3.00, 3.10, 3.20, 3.30, 3.40, 3.50, 3.60, 3.70, 3.80, 3.90, 4.00, 4.10, 4.20, 4.30, 4.40, 4.50, 4.60, 4.70, 4.80, 4.90, 5.00, 5.10, 5.20, 5.30, 5.40, 5.30, 6.50, 6.90, 6.50, 6.5.5, 6.5, 6.30, 6.60, 6.30, 6, 6.30, 6 mg.

In particular, the present invention is directed to the composition described above, characterized in that said solid polymer with extended release is a polyester, preferably a lactic-glycolic acid copolymer (PLGA) or a lactic acid Polymer (PLA), and the loading of active ingredient is lower than or equal to 85%, and preferably between 20 and 70%, by weight.

In particular, the present invention is directed to the composition described above, characterized in that it comprises 0.04 to 6.50mg of terbinafine hydrochloride or terbinafine, and PLGA.

In particular, the present invention is directed to a composition as described above, characterized in that said composition comprises 0.04 to 6.50mg of ciclopirox or ciclopirox olamine, and PLGA.

In particular, the present invention is directed to the composition described above, characterized in that it comprises between 0.04 and 6.50mg of itraconazole, and PLGA.

The composition according to the invention may have up to about 30mm³The total volume/implant or injection of (a), which may be about 5mm in volume³To about 30mm³Preferably about 10mm³To 30mm³. However, they may have a thickness of more than 30mm³Total volume of (c).

The diameter of the implant may be 0.1 to 1mm, preferably 0.1 to 0.9mm, more preferably 0.3 to 0.8mm, and in particular the diameter may be 0.1, 0.25, 0.3, 0.4, 0.45, 0.50, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.65, 0.70, 0.75, 0.85 or 0.90 mm.

The length of the implant per injection may be up to 25mm, it is preferably 4 to 15mm, it may for example be 4, 6, 8, 9 or 10 mm. The overall length may be greater than 25mm and the implant is cut to the size required for each implantation.

The invention therefore aims at a composition for its use in the treatment of nail mycoses of the fingers or toes (also known as onychomycosis), characterized in that it comprises one or more biodegradable solid polymers with prolonged release, and optionally one or more antifungal agents, and in that it is presented in the form of an implant with a maximum injection length of 25mm, preferably 4 to 15mm, and a diameter of 0.1 to 1mm, preferably 0.3 to 0.8mm, intended to be administered by subcutaneous route at a distance greater than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last finger or knuckle.

In other words, the object of the present invention is therefore a composition in the form of an implant having a maximum injection length of 25mm, preferably 4 to 15mm, and a diameter of 0.1 to 1mm, preferably 0.3 to 0.8mm, said implant comprising one or more biodegradable solid polymers with extended release and one or more antifungal agents, said composition being for its use in the treatment of onychomycosis by: administration is carried out by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle.

The present invention therefore also aims at the above-described composition for its use in the treatment of nail diseases and/or for accelerating nail growth, characterized in that said composition is in the form of an implant, a cylindrical tube or a wire, optionally with a sharp tip; and applying the composition in the finger or toe, except in the last digit, in the first and second, preferably the second, digit of the finger or toe, and in the first digit or toe of the thumb or toe; and one or more compositions, preferably one to eight compositions, more preferably one to six compositions, are applied simultaneously in the same finger or toe.

In particular, the present invention is directed to a composition as described above, characterized in that the treatment is continuous, preferably for a minimum duration of 48 weeks when the whole nail is affected, for a minimum duration of 24 weeks when less than half of the nail is affected, or for a minimum duration of 12 weeks when less than one quarter of the nail is affected, or for a duration of 6 weeks, preferably for a duration of less than 6 weeks when less than 10% of the nail is affected.

For the avoidance of any doubt, it is clear that the compositions according to the invention may comprise one or more active ingredients selected from any of the above mentioned active ingredients when they are used in the claimed application.

It is possible to mix various active ingredients in the same implant or in the same thread. It is also possible to prepare implants or threads with each active ingredient and to combine the administration of two or more of these implants and threads, according to the specific needs of each patient, for example according to the type of fungus involved in its mycosis, or in order to treat simultaneously with the fungus causing the mycosis the inflammation associated with the mycosis.

Administration of the composition according to the invention is performed by the subcutaneous route. As indicated above, devices suitable for achieving this administration may be used, and one example of such a device is described in international application WO 96/08289.

The present invention therefore aims at the above-described composition for its administration by subcutaneous route in the first or second, preferably penultimate, digit, i.e. the second digit, of the finger or toe and in the first digit or toe of the thumb or toe.

Thus, the composition according to the invention is administered or injected by subcutaneous route, away from the end of the finger or toe and at a distance of more than 1cm from the stratum corneum, and in particular, the composition is administered by subcutaneous route, outside the distal digit, in the middle or proximal digit or (for the foot) proximal digit or first or second digit or knuckle, preferably the second digit or knuckle, of the finger or toe, and in the first digit or knuckle of the thumb or toe.

Preferably, the compositions are administered on the dorsal part of the finger or toe or on each of the dorsal and non-palmar sides of the penultimate digit, in the middle of the digit, at an equal distance from the two joints defining it.

The new and inventive feature of the present invention lies in particular in the fact that the application or injection of the composition according to the invention is not carried out under or in the immediate vicinity of the nail (as this is done with injections known for these types of treatment, or as this is suggested in several prior art applications, in particular in the following patent USP 8747820, international application WO2011/087867 or WO2006/063350), but at a distance of more than 1cm from the proximal end of the nail, outside the finger or toe carrying the nail.

As noted above, administration or injection in living tissue outside of the diseased area of the nail or its immediate environment avoids interference with areas that are traumatized due to mycoses, interfering with delayed healing. Furthermore, the unaffected area is larger and where row injection is much easier and less painful than in the nail area, and this space allows the administration of several implants if needed.

On the other hand, the small injectable available volume under or in the immediate vicinity of the nail generally does not allow the delivery of a dose of active substance sufficient for the treatment considered: this does not allow targeting the base of nail growth or renewal that constitutes the matrix.

The present invention therefore aims at the compositions described above, characterized in that one or more compositions, preferably one to six compositions, more preferably 1 to 4 compositions, are applied simultaneously in the same finger or toe.

This region upstream of the nail enables the injected treatment to be preferentially or preferentially directed to the matrix at a deep source of the nail, in a region that is not accessible to external local forms. This enables the consideration of basal treatment of mycoses, for example in the case of whole or significant portions of infected nails, without the disadvantages of oral forms, and thus covering the need to avoid relapse or reinfection after more than one year over a much longer period of time.

In order to carry out the injection or the deposition while avoiding that the treatment is painful for the patient, local anaesthesia (local or injectable) of the subcutaneous implanted area will be carried out beforehand.

The specific application treatment will be immediately and rapidly performed by a professional dermatologist or podiatrist or authorized medical personnel, depending on the area. It avoids any topical treatment for the patient, for example with cream, a treatment which is often difficult, long and complicated to apply to patients with age. This ensures monitoring of the treatment, which is no longer dependent on patient compliance.

The deposition will be under the skin or in the dermis.

The treatment with the composition according to the invention enables better results to be obtained with much less binding and at very low cost compared to laser treatment of the perforation sometimes containing a nail.

Recently, however, new treatments for nail diseases and in particular onychomycosis have been developed. These treatments consist in causing the rupture of spores and the destruction of fungi by the photobiological thermal effect of the laser on the nail plate. The treatment is typically repeated at least 3 times with 4 to 6 weeks between each treatment.

During laser treatment, a laser beam of controlled wavelength is directed at the nail bed to generate heat under the nail by thermal effects at wavelengths determined to destroy fungal colonies.

The results obtained with this technique have been reported, for example, in the following publications: novel LASER Therapy in treatment of Onychomycosis, Jasmina Kozarev et al, Journal of the LASER and Health academic, Vol.2010, No.1, p.1.

Several commercial laser radiation generating instruments, PinPointe, can be used^TM、FootLASER^TMOr ND YAG, or in particular instrument S30 PODYLAS^TM. Frequently used wavelengths are 870, 930 or especially 1064 nm.

However, these laser treatments do not allow access to deep infected areas at all times, and therefore their effectiveness can be limited and their expensive expense can be a limitation to their use. Furthermore, the efficacy of the treatment is directly dependent on the practitioner's adherence to the strict procedures of laser application.

Thus, the composition according to the invention can usefully be combined with laser treatment to reach deep infected areas that are not accessible to laser light and improve their efficacy.

Obviously, although repeated injections may be considered for these treatments, the most suitable method is that of only one deposition injection or of the minimum, which will then locally release the active ingredient, in particular the antifungal agent, for a sufficient period of time compatible with the complete treatment, preferably several months to 1 year.

Advantageously, it is thus possible thanks to the invention to administer such doses of 0 to 50mg of active ingredient/affected area, or different doses of active ingredient, once a year, half a year, quarterly, monthly or weekly, depending on the severity of the infection.

It is possible, depending on the type of fungus and other concomitant nail diseases, to increase the treatment and administration for the same treatment and thus optimally cover the needs of the patient, without the need to administer high doses or the conventional therapeutic doses used by oral or topical routes.

It is also possible to adapt the release profile, both in terms of dose and in terms of quantity released over time, in single or multiple doses, according to the needs of the patient and to the pathological conditions thereof.

Preferably, the administration of the active ingredient by means of the composition of the invention is carried out for at least 48 weeks. Preferably, the administration is performed for more than 48 weeks.

Preferably, this administration replaces conventional treatment at high doses delivered by the oral route at the beginning of a severe mycosis situation, and may continue throughout the treatment period until recovery, even after a year or when other treatments (e.g. topical treatments) are discontinued, to avoid maternal reinfection and recurrence risk, and to protect the mother matrix as distal onychomycosis progresses.

The present invention therefore aims at the composition described above for its use in the treatment of nail diseases, characterized in that one or more compositions are administered simultaneously in the same finger or toe and the treatment is continuous, preferably for a minimum duration of 48 weeks. Preferably, the administration occurs every month, every three months, or every six months, and the treatment is delivered for at least twelve months, even eighteen months.

Another object of the present invention is to treat certain nail diseases in which the entire nail is untouched but only a portion is infected or diseased. In these particular cases, the duration of treatment will be less than 48 weeks; for example, the minimum treatment duration would be 24 weeks if less than half of the area of the nail is affected by the disease, or the minimum treatment duration would be 12 weeks if less than one-fourth of the area of the nail is affected by the disease, or the minimum treatment duration would be less than 12 weeks if less than one-tenth of the area of the nail is affected by the disease or is likely to be infected.

The present invention therefore aims at the compositions described above for their use in the treatment of nail diseases, characterized in that one or more of the compositions are administered simultaneously in the same finger or toe and the treatment comprises one or more intervals during which the treatment is delivered starting from these on-time administrations.

Administration by subcutaneous injection of an implant or wire may be performed with a solid composition loaded inside a hollow needle having a larger diameter than the implant or wire. Thus, these administrations may be performed starting from a single needle with the solid composition fixed at the other end of a solid needle having the same diameter as the implant or wire.

One of the other benefits of this method of treatment and in particular antifungal treatment according to the invention with respect to oral treatment is to limit the amount of active product in the whole body in the areas where they are undesirable and therefore also to greatly reduce the total amount of product used for the same treatment.

Furthermore, this enables the control of the risks of environmental pollution due to emerging molecules from drug discards and wastes, which constitutes a serious threat that is increasing and difficult to avoid, but is much better controlled upstream in the method according to the invention, up to 1000 times or even up to 5000 times lower amounts of these molecules for the same treatment, 100% of the useful drug dose, and no product removed because of non-use by the patient, as is often the case with the remainder of the liquid in tablets or bottles of conventional treatments.

One of the other benefits of the treatment method according to the invention obtained with a long-acting or controlled composition that releases its active ingredient in a prolonged manner over time is to enable having an active ingredient that is persistent at its site of action. In addition, it is known that some of these molecules are capable of accumulating at the level of the nail, which contributes to their efficacy and the possibility of reducing the dosage in the use according to the invention.

The object of the present invention is therefore also the use of these compositions in combination with other treatments, such as oral, topical or laser treatments, for ensuring, in particular, the treatment of infections at the level of the deep layers of the matrix to ensure the persistence of the required treatment in situ, or to prolong the treatment after these treatments to avoid relapse or to protect the area (during infections with rapid progression) or the population at high risk of complications.

Another object of the invention is to propose an external local area treatment of nail diseases with prolonged duration starting from these same solid compositions by insertion between the nail plate and the nail bed (when they are separated or easily separable).

The inventors have thus found that these diseases can also be treated in an external manner by inserting one or more solid compositions according to the invention having significant advantages between the nail plate and the nail bed. On the one hand, it offers the advantage of easy and precise positioning, due to its solid monolithic form of controlled shape and size that can be easily manipulated for its insertion through the network and tortuous of the filamentous hyphae of the fungus. Furthermore, once in contact with the affected tissue under the influence of humidity, either ambient or provided frequently at this level, the composition will quickly fit fully into the available volume by becoming pliable and softening and thus avoiding the creation of a solid physical barrier that may impede regrowth of healthy nails. This is because, when the compositions according to the invention are in contact with an aqueous medium for a prolonged period of time, they become flexible and until they become liquid or semi-solid, which is the preliminary stage of biodegradation of the polymers constituting said compositions.

Accordingly, the present application also aims at a solid composition for its use in the treatment of nail diseases and/or for accelerating nail growth, said composition comprising one or more biodegradable or non-biodegradable solid polymers with extended release and optionally one or more active ingredients; and the composition is presented in the form of a device intended to be applied by insertion into the space between the nail bed and the nail plate; and optionally the composition is used simultaneously or staggered in time with the administration of these same compositions by subcutaneous route of one or more of the above described and comprising one or more biodegradable solid polymers with prolonged release and optionally one or more active ingredients at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle.

Depending on the case, this external method of insertion will be used either separately or in combination with the internal use of the implantation of the solid composition of the invention to achieve the same result.

The two internal and external long-acting treatment methods may optionally be combined and release one or more active ingredients in the same formulation or in separate formulations administered separately, according to the needs of each patient.

The inventors have found that this type of long acting formulation enables a much longer lasting long acting effect to be obtained when it is inserted into a less flushed area, such as subcutaneous tissue, which has less exchange because there is no vascularity, wherein the active ingredient is kept in situ. Thus, it is contemplated that the same formulation that needs to be renewed when implanted under the skin, for example every 3 months, may produce a therapeutic effect within a year when inserted over the nail bed. Thus, external treatment of this type will be possible only once, thereby obtaining treatment until complete recovery.

At the level of the nail bed, in areas that may be separated from the keratinized nail plate due to infection by mycoses or in the nail plate itself that is thickened due to mycoses and difficult to access by external local treatment, it would be possible to combine the treatments by inserting the same active ingredients. Advantageously, the composition according to the invention, due to its composition, its size and its rigidity, has such characteristics as to be able to be inserted, with or without an applicator, into the subungual space between the nail and the nail bed.

The affected nail often experiences a phenomenon in which the cornified nail plate lifts up slightly and thickens relative to the nail bed, known as nail detachment and nail dystrophy. These nail detachment and nail dystrophy are due to the excessively rapid renewal of nail bed cells through an inflammatory response to infection by mycoses. This nail detachment can be advantageous for administering formulations comprising anti-infective active agents, where a space is created between the nail and the nail bed to allow more effective release of the active agent directly in the affected area, while remaining non-invasive and thus painless.

In addition, the nail detachment may also be a site of attack for fungal infections that have priority in the case of nail dystrophies that are not initially directly associated with mycological infections. When this is possible, it is also appropriate to protect the nail so diseased by administering prophylactic treatment.

In particular, the inventors have found that without the need to create a prior passage by means of a sharp drilling tip, the composition can be pushed directly into free space without creating trauma to the area to be treated for this purpose and without having to resort to tools capable of creating tissue wounds or excessively large openings with dead spaces (which may promote high exposure to sources of contamination and external aqueous media).

In particular, the inventors have found that if an instrument is used for insertion of the composition, it is ideally equipped with a blunted blunt tip. It may be hollow and contain the composition inside it to be placed in the exact place by reverse placement by means of a piston or mandrel. It may also be solid and thus enable the creation of through channels of suitable dimensions for the composition among the residues and hyphae of the fungus which penetrate into the space.

The inventors have found that the composition or compositions for covering the entire surface to be treated according to the invention thus inserted and deposited continues to remain in said space in a prolonged manner and, thanks to its prolonged release system and its softening, allows the hyphae and fibrils of the fungus to be completely exposed directly to the accompanying antifungal therapeutic agent without hindering the nail growth, thus creating a reservoir of antifungal agent that is mobile but not in contact with the outside.

These external long-acting treatments according to the invention need not be applied daily, but weekly or monthly or quarterly or semi-annually or annually, as with the new injectable treatments.

They can be administered to the patient at the same time and at the same frequency of intervals as the injectable internal treatment. They may also be administered less frequently than internal treatments.

The invention therefore also aims at one or more compositions according to the invention for its use in the treatment of nail diseases and/or for accelerating nail growth, comprising one or more biodegradable or non-biodegradable polymers with prolonged release and one or more active ingredients, characterized in that said compositions are presented in the form of a device intended to be administered by insertion into an empty or prepared space between the nail bed and the nail plate; and optionally, said composition is used simultaneously or staggered in time with the administration by subcutaneous route of one or more solid compositions described above and comprising one or more biodegradable polymers at a distance of more than 1cm from the proximal end of the nail, preferably in the finger or toe except for the last digit.

In other words, the object of the present invention is therefore also a solid composition comprising one or more biodegradable or non-biodegradable monomers or polymers with extended release and one or more antifungal agents, for its use in the treatment of nail diseases, by: administration is carried out by direct insertion into the empty space between the nail bed and the nail plate or into the space previously pushed into the previously created channels of the dimensions of the implant in the hyphal network and the fragments present between the nail bed and the nail plate, optionally simultaneously or temporally staggered with subcutaneous administration of one or more of the solid compositions described above and comprising one or more biodegradable polymers in the finger or toe at a distance of more than 1cm from the proximal end of the nail, preferably except for the last knuckle.

Another object of the invention is to propose an external topical area treatment of nail diseases with prolonged duration by inserting between the nail plate and the nail bed (when they are separated or easily separable) with other long-acting or controlled liquid or non-solid compositions. The expression "non-solid composition" includes liquid compositions.

The inventors have also found that these diseases can also be treated externally by inserting a liquid or non-solid, long-acting or controlled formulation between the nail plate and the nail bed that will fit the available volume and not create a solid physical barrier that may impede regrowth of healthy nails.

Depending on the case, the process will be used either separately or in combination with the use of the solid composition of the invention to achieve the same result.

The two internal and external long acting forms may optionally be combined and release one or more active ingredients in the same formulation or in separate formulations administered separately, according to the needs of each patient.

At the level of the nail bed, in areas that may be separated from the keratinized nail plate due to infection by mycoses or in the nail plate itself, which is thickened due to mycoses and difficult to access by external local treatments, it would be possible to combine the treatments by: the insertion or infiltration of a suspension with the same active ingredient, in liquid or non-solid form, which may be polymerizable, curable or not by various means (thermal, light, solvent, etc.), is achieved, for example, starting from monomers which form a gelled network in aqueous or non-aqueous solvents, which will form a hydrogel, organogel or any other gel which can contain and release the active agent.

An example of a polymer that can be used to contain an active ingredient for external administration or insertion of this type with prolonged or prolonged effect may belong to the family of polyhydroxyethylmethacrylate, hydroxyethylmethacrylate, carboxymethylcellulose, hyaluronic acid, or any other biodegradable or non-biodegradable hydrogel-forming polymer, in a formulation alone, in combination with each other or formulated with other excipients.

An example of a formulation for topical and transdermal or ungual application without long-lasting effects that can be used containing organogel-forming active ingredients is described in Mediquest Therapeutics WO 2009/097471 and WO 2006/042059.

Another example of an associated polymer or formulation that may be used to contain an active ingredient for external application is described in the Gecko Biomedical patent WO2016202985, which will have the effect of a binder that will release the active ingredient as it biodegrades. In this case, the polymerization can be carried out in situ after application, as with the previous biopolymers.

Another example of a formulation which may contain an active ingredient for external administration is described in patent US 2010/0048724 to Hallux. Here, the proposed area of application is between the nail plate and the nail bed, but the compositions under consideration are not long-lasting and therefore mean frequent and repeated applications, which do not provide a satisfactory response for this treatment area, in which it is preferable to intervene infrequently.

Finally, the polymer comprising the active ingredient in suspension will be in a form that is non-aqueous and that is neither solid nor curable, prepared for example starting from PLGA, according to patents WO2004/067602, WO2005/100439, WO2006/018524, WO2007/085729, WO2008/049631, WO2009/138589, WO2012/06619 and WO 2012/066194. The formulation, which is not solid nor contains organic solvents and does not dry out, may have a prolonged topical effect without hindering re-growth of the nail. These suspensions and these treatments constitute another object of the invention.

These new long-acting treatments according to the invention need not be applied daily, but weekly or monthly or quarterly, as with the new injectable treatments.

They can be administered to the patient at the same time and at the same frequency of intervals as the injectable internal treatment.

The internal treatment can continue for the entire required duration, optionally in addition to and simultaneously with the long-acting external treatment inserted at the level of the nail plate or at the level of the nail bed.

The invention therefore also aims a liquid or non-solid composition for its use in the treatment of nail diseases and/or for accelerating nail growth, said composition comprising one or more biodegradable or non-biodegradable polymers with prolonged release, and optionally one or more active ingredients, characterized in that said composition is presented in the form of a device intended to be administered by insertion into the empty or prepared space between the nail bed and nail plate; and optionally, said composition is used simultaneously or staggered in time with the administration by subcutaneous route of one or more solid compositions described above and comprising one or more biodegradable polymers at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last finger or toe.

In other words, the object of the present invention is therefore also a liquid or non-solid composition comprising one or more biodegradable or non-biodegradable monomers or polymers with prolonged release and optionally one or more antifungal agents, for its use in the treatment of nail diseases, by: administration is carried out by insertion into the empty or prepared space between the nail bed and the nail plate, optionally simultaneously or temporally offset with the subcutaneous administration of one or more solid compositions described above and comprising one or more biodegradable polymers, at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last finger or toe segment.

The polymer of the biodegradable non-solid composition for use by administration via insertion into the space between the nail bed and the nail plate may for example be selected from the polymers described in for example international patent application No. WO 2008/049631.

Thus, these polymers may preferably be selected from biodegradable polymers having a very low molecular weight and optionally capped at one end with an alkyl group comprising 5 to 18 carbon atoms (instead of its carboxy terminus), selected from polylactic acid, polyglycolic acid, poly (lactide-co-glycolide) acid and mixtures thereof.

These non-solid and non-curable compositions thus comprising one or more biodegradable polymers with extended release may use the same active ingredients as these solid compositions of the invention comprising a polymer, preferably in PLGA-based form.

These polymers or copolymers for biodegradable non-solid (also referred to as semi-solid) compositions preferably have a molecular weight of 700 to 3000 daltons, preferably 800 to 2000 daltons.

The present invention is particularly directed to the above-described composition comprising one or more biodegradable non-solid polymers, characterized in that said non-solid polymer with extended release is selected from polylactic acid, polyglycolic acid, poly (lactide-co-glycolide) acid and mixtures thereof, and the molecular weight of these polymers or copolymers is preferably between 700 and 3000 daltons, preferably between 800 and 2000 daltons.

The present invention is also directed to nail polish having an antifungal effect comprising one or more antifungal agents, preferably selected from nystatin, amphotericin B, abafungin, benzalkonium chloride, caspofungin, cetyltrimethylammonium bromide, clioquinol, copper sulfate, haloprogin, echinocandins, flucytosine, Mycobactovir, novexantine, natamycin, cetylpyridinium chloride, benzylamine butenafine, benzazoles (cyclic derivatives of boric acid), abaconazole, araconazole, bifonazole, butoconazole, clotrimazole, itraconazole, econazole, eficonazol, fenticonazole, fluconazole, fosraconazole, isoconazole, itraconazole, isazole, isaconazole, ketoconazole, piroctone, climbazole, riluzole, lioconazole, cleboconazole, cloconazole, miconazole, oxpoconazole, oxadiazole, and ribavirin, Sertaconazole, sulconazole, terconazole, thiazole, thiabendazole, oteconazole, thiadiazole, methimazole, tioconazole, voriconazole, amiodarone, naftifine, tavaborole, butenafine, flucytosine, griseofulvin, caspofungin, micafungin, nitric oxide, oxichlorogenic sodium, povidone iodine, tolnaftate, sulbenine, zinc pyrithione, and more particularly selected from terbinafine, terbinafine hydrochloride, ciclopirox, itraconazole, and amorolfine, for use thereof in the treatment of nail diseases, by: the application on the nail is carried out simultaneously or staggered in time with the administration by subcutaneous route of one or more of the solid compositions comprising one or more biodegradable polymers described above at a distance of more than 1cm from the edge of the nail, preferably in the finger or toe except for the last knuckle, and/or simultaneously or staggered in time with the administration of one or more of the non-solid compositions comprising one or more biodegradable polymers described above by insertion into the space between the nail bed and the nail plate.

As indicated above, the nail polish used comprises one or more antifungal agents, which may be selected from the antifungal agents mentioned above. These nail oils contain up to 10% of therapeutic agents, except for PfizerFurthermore, it may contain up to 28% of active ingredient.

For example, those of Valerant Pharmaceuticals approved by the FDA can be usedNail polish (ciclopirox solution, 8%).

The present invention is also directed to antifungal pharmaceutical compositions comprising one or more antifungal agents preferably selected from the group consisting of nystatin, amphotericin B, abafungin, benzalkonium chloride, caspofungin, cetrimide, clioquinol, copper sulfate, haloprogin, echinocandins, flucytosine, Mycobactovir, novexatide, natamycin, cetylpyridinium chloride, benzylamine butenafine, benzoborazole (a cyclic derivative of boric acid), abaconazole, araconazole, bifonazole, butoconazole, clotrimazole, itraconazole, econazole, eficonazol, fenticonazole, fluconazole, itraconazole, fosraconazole, isoconazole, itraconazole, isazole, isaconazole, ketoconazole, linanozole, lanoconazole, clenoliconazole, miconazole, oxpoconazole, piroxicam ethanolamine, climconazole, climbazole, miconazole, climbazole, saperconazole, etc, Sertaconazole, sulconazole, terconazole, thiazole, thiabendazole, thiadiazole, methimazole, tioconazole, voriconazole, amiodarone, naftifine, tavalorol, butenafine, flucytosine, griseofulvin, caspofungin, micafungin, Viabecline, nitric oxide, sodium oxichloride, povidone iodine, tolnaftate, sulbenstine, zinc pyrithione, and more particularly selected from terbinafine, ciclopirox olamine, itraconazole, and amorolfine, for its use in the treatment of nail diseases by: administration is carried out by the oral or injectable route simultaneously or chronologically staggered with the subcutaneous administration of one or more of the above-described solid compositions comprising one or more biodegradable polymers by the subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last finger or toe, and/or simultaneously or chronologically staggered with the administration of one or more of the above-described non-solid compositions comprising one or more biodegradable polymers by insertion into the space between the nail bed and the nail plate, and/or simultaneously or chronologically staggered with the application of the above-described nail polish having antifungal effect on the nail.

The present invention is also directed to nail polish having antifungal effect comprising one or more antifungal agents, preferably selected from fluconazole, ketoconazole, miconazole, tioconazole, tavabororo, terbinafine hydrochloride, tolnaftate, amorolfine, ciclopirox olamine, terbinafine hydrochloride or miconazole, for its use in the treatment of nail diseases and/or for accelerating nail growth by: one or more of the compositions described above are applied to the nail simultaneously or staggered in time with the subcutaneous administration of the composition or compositions in the finger or toe at a distance of more than 1cm from the edge of the nail on its proximal side, preferably except for the last digit, and/or simultaneously or staggered in time with the administration of the solid, liquid or non-solid composition or compositions described above by insertion into the space between the nail bed and the nail plate.

The antifungal agent used by the oral route may be selected from the list mentioned above, and is preferably selected from ketoconazole, itraconazole, terbinafine hydrochloride, fluconazole, griseofulvin, and posaconazole or voriconazole in the case of hospital emergency treatment.

As indicated above, the treatment with nail varnish and/or oral treatment has the disadvantage that for these disadvantages the administration of one or more of the above described compositions comprising one or more biodegradable polymers by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last finger or toe node, provides a very advantageous therapeutic solution.

However, in certain cases, it may be of interest to combine these treatments by nail polish and/or oral route with the administration of one or more of the above described compositions comprising one or more biodegradable solid polymers by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle, for a limited duration and in optionally reduced doses.

Thus, these different treatments can be combined in order to enhance (potentiate) their efficacy. Thus, the use of a composition comprising one or more biodegradable solid polymers with extended release and optionally one or more active ingredients can be added, for example, to the treatment by the oral route described above.

The present invention therefore has as an object a composition for its use in the treatment of onychomycosis characterized in that it comprises one or more polymers selected from PLA and PGLA, 0.04 to 6.5mg of terbinafine hydrochloride, terbinafine, ciclopirox or ciclopirox olamine, itraconazole; and the composition is in the form of an implant having a length of 4 to 15mm and a diameter of 0.3 to 0.8mm, the implant being intended to be administered by subcutaneous route in the finger or toe, except for the last digit or knuckle, at a distance of more than 1cm from the edge of the nail at its proximal side.

The present invention also features a composition as described above, characterized in that the composition is preferably in the form of an implant, a cylindrical tube or a wire, optionally having a sharp tip, and the composition is administered at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last knuckle, for its use in the treatment of nail diseases, by administration simultaneously or staggered in time with:

-applying one or more solid compositions according to the invention comprising one or more biodegradable polymers with extended release, and optionally one or more active ingredients, preferably one or more antifungal agents, and/or one or more active ingredients, by insertion into the space between the nail bed and the nail plate

-applying a non-solid composition comprising one or more biodegradable polymers with extended release, and optionally one or more active ingredients, preferably one or more antifungal agents, and/or by insertion into the space between the nail bed and the nail plate

-applying to the nail a nail varnish having an antifungal effect, said nail varnish comprising one or more antifungal agents, preferably selected from fluconazole, ketoconazole, miconazole, terbinafine hydrochloride, tolnaftate, amorolfine, ciclopirox olamine or miconazole, and/or

Treatment with a laser that causes destruction of the fungus by a photobiological thermal effect.

The present invention also aims at a composition as defined above, comprising one or more biodegradable or non-biodegradable solid polymers with prolonged release, and optionally one or more active ingredients, characterized in that said composition is preferably in the form of an implant, a cylindrical tube or a wire, optionally with a sharp tip, and is administered in the finger or toe, at a distance of more than 1cm from the edge of the nail at its proximal side, except for the last knuckle, for its use in the treatment of nail diseases, by administration simultaneously or staggered in time with:

-applying a solid composition comprising one or more biodegradable polymers with extended release, and optionally one or more active ingredients, preferably one or more antifungal agents, and/or by insertion into the space between the nail bed and the nail plate

-applying a liquid or non-solid composition comprising one or more biodegradable polymers with extended release, and optionally one or more active ingredients, preferably one or more antifungal agents, and/or

Treatment with a laser that causes destruction of the fungus by a photobiological thermal effect.

The present invention also features a composition as described above, characterized in that the composition is preferably in the form of an implant, a cylindrical tube or a wire, optionally having a sharp tip, and is administered in the finger or toe, except for the last knuckle, at a distance of more than 1cm from the edge of the nail at its proximal side, for its use in the treatment of nail diseases, by administration simultaneously or chronologically staggered with:

-applying to the nail a nail varnish having an antifungal effect, said nail varnish comprising one or more antifungal agents, preferably selected from fluconazole, ketoconazole, miconazole, terbinafine, tolnaftate, amorolfine, ciclopirox, terbinafine hydrochloride, ciclopirox olamine, tioconazole or miconazole, and/or

Treatment with a laser that causes destruction of the fungus by a photobiological thermal effect.

The use of laser beams for the destruction of fungi is known to the person skilled in the art and is described above.

The applicant has also found that according to one advantageous process it is possible to obtain certain preparation conditions of said composition according to the invention. This is because one of the limitations of topical regional application of the composition according to the invention is that the area of application is a limited space and thus the amount of formulation that can be applied is greatly limited. Furthermore, it is therefore very important that formulations with high active ingredient contents can be administered there, which is contradictory to the need to add pharmaceutical ingredients to the active substance that help control the slow release of the active agent in sufficient amounts for a long duration of action and thus avoid having to repeat the administration with too close a frequency (less than one month, even one week).

Furthermore, it is obvious to the person skilled in the art that increasing the content (or core loading) of the active ingredient in a pharmaceutical composition with extended release, the more difficult it is to obtain a controlled precipitation and thus an extended duration of action.

Surprisingly and unexpectedly, the solution found in our new composition is to associate a large amount of active substance in the form of particles and to keep them associated but isolated during the preparation, by a small amount of polymer which will cover its particles in order to isolate them (even with a low percentage of this polymer in the mixture).

It has been observed that, under certain manufacturing conditions, it is possible to obtain such formulations in the solid form of implants constituted by particles of said substance surrounded by a polymer, the appearance of the surface of which is therefore rough, fibrillar or non-smooth and the cross-section of which shows this assembly of the active substance, in the form of transparent, crystalline or glassy particles surrounded by an opaque, white and polymer with a fibrillar appearance.

Surprisingly/unexpectedly, this assembly enables controlled and prolonged long-lasting effects to be obtained, for example within a few months, as the active substance particles are exposed to the biological tissue or the surrounding environment at the site of application, so that the product can then be released, when the polymer will bioabsorb.

Furthermore, the biocompatible and bioabsorbable non-smooth surface of the obtained composition allows a good adhesion to the subcutaneous tissue or to the surrounding environment, wherein the irregularities thus increase the contact area with the tissue upon implantation or insertion and thus ensure local area retention at the desired location.

The composition according to the invention can be prepared by techniques known to the skilled person in order to obtain a sterile parenteral pharmaceutical form comprising the biodegradable polymer.

Preferably, but not limitatively, the various constituent ingredients of the composition may, after weighing, sieving and mixing (for non-solid forms), undergo processes of extrusion melting, injection moulding, 3D printing or compaction to obtain the final form of the solid form with the desired geometry and lengthening effect.

Preferably, during the process of melt-extrusion, the temperature will advantageously be chosen to melt the polymer or polymer mixture around the unmelted solid active substance, thus allowing partial or complete coverage of the active substance to obtain the desired effect of prolonged release. The melting operation is performed simultaneously with the extrusion operation, with or without drawing, to allow such spinning of the various components.

The selection of the operating conditions related to the composition makes it possible to control the internal and external tissue architecture of the various ingredients and thus to ensure their activity.

Surprisingly, the mixture of compositions according to the invention enables homogeneous compositions to be obtained without a pre-treatment operation with a solvent or drying of the solid particles before their mixing.

Depending on the grade and manufacturer of the polymer, the polymer is provided in solid form as pelletized pellets, "filaments" or ready-to-use powders, which are in most cases obtained by cryogenic grinding of the polymer.

In the case where the polymer is not provided in the powder state for its direct mixing with the active substance or other components, it is advantageously possible to apply operations intended to reduce its apparent density and to facilitate the powder mixing before shaping.

By way of non-limiting example, the person skilled in the art can choose to grind the polymer at low temperature, compact it, and dry granulate it at a temperature lower than or equal to 25 ℃, even to carry out a granulation or extrusion grinding step in an organic solvent.

Once the polymer is in a powder state and mixed with or without other ingredients, the mixture is introduced into the chamber of an extruder where it is then brought directly and rapidly to its melting temperature during the extrusion process.

Likewise, in the case where one of the ingredients is not directly available in the solid state, it will only be converted to this by applying one of the techniques known to the person skilled in the art for making it into galenic form.

The mixture of the active substance with polymers or copolymers of lactic acid and/or glycolic acid or a mixture of polymers and/or copolymers of lactic acid and/or glycolic acid forms a molten mixture paste in the presence of the active substance.

Thus, according to one method, the mixture is fed into an extrusion screw, whereby the time for liquefaction-melting and transfer of the mixture to the extrusion nozzle is reduced and is less than 30 minutes, and preferably less than 15 minutes.

According to this advantageous variant of the preparation process, it is possible to operate without a pre-treatment of the mixture, hence without an aqueous or organic solvent and/or without a cold drying of the mixture and without a different pre-heating for compression before extrusion, which makes it possible to control (if necessary) the low hydration state of the mixture and to extrude within a short heating time (less than 15 minutes, preferably 5 to 10 minutes), without degradation of the active ingredient, at a temperature which can be higher than 100 ℃, preferably 110 ℃ to 185 ℃, and more preferably 125 ℃ to 175 ℃ or 137 ℃ to 173 ℃, for example at about 170 ℃.

In the case of extrusion, this thermal arrangement will directly give the desired shape due to the mixing of the screws and the diameter of the extrusion nozzle. It is also possible to carry out the control of the solid form and in particular of its diameter by means of a wire-drawing machine which adjusts the diameter of the extrudate.

In this case and depending on the desired diameter, the wire-drawing machine will be able to function at the outlet of the extruder at ambient temperature. The extrudate will also be able to pass through a thermostatic chamber at elevated temperatures (equal to or below the extrusion temperature) to allow greater stretching and in particular to obtain very small diameters (e.g. less than 0.1mm or less than 0.05 mm).

The continuous extrudate will then be cut to a size (exchange area) that provides the desired profile of precipitation characteristics, for example by cryogenic grinding or with the aid of a guillotine at the extrusion outlet.

Depending on the desired shape, dosage and precipitation profile, the preparation method will also be applicable to forms of active ingredient with low loading (below 20%, especially from 0.1 to 10%) or high loading (above 50%, and especially from 60 to 80%).

The implant can then be placed in an injection device and irradiated with gamma radiation prior to administration.

The injection device may be prefilled and already contain the implant, or may be filled immediately prior to administration. Likewise, where it is desired to inject several implants per digit or per person, it may be of interest in packaging and economic terms to use a reusable device. In this case, the implant is directly contained in the needle for administration, which can be replaced at each administration.

In case the device is not envisaged for re-use, it may be equipped with a locking system to prevent it from being possible to re-use. The system may also hide the needle from the user's view to reduce the potential risk of injury from needle sticks.

In another embodiment of the invention, the application is directed to a method of treating nail diseases comprising the use of an injectable composition with an extended duration of action, more particularly one or more biodegradable solid polymers with extended release, and optionally one or more active ingredients, characterized in that said composition is presented in the form of a device intended to be administered by subcutaneous route at a distance of more than 1cm from the edge of the nail at its proximal side, preferably in the finger or toe except for the last digit.

Experimental part

I-general procedure

A general procedure for preparing the compositions of the examples

The compositions according to the invention given in the examples below are obtained starting from pharmaceutical methods known to the person skilled in the art.

Depending on the use to which the various compositions are put, the batch sizes may vary from a few milligrams to hundreds of grams (or even kilograms).

Advantageously, the biodegradable polymers, polymers or blends of (co) polymers to be used in the examples below are screened beforehand on a mesh opening of 600 μm or SPEX 6775Freezer @Grinding is carried out in a refrigerated mill of the type.

At the end of the experimental protocol, a fine and homogeneous powder was recovered and could be used in various different preparation procedures.

Subsequently, the polymer or (co) polymer mixture, the active ingredient, the various excipients or the mixture of active ingredient and excipient are weighed separately.

Then, by means of T2F typeA tumble mixer of the type (agitator mixer or stirrer) mixes the components at a speed of 49 revolutions per minute for 10 minutes.

The percentages (%) in the following examples are expressed by mass (m/m).

(1) Extrusion

After mixing the powders constituting the composition, the mixture is then subjected to a continuous melt-extrusion process on a single screw extruder equipped with a screw with a pitch of 8mm, pressure control, a die or nozzle with variable diameter and a continuous drawing system at the die outlet, to adjust the diameter of the implant.

The temperature during this process is adjusted depending on the composition and active ingredient and is detailed in each of the examples that follow. The stretching may also be adjusted according to the desired final diameter.

After chemical analysis of the active ingredient content and purity, the implants were cut to the desired length and sterilized with 25kGy of gamma radiation.

(2) Compression

In this preparation, in order to reduce the apparent volume of the polymer used, a first step of dry granulation is carried out. The components are then mixed and used to feed the hopper of the compression machine.

The polymer or (co) polymer mixture, the active ingredient or the active ingredient mixture is compressed by means of a press, for example a rotary compression machine of the Korsch PH106DMS type.

Depending on the size and shape of the punch used during compression, it is possible to obtain implants with variable dimensions, active ingredient loading and mass.

The resulting implant was then sterilized with 25kGy of gamma radiation.

(3)3D printing

The extrudate obtained by extrusion according to the process described above in (1) may be flexible and thus rolled into a wire or filament. It is possible to prepare extrudates with a diameter of 1.75mm in order to be able to be used with a 3D printer of the FDP (fused deposition modeling) type, for example prua i3 HD, which has the following characteristics:

diameter of the filaments: 1.75mm

Height of the extruded layer: 0.10mm

Extruder hot end pack V5: PEEK-Brass nozzle, 0.35mm diameter

-an electron: ARDUINO MEGA 2560 RAMPS v1.4

-a platform: glass bed with temperature regulation.

Once printed out and cooled, the implant was recovered on a glass platform with forceps prior to analysis. The resulting implant was then sterilized with 25kGy of gamma radiation.

B-general procedure for analyzing implants

In the procedures described below in B (1) to (6), the analysis is carried out on a reversed-phase high-performance liquid chromatograph (RP-HPLC), for example, on an Alliance system from Waters. The detection is carried out with a UV/visible detector, for example 26952489 UV/visible detector from Waters, at variable wavelengths according to the active ingredient.

The chromatograph was equipped with a Waters X Bridge C18,20x4.6mm,5 μm type pre-column and a Waters X Bridge C18,150x4.6mm,5 μm type column. The column temperature was maintained at 35 ℃.

(1) RP-HPLC method for determining purity, identifying and quantifying terbinafine

Sample preparation

Blank: acetonitrile/Milli-Q Water (25/75, v/v)

Standards were prepared in acetonitrile/Milli-Q water (25/75, v/v) solution at a concentration of 30. mu.g/mL terbinafine.

The sample to be analyzed was dissolved in acetonitrile/Milli-Q water (25/75, v/v) solution and then diluted to a concentration of terbinafine of about 30. mu.g/mL.

Conditions for HPLC chromatography

Elution gradient was applied starting from 2 mobile phases:

mobile phase A: THF/ACN/citrate buffer, pH4.5(10/20/70) (v/v/v)

Mobile phase B: acetonitrile

t (minutes)	A(％)	B(％)
			0	80.0	20.0
25.0	55.0	45.0
			26.0	80.0	20.0
31.0	80.0	20.0

-flow rate: 0.9 mL/min

-injection volume: 30 μ L of

-analysis time: for 32 minutes.

The detection of the main peak of terbinafine is carried out at a wavelength of 280nm/226 nm. For quantification and evaluation of purity, only a wavelength of 280nm was used.

The results of active agent content and purity were determined starting from the chromatogram of the reference standard and the chromatogram of terbinafine, at a retention time of about 13.5 minutes.

(2) Simplified method for quantifying terbinafine

In vitro testing

To evaluate the release profile of the active ingredient contained in the implant, an in vitro release test was carried out at 37 ℃ for 7 days, then after 7 days the temperature was increased to 55 ℃, in a physiologically acceptable medium (0.9% NaCl). A minimum of 3 individual samples from the same batch were tested.

A pre-weighed amount of the implant was introduced directly into the reservoir containing 5mL of physiological medium. 100 μ L of the solution was extracted at a predetermined time and stored at ambient temperature until analysis.

The predetermined time is the following: t is 0, t is 1 hour, t is 5 hours, t is 1 day, t is 2 days, t is 4 days, t is 7 days, t is 8 days, t is 9 days and t is 15 days.

Sample preparation

The sample is analyzed directly or can be diluted a priori according to concentration (dilution with acetonitrile/Milli-Q water (25:75, v/v) solution).

Blank: acetonitrile/Milli-Q Water (25:75, v/v)

Standards were prepared in acetonitrile/Milli-Q water (25:75, v/v) mixtures at a concentration of 30. mu.g/mL terbinafine.

Conditions for HPLC chromatography

Elution gradient was applied starting from 2 mobile phases:

mobile phase A: THF/ACN/citrate buffer, pH4.5(10/20/70) (v/v/v)

Mobile phase B: acetonitrile/Milli-Q Water (95/5, v/v)

t (minutes)	A(％)	B(％)
			0	80.0	20.0
4.0	10.0	90.0
			6.0	80.0	20.0
10.0	80.0	20.0

-flow rate: 0.9 mL/min

-injection volume: 30 μ L of

-analysis time: for 10 minutes.

The detection of the main peak of terbinafine was carried out at a wavelength of 280 nm.

The results of active ingredient content and purity were determined starting from the chromatogram of the reference standard and the chromatogram of terbinafine, at a retention time of about 6.4 minutes.

(3) Method for determining purity, identifying and quantifying ciclopirox

Sample preparation

Blank: acetonitrile/Milli-Q Water (15/85, v/v)

Standards were prepared in acetonitrile/Milli-Q water (15/85, v/v) solution at a concentration of ciclopirox of 25. mu.g/mL.

Samples were diluted in acetonitrile/Milli-Q water (15/85, v/v) to a concentration of ciclopirox of approximately 25. mu.g/mL.

Samples, blanks and standards were prepared (before injection into the HPLC system) according to the following procedure:

● 800 μ L of sample

● 400 μ L of 0.1M NaOH

● 80 μ L dimethyl sulfate

● vortex mixer (stirrer) (15 seconds)

● incubation at 37 deg.C (15 minutes)

● 80 uL of triethylamine

● vortex (15 seconds).

Conditions for HPLC chromatography

Elution gradient was applied starting from 2 mobile phases:

mobile phase A: Milli-Q water

Mobile phase B: acetonitrile

t (minutes)	A(％)	B(％)
			0	85	15
25	50	50
			26	20	80
27	85	15
			32	85	15

-flow rate: 1.0 mL/min

-injection volume: 60 μ L

-analysis time: for 32 minutes.

The detection of the major peak of ciclopirox was carried out at a wavelength of UV @305 nm.

The results of active agent content and purity were determined starting from the chromatogram of the reference standard and the chromatogram of ciclopirox, at a retention time of about 20.2 minutes.

(4) Simplified method for quantifying ciclopirox

In vitro testing

To evaluate the release profile of the active ingredients contained in the implants, an in vitro release test was carried out in a physiologically acceptable medium (PBS pH 7.4) at 37 ℃ for 7 days. A minimum of 3 individual samples from the same batch were tested.

A pre-weighed amount of the implant was introduced directly into the reservoir containing 15mL of physiological medium. 100 μ L of the solution was extracted at a predetermined time and stored at 5 ℃ until analysis.

The predetermined time is the following: t is 0, t is 1 hour, t is 5 hours, t is 1 day, t is 2 days, t is 4 days and t is 7 days.

Sample preparation

Blank: acetonitrile/Milli-Q Water (15/85, v/v)

Standards were prepared in acetonitrile/Milli-Q water (15/85, v/v) solution at a concentration of ciclopirox of 25. mu.g/mL.

Samples were directly injected from the in vitro test.

Samples, blanks and standards were prepared (before injection into the HPLC system) according to the following procedure:

● 800 μ L of sample

● 400 μ L of 0.1M NaOH

● 80 μ L dimethyl sulfate

● vortex mixing (approximately 15 seconds)

● vortex mixing (15 seconds)

● 80 uL of triethylamine

● vortex (15 seconds).

Conditions for HPLC chromatography

Elution gradient was applied starting from 2 mobile phases:

mobile phase A: Milli-Q water

Mobile phase B: acetonitrile

T (minute)	A(％)	B(％)
			0	85	15
4	0	100
			5	0	100
6	85	15
			9	85	15

-flow rate: 1.0 mL/min

-injection volume: 60 μ L

-analysis time: for 9 minutes.

The detection of the major peak of ciclopirox was carried out at a wavelength of 305 nm.

The results of active agent content and purity were determined starting from the chromatogram of the reference standard and the chromatogram of ciclopirox, at a retention time of about 5.3 minutes.

(5) RP-HPLC method for determining purity, identifying and quantifying amorolfine

In vitro testing

To evaluate the release profile of the active ingredient contained in the implant, an in vitro release test was carried out at 37 ℃ for 7 days, then after 7 days increased to 55 ℃ in a physiologically acceptable medium (0.9% NaCl). A minimum of 3 individual samples from the same batch were tested.

The predetermined time is the following: t is 0, t is 1 hour, t is 5 hours, t is 1 day, t is 2 days, t is 4 days, t is 7 days, t is 8 days, t is 9 days and t is 15 days.

Sample preparation

Blank: acetonitrile/Milli-Q Water (25/75, v/v)

Standards were prepared in acetonitrile/Milli-Q water (25/75, v/v) solution at a concentration of 200. mu.g/mL of amorolfine.

Samples were diluted in acetonitrile/Milli-Q water (25/75, v/v) to a concentration of approximately 200. mu.g/mL of amorolfine.

Conditions for HPLC chromatography

Elution gradient was applied starting from 2 mobile phases:

mobile phase A: THF/ACN/citrate buffer, pH4.5(10/20/70) (v/v/v)

Mobile phase B: acetonitrile

-flow rate: 0.9 mL/min

-injection volume: 30 μ L of

-analysis time: for 32 minutes.

The detection of the major peak of amorolfine was performed at a wavelength of 224/265 nm. For quantification and evaluation of purity, only a wavelength of 265nm was used.

The results of active agent content and purity were determined starting from the chromatogram of the reference standard and the chromatogram of amorolfine, at a retention time of about 12.6 minutes.

(6) RP-HPLC method for determining purity, identifying and quantifying itraconazole

In vitro

The predetermined time is the following: t is 0, t is 1 hour, t is 5 hours, t is 1 day, t is 2 days, t is 4 days, t is 7 days, t is 8 days, t is 9 days and t is 15 days.

Sample preparation

Blank: THF/ACN/mobile phase A (15/10/75) (v/v/v)

Standards were prepared in THF/ACN/mobile phase a (15/10/75) (v/v/v) solution at a concentration of 50 μ g/mL itraconazole.

The sample was diluted with THF/ACN/mobile phase A (15/10/75) (v/v/v) solution to a concentration of itraconazole of about 50. mu.g/mL.

Conditions for HPLC chromatography

Elution gradient was applied starting from 2 mobile phases:

mobile phase A: THF/ACN/citrate buffer, pH4.5(10/20/70) (v/v/v)

Mobile phase B: acetonitrile

t (minutes)	A(％)	B(％)
			0	80	20
25	55	45
			26	80	20
31	80	20

-flow rate: 0.9 mL/min

-injection volume: 25 μ L

-analysis time: for 32 minutes.

The detection of the main peak of itraconazole was performed at a wavelength of 265 nm.

The results of active agent content and purity were determined starting from the chromatogram of the reference standard and the chromatogram of itraconazole, at a retention time of about 19.0 minutes.

C-evaluation of the in vitro antifungal Activity of the compositions according to the invention

The antifungal activity (or inhibitory capacity) over time of the compositions described in examples 1, 2, 6, 8, 10, 12, 18 and 19 below was evaluated by diffusion tests of the compositions in agar (growth inhibition in petri dishes) on seeds of isolated strains of trichophyton rubrum, Candida krusei and/or Candida parapsilosis (human clinical samples of onychomycosis). The antifungal agent released by the composition in the culture medium more or less inhibits the development of the inoculum; this data is then compared to the corresponding MIC.

Prior to diffusion testing, the Minimum Inhibitory Concentration (MIC) was achieved by microdilution in liquid medium according to standard experimental protocol CLSI M38-a2 to understand the sensitivity to the antifungal agents used in the agar test. In this protocol, the MIC of an antifungal agent corresponds to an inhibition of 80% (relating to the control of the growth of the fungal strain).

Method: samples of the compositions described in examples 1, 2, 6, 8, 10, 12, 18 and 19 were placed in the center of a petri dish (modified Muller-Hinton) and incubated. The growth change (diameter in mm) of the zone of inhibition was measured at a predetermined time (in "days").

The experiment was performed according to the standard protocol CLSI M44-A2-in modified Muller Hinton medium.

The incubation of the plates was carried out in parallel at two incubation temperatures (27 ℃ and/or 35 ℃) in a humidified chamber.

Procedure for D-stabilization

The gamma-irradiated implants prepared according to example 1 and example 18 were stabilized under ICH stability conditions, under different conditions selected from the group consisting of: 5 ℃,25 ℃/60% relative humidity, and 40 ℃/75% relative humidity.

The dose and purity of the active agent were evaluated at various reference times according to the method described above in B.

E-in vivo test procedure

The implants prepared according to example 1, example 3 and example 18 were implanted subcutaneously into Sprague-Dawley male rats.

The implant was pre-filled with 1ml of 1ml equipped with a 20G Henke Sass Wolf needle (0.9mm outer diameter, 0.6mm inner diameter, length of 16 mm)Syringe (Becton Dickinson).

After implantation of the implants, the implants were removed from the subcutaneous tissue of the animals and analyzed for the content of active ingredient by RP HPLC-UV according to the method described above in B (1) to B (4) at times corresponding to 7 days, 28 days, 56 days, 91 days and 112 days for the implant described in example 1, at times corresponding to 24 days and 84 days for the implant described in example 3 and at times corresponding to 7 days, 30 days and 84 days for the implant described in example 18.

II-examples of the detailed description

Example 1

4 batches of implants containing terbinafine in PLGA85:15 at various concentrations were prepared according to the method described above in A (1).

The extrusion conditions were as follows:

an implant having a length of 10mm and a diameter of 0.56mm was cut.

The batches were then evaluated analytically according to the methods described above in B (1) and/or B (2).

The in vitro release test was performed as described above in B (2). The results are shown in FIG. 1.

In vitro antifungal activity evaluation was performed as described above in C. FIG. 5 shows photographs of agar plates after implantation of the composition according to example 1(1) in Candida parapsilosis at 35 ℃.

In vivo testing was performed as described above in E. The results of the in vivo test are shown in figure 12.

The stability of batch (3) was determined at 1 month, 3 months and 6 months, at 5 ℃,25 ℃/60% relative humidity and 40 ℃/75% relative humidity, according to the method described above in D. The results for terbinafine hydrochloride content and purity and dose of the active agent obtained are the following:

the stability of batch (4) was determined at 9 and 12 months, at 5 ℃ according to the method described above in D. The results for terbinafine content and purity and dose of the active agent obtained are the following:

example 2

A batch of implants containing terbinafine hydrochloride and PLGA85:15 was prepared according to the method described above in A (1).

An implant having a length of 25mm and a diameter of 0.80mm was cut.

An implant having a length of 10mm and a diameter of 0.80mm was cut.

The in vitro release test was performed with an implant having a length of 10mm, as described above in B (2). The results are shown in fig. 3.

In vitro antifungal activity evaluation was performed according to the method described above in C. FIG. 6 shows a photograph of an agar plate after implantation of the compound according to example 2 in Candida parapsilosis. The results are summarized in fig. 9.

Example 3

A batch of implants containing dexamethasone and PLGA 75:25 was prepared according to the method described above in A (1).

An implant having a length of 6mm and a diameter of 0.45mm was cut.

In vivo testing was performed as described above in E.

Example 4

A batch of implants containing 60% ciclopirox olamine and 40% PLGA85:15 was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.60mm was cut.

Example 5

A batch of implants containing 50% miconazole and 50% PLGA85:15 was prepared according to the method described above in A (1).

An implant having a length of 9mm and a diameter of 0.58mm was cut.

Example 6

A batch of implants containing amorolfine and PLGA85:15 was prepared according to the method described above in A (1).

An implant having a length of 10.90mm and a diameter of 0.58mm was cut.

The analysis was carried out in accordance with the method described above in B (5).

API content (% m/m)	Purity of active agent (%)	Implant dosage
			46.30	100	1.54

In vitro release was performed as described above in B (5). The results are shown in fig. 3.

In vitro antifungal activity evaluation was performed as described above in C.

Example 7

A batch of implants containing 30% horsetail and 70% PLGA85:15 was prepared as described above in A (1).

The extrusion conditions were as follows:

then, an implant having a length of 10mm and a diameter of 0.4-0.8mm was cut out. Fig. 15 shows a photograph of the implant made in example 7 taken with a binocular magnifier.

Example 8

One batch of implants containing itraconazole and PLGA85:15 was prepared according to the method described above in a (1).

Then, an implant having a length of 6mm and a diameter of 0.7mm was cut out.

The analysis was carried out in accordance with the method described above in B (6).

Content (% m/m)	Purity of active agent (%)	Implant dosage
			60.90	99.3	1.9

Fig. 16 shows a photograph of the implant made in example 8 taken with a binocular magnifier.

Example 9

A batch of implants containing 12% lactate, PLGA85:15 and terbinafine hydrochloride was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.8mm was cut.

The analysis was carried out according to the method described above in B (1) and B (2).

Content (% m/m)	Purity of active agent (%)	Implant dose (mg)
			58.20	99.53	2.15

In vitro release was performed as described above in B (2).

Example 10

A batch of implants containing 50% PLGA85:15 and 50% L-lactate was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.8mm was cut.

Example 11

A batch of implants containing 12% PLGA 50:50, 28% PLGA85:15 and 60% terbinafine hydrochloride was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.6mm was cut.

The analysis was carried out according to the method described above in B (1) and B (2).

Content (% m/m)	Purity of active agent (%)	Implant dose (mg)
			59.60	99.53	1.65

Example 12

A batch of implants containing 100% PLGA85:15 was prepared as described above in A (1).

An implant having a length of 10mm and a diameter of 0.80mm was cut.

Antifungal activity assays were performed as described above in C, using two strains: candida krusei and Candida parapsilosis. The results of the halo suppression are given in the table below in millimeters around the implant.

t	10 days	14 days	20 days	28 days
					Candida Krusei	4mm	-	3mm	3mm
Candida parapsilosis	4 mm	5mm	3mm	3mm

Example 13

A batch of implants containing 12% PLA 202S, 28% PLGA85:15 and 60% terbinafine hydrochloride was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.55mm was cut.

The analysis was carried out according to the method described above in B (1) and B (2).

Content (% m/m)	Purity of active agent (%)	Implant dose (mg)
			59.30	99.53	1.51

Example 14

A batch of implants containing 50% PLA 202S and 50% PLGA85:15 was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.55mm was cut.

Example 15

A batch of implants containing 25% chitosan and 75% PLGA85:15 was prepared as described above in A (1).

An implant having a length of 10mm and a diameter of 0.60mm was cut.

Example 16

A batch of implants containing 20% chitosan, PLGA85:15 and terbinafine hydrochloride was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.60mm was cut.

The analysis was carried out according to the method described above in B (1) and B (2).

Content (% m/m)	Purity of active agent (%)	Implant dose (mg)
			8.80	99.63	0.33

The in vitro diffusion test was performed as described above. The results are shown in fig. 4.

Example 17

A batch of implants containing minoxidil and PLGA85:15 was prepared according to the method described above in A (1).

An implant having a length of 8mm and a diameter of 0.75mm was cut.

Example 18

Several batches of implants containing various concentrations of ciclopirox in PLGA85:15 were prepared according to the method described above in A (1).

(1)

The analysis was carried out according to the method described above in B (3) and B (4).

	Content (% m/m)	Purity of active agent (%)	Implant dose (mg)
				(1)	15.50	97.60	0.15
(2)	34.	98.10	0.52
				(3)	59.690	98.40	2.50
(4)	65.80	98.20	1.80

The in vitro release test was performed as described above in B (4). The results are shown in fig. 2.

In vitro antifungal activity evaluation was performed as described above in C.

In vivo testing was performed as described above in E.

FIG. 11 shows a photograph of an implant of the composition described in 18(3) above after 84 days of implantation.

The results of the in vivo implantation are summarized in fig. 13.

The stability of batch (2) was determined as described in D above at 5 ℃,25 ℃/60% relative humidity and 40 ℃/75% relative humidity at 1 month, 3 months and 6 months. The results for ciclopirox content and purity and dose of the active agent obtained are the following:

the stability of batch (3) was determined at 1 month, 3 months and 6 months, at 5 ℃,25 ℃/60% relative humidity and 40 ℃/75% relative humidity, according to the method described above in D. The results for ciclopirox content and purity and dose of the active agent obtained are the following:

example 19

A batch of implants containing ciclopirox and PLGA85:15 was prepared according to the method described above in A (1).

An implant having a length of 7mm and a diameter of 1mm was cut.

The analysis was carried out according to the method described above in B (3) and B (4).

Content (% m/m)	Purity of active agent (%)	Implant dose (mg)
			55.00	98.9	1.98

In vitro antifungal activity evaluation was performed according to the method described above in C. FIG. 7 shows a photograph of an agar plate after implantation of the compound according to example 19 in Candida parapsilosis at 35 ℃.

The results are summarized in fig. 10a and 10 b.

Example 20

A mixture of 50% PLGA85:15 and 50% PLA 202S was prepared as described above in A (2). The punches were placed in a configuration such that: i.e. 1.4mm for a thickness of 4. The batch comprised 19 implants.

The process uses a compressive force of 220-250N to produce a jetting force of 20-25N.

The implant obtained has the following characteristics:

mass (mg)	Length (mm)	Diameter (mm)	Density (g/mL)	Volume (μ L)
					1.05	1.61	0.91	1.11	1.05

Example 21

Filaments containing 100% PLGA85:15 were prepared according to the printing method described above in a (3).

The filaments having a diameter of 1.55-1.75mm were then used for 3D printing as described above in a (3). The printing conditions were as follows:

-extrusion temperature: 190 deg.C

Glass (bed) temperature: 50 deg.C

-feeding: 60% of maximum feed

-speed: 80% of maximum speed

The implants were printed in 10 batches and were 10mm x 0.4mm in diameter.

Example 22

A batch of implants containing ciclopirox and PLA 202H was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.8mm was cut.

The analysis was carried out according to the method described above in B (3) and B (4).

Content (% m/m)	Purity of active agent (%)	Implant dose (mg)
			41.90	99.95	2.37

Example 23

A batch of implants containing approximately 30% (w/w) arginine and PLGA85:15 was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.9mm was cut.

Example 24

A batch of implants containing approximately 30% (w/w) ciclopirox and 30% (w/w) terbinafine hydrochloride to obtain in total a mixture with PLGA85:15 with an active ingredient content of 60% (w/w) was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.8mm was cut.

Example 25

A batch of implants containing approximately 60% (w/w) terbinafine hydrochloride in PLGA85:15 was prepared according to the method described above in A (1).

The extrusion conditions were as follows:

an implant having a length of 10mm and a diameter of 0.56mm was cut.

The batches were then evaluated analytically according to the methods described above in B (1) and/or B (2).

In vivo testing was performed as described above in E. The results of the in vivo tests are shown in figure 14.

Example 26

A batch of implants containing approximately 60% (w/w) terbinafine hydrochloride in PLGA85:15, having a larger size (16.1g, 6000 units of theoretical equivalent) was prepared according to the method described above in A (1).

The extrusion conditions were as follows:

an implant having a length of 10mm and a diameter of 0.56mm was cut.

The batches were then evaluated analytically according to the methods described above in B (1) and/or B (2).

The in vitro release test was performed as described above in B (2). The results are shown in fig. 15.

Example 27

A batch of implants containing approximately 60% (w/w) ciclopirox and PLGA85:15, having a larger size (3.9g, i.e. 1441 units of theoretical equivalent), was prepared according to the method described above in A (1).

An implant having a length of 10mm and a diameter of 0.56mm was cut.

The analysis was carried out according to the method described above in B (3) and B (4).

Content (% m/m)	Purity of active agent (%)	Implant dose (mg)
			58.8	99.0	1.64

The in vitro release test was performed as described above in B (2). The results are shown in fig. 16.

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