EP2978424A1 - Use of a macrocyclic lactone for treating a complication from a papillomavirus infection - Google Patents

Abstract

The present invention relates to a compound selected from among macrocyclic lactones for the use thereof for treating and/or preventing a complication from a human papillomavirus infection selected from among malignant melanomas, skin carcinomas, in situ or invasive carcinomas, epidermoid carcinomas, Bowen's disease, head and neck cancers, upper aerodigestive tract cancers, laryngeal cancers, esophageal cancers, stomach cancers, oral papillomas, pharyngeal papillomas, laryngeal papillomas, esophageal papillomas, lung cancers, intravulval neoplasias, intravaginal neoplasias, intracervical neoplasias, cervical dysplasias, cervical carcinomas, penile cancer, intrapenile neoplasias, and in situ or invasive anal carcinomas.

Description

 Use of a macrocyclic lactone for the treatment of a complication of a papillomavirus infection

The present invention provides a compound selected from macrocyclic lactones for use in treating and / or preventing a complication of human papillomavirus infection.

Papillomaviruses belong to the family Papovaviridae (genus Papillomaviridae). They are small viruses (50 to 55 nm in diameter), consisting of a nucleocapsid of 72 capsomeres. Their genome consists of a double-stranded DNA molecule of about 8000 base pairs. These viruses have been identified in many mammalian species, in birds and reptiles. However, papillomaviruses are highly specific for the host species, and no cross-infection with other species has been observed ("Papillomavirus Infections," Medico-Surgical Encyclopedia, 2004, 8-054-A-10).

 Papillomaviruses have a particular tissue tropism for the skin and squamous mucous membranes. Human papillomavirus (HPV) is thus associated with specific anatomical localizations and characteristic lesions. However, these localizations are not exclusive since under certain conditions, such as in the case of immunosuppression, usually genital papillomaviruses may be associated with cutaneous lesions for example. Cutaneous or mucosal infections and their complications can affect the hands, feet, limbs, trunk, head, neck, face or mucosa anogenital, oral and laryngeal.

HPV plays an etiological role in the development of precancerous and cancerous lesions. Initiated since 1976, this link was confirmed in the mid-1990s, thanks to molecular biology techniques, especially between certain HPV (including HPV 16 and 18) and cervical cancers. There is currently no treatment for the destruction of viruses.

Visible lesions can, however, be more or less easily removed. Lesions of the cervix, for example, are treated by cryotherapy, laser, or even surgery (removal of part or all of the cervix). In order to suppress condyloma (or genital warts), local medicinal treatments exist, in particular based on podophyllotoxin, trichloroacetic acid or imiquimod. To be effective, these assets require a prolonged application over time. Other treatments exist as physical treatments such as laser vaporization, curettage electrocoagulation or cryotherapy. These treatments may have the disadvantage of leaving scars after treatment. In addition, current treatments rely primarily on the destruction of infected cells and not on the virus itself. Insofar as subclinical infection is not detectable (that is to say without visible clinical manifestations), these treatments are carried out only on the lesions themselves and not on a sufficiently large surface to avoid relapses.

In addition, the HPV treatments described above have disadvantages such as irritation and intolerance phenomena, especially when they are used for a long time. On the other hand, these treatments are only suppressive and non-curative, acting in particular on the visible lesions and not on the infection itself.

 The ideal treatment of HPV requires prolonged use and this in a safe and effective way.

 In view of the foregoing, there is therefore a need to find an active which shows improved efficacy in treating complications of HPV infections, and which does not exhibit the side effects described in the prior art. The subject of the present invention is thus a compound chosen from macrocyclic lactones for use in treating and / or preventing a complication of infection by a human papillomavirus chosen from malignant melanomas, cutaneous carcinomas, in-situ or invasive carcinomas. , squamous cell carcinomas, Bowen's disease, head and neck cancers, upper aerodigestive tract cancers, laryngeal cancers, esophageal cancers, stomach cancers, oral papillomas, pharyngeal papillomas, laryngeal papillomas, oesophageal papillomas, lung cancers, intravascular neoplasia, intravaginal neoplasia, intracervical neoplasia, cervical dysplasia, carcinoma of the cervix, penile cancer, intrapenous neoplasia, and in-situ or invasive carcinomas.

In a preferred embodiment, the complications of infection with a human papillomavirus are selected from malignant melanomas, cutaneous carcinomas, in-situ or invasive carcinomas, squamous cell carcinomas, Bowen's disease, head cancers. and neck. The invention also relates to the use of a compound among macrocyclic lactones or their pharmaceutically acceptable salts for the preparation of a medicament for treating complications of infection with a human papillomavirus as defined above.

The invention also relates to a method comprising administering a compound selected from macrocyclic lactones or pharmaceutically acceptable salts thereof to a patient for treating complications of human papillomavirus infection as defined above.

In one embodiment, the term "treatment" or "treating" refers to an improvement, prophylaxis of a disease or disorder, or at least one symptom discernible therefrom. In another embodiment, "treatment" or "treating" means an improvement, the prophylaxis of at least one measurable physical parameter associated with the disease or disorder being treated, which is not necessarily discernible in or by the subject treaty.

 In another additional embodiment "treatment" or "treating" means inhibiting or slowing down the progression of a disease or disorder, physically, for example, stabilizing a discernible symptom, physiologically, for example, the stabilization of a physical parameter, or both. In another embodiment, "treatment" or "treating" means delaying the onset of a disease or disorder.

 In some embodiments, compounds of interest are administered as a preventive measure. In the present context, "prevention" or "prevention" means a reduction in the risk of acquiring a specified disease or disorder.

The patient is a human patient, man or woman.

According to the invention, the human papillomavirus is any type of HPV. Preferably, the human papillomavirus is selected from HPV-1, HPV-2, HPV-3, HPV-4, HPV-5, HPV-6, HPV-7, HPV-8, HPV-1, HPV-16, HPV-18, HPV-31, HPV-33 and HPV-35.

The macrocyclic lactones are preferably selected from avermectins and milbemycins.

The avermectin and milbemycin families constitute a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds JEF (Ed) (1993) Martindale, The extra pharmacopoeia, 29th Edition, Pharmaceutical Press, London). Among the avermectins is ivermectin. Natural avermectins are a series of 16-membered macrocyclic lactones isolated from the fermentation products of Streptomyces avermitilis.

 The compounds of the avermectin family that may be used according to the present invention may be chosen from ivermectin, avermectin A [1 a], avermectin A [1 b], avermectin A [2a], avermectin A [2b], avermectin B [1 a], avermectin B [1b], avermectin B [2a], avermectin B [2b], emamectin, abamectin, doramectin, eprinomectin, latidectin and selamectin.

Preferably, the compound of the avermectin family is ivermectin. In the present context, ivermectin is a mixture of 22,23-dihydroavermectin Bi _a and 22,23-dihydroavermectin Bib. Ivermectin contains mainly 22,23-dihydroavermectin Bia.

The compounds of the milbemycin family that can be used according to the present invention may be chosen from milbemycin, lepimectin, milbemectin, milbemycin oxime, moxidectin and nemadectin.

 Preferably, the compound of the milbemycin family is milbemycin.

The pharmaceutically acceptable salts of the compounds of the invention are also included in the invention.

The term "pharmaceutically acceptable salt (s)" as used herein refers to the salts of a compound of interest, preferably for topical use, and which possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compounds. The pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, hydrochloride, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate salts. , bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate (i.e., 1, 1 '- methylene -bis- (2-hydroxy-3-naphthoate)). Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review of pharmaceutically acceptable salts, see Berge et al. (J Pharm Sci 1977 Jan; 66 (1): 1-19). By an antiviral action, the macrocyclic lactone according to the invention makes it possible to treat the complications of infection by a human papillomavirus. By penetrating the site of HPV viral multiplication, the macrocyclic lactone according to the invention makes it possible to prevent complications due to HPV infections.

 Indeed, when HPV enters the germinal cells of the basal epithelial layer, following microlysis, it multiplies in the tissue, taking advantage of the differentiation of keratinocytes. Thus, viral multiplication with complete synthesis of the virion is observed only in the most superficial layers of the epidermis, when the cell is well differentiated. During the early stages of infection, the viral genome multiplies in the basal layers of the epithelium in episomal form, at 50 to 100 copies per cell. This step does not seem specific to the fabric. On the other hand, the establishment of the productive viral cycle involves a modification of the host cell, the viral production being possible only in the differentiated keratinocytes.

The cytopathic effect is characterized by koilocytosis; it is a cell of the intermediate or most external layers with an edematous nucleus, an irregular chromatin (witness of the viral activity) and especially the existence of a perinuclear intracytoplasmic vacuole pushing back the cytoplasm at the periphery; this vacuole seems optically empty. At the tissue level, there is epithelial proliferation and architectural modification with the appearance of micropapiles. There are large variations in the amount of virus produced, depending on the site and the nature of the lesions.

By a targeted action, the topical administration of a macrocyclic lactone according to the invention results in the treatment and / or prevention of complications of infection by a human papillomavirus in humans, women and children.

Typically, the complications of HPV infections are chosen from malignant melanomas, cutaneous carcinomas, in-situ or invasive carcinomas, squamous cell carcinomas, Bowen's disease, cancers of the head and neck (especially the eyes, the cornea, eyelids, ears, lips and oral cavity - tongue, gums, floor of the mouth and palate), cancers of the upper aerodigestive tract (including oropharynx, nasopharynx, hypopharynx, nasal cavity, paranasal sinuses, salivary and tonsil glands), larynx, esophageal cancers, stomach cancers, oral papillomas, pharyngeal papillomas, laryngeal papillomas, oesophageal papillomas, lung cancers, intravascular neoplasia, intravaginal neoplasia, intracervical neoplasia, cervical dysplasia, cervical carcinoma, penile cancer, intrapenous neoplasia, and in-situ or invasive carcinoma ow. Preferably, the complications of HPV infections are selected from malignant melanomas, cutaneous carcinomas, in-situ or invasive carcinomas, squamous cell carcinomas, Bowen's disease, head and neck cancers. In the compositions according to the invention, said compound of the family avermectins or milbemycins is present in a composition, and represents between 0.001 and 10% by weight relative to the total weight of the composition, preferably between 0.01 and 5 % in weight. Throughout this text, unless otherwise specified, it is understood that when concentration ranges are given, they include the upper and lower limits of said range.

The composition comprises, in addition to the compound of the family of avermectins or milbemycins, a pharmaceutically or physiologically acceptable medium.

In the case of topical or mucosal administration, any medium that is compatible with the skin, mucous membranes and / or integuments is meant.

Advantageously, the compositions of the invention comprise, in addition to at least one compound of the family of avermectins or milbemycins, at least one other therapeutic agent capable of increasing the effectiveness of the treatment.

By way of nonlimiting examples of such agents, mention may be made of antibiotics, antibacterial agents, antiviral agents, antiparasitic agents, antifungal agents, anesthetics, analgesics, keratolytics such as trichloroacetic acid, podophyllotoxin, imiquimod immunostimulatory products, or a mixture thereof.

The compositions according to the invention may furthermore comprise any adjuvant usually used in the dermatological field compatible with said compound of the family of avermectins or milbemycins. Particularly in the preferred case of a cutaneous application, there may be mentioned in particular chelants, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, dyes, bases or usual acids, minerals or organic, fragrances, moisturizers, vitamins, sphingolipids, self-tanning compounds, soothing and skin-protecting agents, propenetrating agents, gelling agents or a mixture thereof. These adjuvants, as well as their concentration, must be such that they do not adversely affect the advantageous properties of the mixture according to the invention. These additives may be present in the composition in a proportion of 0 to 20% by weight relative to the total weight of the composition, preferably from 1 to 10% by weight.

Examples of preservatives that may be mentioned include benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinylurea, parabens or mixtures thereof.

As humectants, mention may in particular be made of glycerine and sorbitol.

As chelating agents, mention may be made, for example, of ethylenediaminetetraacetic acid (EDTA), as well as its derivatives or its salts, dihydroxyethylglycine, citric acid, tartaric acid or their mixtures.

As propenetrating agents, mention may in particular be made of propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol and ethoxydiglycol.

The compound according to the present invention, and the composition comprising it, may be administered topically, vaginally, rectally, oropharyngeally, nasally, ocularly, aurally, enterally or parenterally.

They are preferably administered by topical application.

Topically, the pharmaceutical compositions, which are therefore more particularly intended for the treatment of the skin, may be in the form of ointments, creams, milks, ointments, powders, soaked swabs, solutions, gels , sprays, lotions or suspensions. They may also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels allowing controlled release of the active ingredients. These compositions topically can also be presented either in anhydrous form or in aqueous form. Vaginal, the compositions according to the invention can be applied in the form of ovules.

Rectally, the compositions according to the invention can be applied in the form of creams or suppositories.

By oropharyngeal, nasal or atrial route, the compositions according to the invention can be applied in the form of liquid compositions of suspensions or lotions type. Parenterally, the compositions according to the invention can be applied subcutaneously or intradermally. By way of nonlimiting example of parenteral preparations, mention may be made of preparations in the form of solutions or suspensions for infusion or for injection.

 Enterally, the compositions may be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles. allowing controlled release.

Eyes are mainly eye drops.

The quantity actually administered to be used according to the invention depends on the desired therapeutic or cosmetic effect, and can therefore vary to a large extent. Those skilled in the art, in particular the physician can easily, on the basis of his general knowledge determine the appropriate amounts. Thus, and according to a preferred embodiment, the pharmaceutical composition (s) are (are) administered 1 to 2 times / day. Preferably, the treatment may have a duration ranging from 1 week to 6 months, renewable, preferably from 2 weeks to 4 months. The courses can be renewed in cycle with or without rest period.

 In the compositions according to the invention, the daily dose of compounds of the invention administered is from 100 μg to 1 g, preferably from 150 μg to 500 mg, more preferably from 200 μg to 150 mg.

Claims

1. A compound selected from macrocyclic lactones or their pharmaceutically acceptable salts, for use in treating and / or preventing a complication of human papillomavirus infection selected from malignant melanomas, cutaneous carcinomas, in-situ or invasive carcinomas, squamous cell carcinomas, Bowen's disease, head and neck cancers, upper aerodigestive tract cancers, laryngeal cancers, esophageal cancers, stomach cancers, oral papillomas, pharyngeal papillomas , laryngeal papillomas, oesophageal papillomas, lung cancer, intravascular neoplasia, intravaginal neoplasia, intracervical neoplasia, cervical dysplasia, cervical carcinoma, penile cancer, intrapenous neoplasia, and in-situ or invasive carcinomas.

2. Compound for its use according to claim 1, characterized in that the complication of an infection with a human papillomavirus is selected from malignant melanomas, cutaneous carcinomas, carcinomas in situ or invasive, squamous cell carcinoma, Bowen, head and neck cancers.

3. Compound for use according to claim 1 or 2, characterized in that it is selected from avermectins and milbemycins.

4. Compound for its use according to one of claims 1 to 3, characterized in that it is an avermectin chosen from ivermectin, avermectin A [1 a], avermectin A [1 b], l avermectin A [2a], avermectin A [2b], avermectin B [1 a], avermectin B [1b], avermectin B [2a], avermectin B [2b], emamectin, abamectin, doramectin, eprinomectin, latidectin and selamectin.

5. Compound for use according to one of claims 1 to 3, characterized in that it is a milbemycin selected from milbemycin, lepimectin, milbemectin, milbemycin oxime, moxidectin and nemadectin.

6. Compound for use according to one of claims 1 to 4, characterized in that it is ivermectin.

7. Compound for its use according to any one of claims 1 to 6, characterized in that it is present in a composition, and represents between 0.001 and 10% by weight relative to the total weight of the composition, preferably between 0.01 and 5% by weight.

8. Compound for use according to any one of claims 1 to 7, characterized in that it is administered orally, topically, vaginally, rectally, oropharyngeal, nasal, ocular, atrial, enteral or parenteral.

9. Compound for its use according to any one of claims 1 to 8, characterized in that the human papillomavirus is selected from HPV-1, HPV-2, HPV-3, HPV-4, HPV-5, HPV-6 , HPV-7, HPV-8, HPV-1, HPV-16, HPV-18, HPV-31, HPV-33 and HPV-35.