EA041376B1 - APPLICATION OF ACETYLSALICYLIC ACID FOR THE TREATMENT OF SKIN INFECTIONS CAUSED BY THE HUMAN PAPILLOMA VIRUS - Google Patents

Description

Technical field

A medical device for the treatment of skin infections caused by the human papillomavirus (HPV), in particular warts and related pathologies, is the object of the present invention.

State of the art

Human papillomavirus (HPV) is a small group of DNA-containing viruses of the papovavirus family. Although they are not encapsulated, HPVs are very robust viruses around 55 nm in diameter. Their genome consists of a double strand of round DNA containing about 8000 base pairs of nucleotides linked to histones, forming structures similar to small chromosome bodies.

According to their trophic influence, HPVs are classified as those that appear on the skin, and those that cause damage to the mucous membranes. Cutaneous types are divided into those that are widespread in the population (HPV 1, 2 and 4) and those associated with epidermodysplasia verrucous, the most undesirable among which are HPV 5 and HPV 8 due to a strong tendency to malignant transformation. Mucous types are generally divided into high and low risk types. In invasive squamous cell carcinomas, low-risk HPVs (HPV 6 and 11) are almost never detected, while high-risk HPVs are always detected (HPV 16 and 18).

Benign skin infections caused by HPV usually refer to warts, papillomas, and condylomas. Papillomas affect the oral cavity, while the manifestation of genital warts is characteristic of both male and female genital organs.

A wart is a skin growth caused by the human papillomavirus (HPV), which is a benign manifestation, consists of a core of internal tissue covered with layers of epithelial tissue and is fed by blood vessels. Infection with the virus occurs by penetrating the epidermis.

The appearance of a wart in a certain place depends on the place of penetration of the viral strain that caused it. Warts are divided into

1) simple warts: skin lesions caused by the papillomavirus are usually irregular in shape and usually (but not always) develop symptomatically;

2) horny warts: wart lesions caused by HPV, typical of the sole of the foot and easily transmitted in swimming pools and gyms;

3) flat warts: slightly raised warty lesions; papilloma virus, affecting the hands, feet, face and legs, can lead to skin lesions that usually disappear within a short time.

Simple warts have a typical rough surface that often crystallizes and is not aesthetically pleasing, and usually appears on the hands, elbows and knees.

Warts are a fairly common problem: it is estimated that they affect about 10% of the world's population with a tendency to spread. In the high-risk category are school-age children, adolescents and young adults. The peak incidence occurs in the age group of 10 to 15 years.

The wart lesion is often asymptomatic and usually disappears even if untreated, although with a longer healing time, up to several years. Patients often resort to treatments aimed at eliminating such skin manifestations, given their unaesthetic appearance.

Currently used methods of treatment include surgical removal, which consists in the complete removal of the infected area of the skin. Despite the effectiveness of the method, it is extremely invasive and in any case does not eliminate the problem of wart recurrence;

cryotherapy consists in freezing the affected area with liquid nitrogen;

keratolytic drugs accelerate the aging cycle of the wart, causing it to rise to the surface, followed by spontaneous exfoliation;

intralesional injections - injections of interferon into the wart itself to provoke the death of cells infected with the virus;

laser therapy consists in burning the wart with a laser;

Use of Vitamin E: Vitamin E in fat preparations, which is also used as a soothing skin cream, is used topically to eliminate the wart, probably by improving the ability to heal.

The treatments listed are invasive in most cases and provide a success rate of 70% or less.

Thus, there is a need for effective and less invasive or non-invasive methods for the treatment of skin infections caused by HPV, in particular benign skin infections such as warts and the like.

Acetylsalicylic acid (ASA) belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs). ASA is a derivative of salicylic acid, which differs from it by the presence

- 1 041376 acetyl group in position 2, responsible for the anti-inflammatory effect of the molecule. ASA inhibits prostaglandin synthesis by acetylation of serine at the active site of the cyclooxygenase (COX) enzyme. At low doses (75-81 mg/day), the action of ASA is selective at the platelet level, where it irreversibly inhibits COX1 serine 530, exerting an antithrombotic effect. At higher doses (650-4000 mg/day), ASA inhibits COX1 and COX2 by blocking prostaglandin synthesis and has antipyretic and analgesic effects. Other mechanisms of action of the molecule have been studied and explanations for its many pharmacological properties have been proposed, however, there is insufficient data regarding the probable antiviral effect of ASA. ASA, like other COX2 inhibitors, is likely to be able to act on cytomegalovirus (CMV) - the causative agent of the herpes virus family. According to scientific evidence, ASA is able to block the influenza virus.

The essence of the invention

It has now been found that the topical application of acetylsalicylic acid for the treatment of skin infections caused by HPV, in particular in benign infections such as warts and similar manifestations, is effective in eliminating the stratum corneum typical of them in a short time.

Without being limited by theory, despite the lack of scientific evidence regarding the action of ASA against HPV, its ability to interfere with the cellular pathway of the virus, intended for its spread in the host body, may explain its effectiveness in the treatment of these skin infections.

Another possible mechanism may be related to the keratolytic effect exerted by ASA directly on the skin manifestation with the separation of the epidermal layer due to accelerated cell death. ASA inhibits the synthesis of COX1 and affects the prostaglandin pathway, weakening the intercellular ties of horocytes that prevent its penetration into the lower stratum corneum, provoking the separation of the upper layer from the newly formed lower layer.

With a greater degree of probability, given the high effectiveness of treatment, ASA acts through a synergy of a combination of various mechanisms.

Thus, one of the objectives of the present invention is the use of acetylsalicylic acid in the treatment of skin infections caused by HPV, in particular in benign infections such as warts, papillomas and condylomas, in which acetylsalicylic acid is contained in a patch according to the attached claims 1-8.

An additional object of the invention is the topical application of a medical device (patch), preferably with controlled release, containing acetylsalicylic acid in solid form or as part of a polymer matrix of various nature according to claims 9, 10.

Additional features and advantages of the proposed method result from the following description of preferred, but not exclusive, embodiments of the invention.

Brief description of the drawings

In FIG. 1 shows a schematic cross section of a first embodiment of a medical device;

in fig. 2 is a schematic cross section of a second embodiment of the medical device;

in fig. 3 is a schematic cross section of a third embodiment of a medical device.

Disclosure of invention

This invention relates to the use of acetylsalicylic acid in the topical treatment of skin infections caused by HPV and representing papillomas, warts, genital warts or simple, horny or flat warts, in which acetylsalicylic acid is contained in a patch (1) containing a solid dose (2) acetylsalicylic acid selected from such forms as tablet, powder, granulate, adhesive layer (3) located around the solid dose (2), dosing pressure plate (4) located above the solid dose (2), outer impermeable layer (5).

In some embodiments, the acetylsalicylic acid treatment according to the invention is for skin infections, which are so-called genital warts, more commonly known as warts, follicles that appear as growths or protrusions on the skin. These warts are a manifestation of a genital infection caused by HPV, which is sexually transmitted, although the possibility of infection by other non-sexual routes is not excluded.

In men, condylomas are found mainly at the level of the gland, the external opening of the urethra, the frenulum, penis and groove of the gland of the foreskin; in women, in turn, areas such as the vulva, cervix and vagina are most affected.

Warts can be embossed or flat, large or small; sometimes they can be

- 2 041376 grouped in a shape similar to a polyp or cauliflower. In some cases, the warts are the same color as the skin and are so small and flat that they can go unnoticed.

Warts are often asymptomatic, although certain forms cause burning, itching, and local irritation.

Acetylsalicylic acid (ASA) in accordance with the present invention is applied topically in solid form or as part of a polymer matrix.

In a preferred embodiment of the invention, the dosage of ASA is from 0.3 to 5 g/day, 0.3-4 or 0.3-1.2 g/day, with an optimal dosage of 0.5-1 g/day.

In general, the presence of ASA is assumed in the patch as a layer of adhesive material facing the surface of the desired skin area with an outer layer of impermeable material.

For the barrier layer, polyethylene terephthalate (PET) film, polyethylene film, polyurethane film, polyamide film, ethylene-vinyl alcohol copolymer (EVA), laminates containing two or more film layers selected from those listed above will preferably be used.

In the case of laminates, they can be made by bonding or co-extrusion.

These films are standard and widely used by specialists.

The layer of adhesive material may be present in stripes arranged, for example, along opposite edges of the patch or along its perimeter in a continuous or broken line. In other embodiments of the invention, the layer of adhesive material takes the form of square, round patches or other forms of patches located in separate areas of the surface of the patch facing the treated area of the skin.

The adhesive material used for the purposes of the present invention is easily removable. In some embodiments of the invention, a hot melt adhesive is used that contains a thermoplastic polymer and zinc oxide, preferably in a portion from 5 to 35% and in a portion from 10 to 20% in the most optimal embodiment.

In some embodiments, the thermoplastic polymer is selected from acrylic polymers, butyl rubber, ethylene-vinyl alcohol (EVA), natural rubber, nitrile polymers, silicone rubbers, styrene copolymers, preferably styrene-butylene copolymer (SBC, SBS), styrene- ethylene-butylene-styrene (SEBS), styrene-ethylene-propylene (SEP) or styrene-isoprene-styrene (SIS) copolymer or vinyl polymers.

In a preferred embodiment of the invention, adhesion promoters are added to the thermoplastic polymer. In a preferred embodiment of the invention, such agents are selected from terpenes and modified terpenes, cycloaliphatic resins, aromatic resins, rosin, hydrogenated hydrocarbon resins, terpene phenolic resins and silicone resins.

In some embodiments of the invention, ASA is used in the form of a tablet applied to the skin manifestation to be treated with a patch, as provided above.

In other embodiments of the invention, ASA is contained in a polymeric matrix, for example, in the form of a hydrophilic or hydrophobic gel or in the form of a tablet.

hydrophilic gels.

The liquid phase of the gelling agent is water.

In preferred embodiments of the invention, the choice of gelling agents is made from polyacrylic acid and its salts, in particular Carbopol-934, carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose 400 and 4000 cP, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC) 25, 100, 4000 and 15000 cP, xanthan gum, acacia (gum arabic), agar-agar, guar gum, locust bean gum, alginates, molasses, mannose and polysaccharides galactose, chitosan,

- 3 041376 modified starch or mixtures thereof.

In preferred embodiments of the invention, the gelling agents are present in the gel formulation in amounts of 0.5 to 6%, or 1 to 4% optimally.

hydrophobic gels.

Hydrophobic gels are anhydrous systems in which the dispersion phase consists of a hydrophobic dispersant.

In preferred embodiments of the invention, the selection of the dispersion phase is made from vegetable oils (triglycerides), vegetable wax, in particular jojoba oil, liquid paraffin, hydrogenated decene polymers, high molecular weight silicone, in particular dimethicone.

The gelling agents are preferably selected from colloidal silica, aluminum salts of fatty acids, high molecular weight fatty alcohols, preferably in the range from 100 to 450 DA, ozocerite, wax of vegetable origin, wax of animal origin.

Hydrophilic, hydrophobic or lipid matrices.

ASA can also be prepared in special hydrophilic, hydrophobic lipid matrices or dried matrices, in particular by directly compressing the drug into a polymer matrix, as well as by mixing the ASA granules and the polymer matrix before compression.

For hydrophilic gels, the mentioned hydrophilic matrices must be used.

The hydrophobic matrices are preferably polyethylene, polyvinyl chloride, ethylcellulose, acrylate polymers or based on their copolymers.

ASA in solid forms is released due to the penetration of steam or sweat into the polymer matrix. The result is a delayed and substantially time-constant release caused by slow dissolution and thus dispersion of the active ingredient through a network of channels between compacted polymer particles.

Lipid matrices are derived from wax and from lipids. The active substance is released both through the pores of the dispersion and during erosion. In some embodiments, carnauba wax is used in combination with stearic acid.

Biodegradable matrices can also be used, as can natural polymers such as proteins and polysaccharides, as such or modified, as well as synthetic polymers such as aliphatic polyesters and polyanhydrides, or matrices derived from seaweed, including alginic acid.

Such dosage forms can be prepared using standard methods and excipients well known to those skilled in the art. Such methods are described, in particular, by Remington in the manual Science and Practice of Pharmacy, edited by Allen L.V. Jr., 22nd ed., 2012.

Acetylsalicylic acid can also be used with other plant-based active ingredients with anti-inflammatory or emollient and soothing effects, such as mallow, tea tree and annual sunflower.

In preferred embodiments, the ASA is present in micronized form.

In the proposed patch, the delayed release of the drug depends on various factors.

The first significant factor is the porosity of the matrix. For the purposes of the present invention, a macro- or microporous matrix may be used, as well as a non-porous matrix.

Macroporous matrices have pores ranging in size from 0.1 to 1 µm. The drug is distributed through these openings.

Microporous matrices have pores ranging from 50 to 200 A. In this case, the drug also spreads through the pores.

In non-porous matrices, the drug is dispersed through a mesh lattice and the release is slower.

Other significant factors are the solubility of ASA, which is high enough to ensure its release by dissolution as a result of matrix erosion;

the coefficient of hydration/swelling of the polymer matrix used, the viscosity of the polymer in that the increase in the molecular weight of the polymer or its viscosity in the gel layer slows down the dissolution of ASA;

polymer concentration in the sense that an increase in its concentration causes an increase

Claims (4)

a change in the viscosity of the gel and, consequently, a slower diffusion of the drug; the thickness of the polymer and hydrodynamic dispersion layer, with an increase in thickness causing a more delayed release of the drug; the surface area of the dispersion, since a smaller area of dispersion accelerates the release of the drug; the presence of diluents or impurities, since water-soluble diluents such as lactose increase the release rate, while insoluble diluents such as dicalcium phosphate reduce diffusion and increase erosion. In FIG. 1, 2 and 3 present specific embodiments of a topical medical device in accordance with the present invention. In such embodiments, the implementation of the polymer matrix, the outer impermeable layer and the adhesive layer are selected from those previously described. In another embodiment of the invention shown in FIG. 1, ASA is applied in the form of patch 1 applied to a skin area C affected by an HPV infection, such as wart V. Patch 1 contains a solid dose of 2 ASA, in particular a tablet, powder, granulate or other standard solid form in which ASA can be present in pure form or with the addition of standard excipients, as well as an adhesive layer 3, which in most cases is located around the solid dose 2. A dosing pressure plate 4 is located on top of the solid dose 2. The surface of the patch 1 is covered with an impermeable layer 5. In the preferred embodiment of patch 1 shown in FIG. 1, a solid dose of ASA 2 contains ASA in the composition of a hydrophilic matrix (in particular, hydroxyethyl cellulose) and/or modified starch. In other embodiments shown in FIG. 2, patch 101 assumes an ASA-containing polymer matrix 102, where the ASA is dispersed in an adhesive polymer that is melted by a solvent or thermally on an impermeable layer 105. The surface of the patch 101 facing the treated skin surface contains an adhesive layer 103. In the preferred embodiment of patch 101 shown in FIG. 2, polymer matrix 102 contains ASA in vaseline-liquid paraffin (7:3) and 20% urea. In other embodiments shown in FIG. 3, patch 201 assumes the presence of a polymer matrix 202 containing ASA in the form of microspheres, which can be obtained by suspending ASA in an aqueous solution of a water-soluble polymer, followed by homogeneous dispersion of the resulting suspension in a lipophilic polymer to form microspheres 206 containing ASA. The outer surface of the patch 201 is an impermeable layer 205, while the surface of the patch 201 facing the treated surface contains an adhesive edge 203 located around the polymer matrix 202. In the preferred embodiment of patch 201 shown in FIG. 3, polymer matrix 202 contains acetylsalicylic acid in a composition of about 5% sodium carboxymethyl cellulose, 12% ethanol, 20% glycerol, 16% propylene glycol, and distilled water in the remaining amount from 100%. Obviously, only some specific embodiments of the present invention have been described, to which a person skilled in the art will be able to make all the modifications necessary to adapt it to specific applications, without departing from the scope of protection of the present invention. CLAIM 1. The use of acetylsalicylic acid in the local treatment of skin infections caused by HPV and representing papillomas, condylomas, genital warts or simple, horny or flat warts, in which acetylsalicylic acid is contained in a patch (1) containing a solid dose (2 ) acetylsalicylic acid selected from such forms as tablet, powder, granulate, adhesive layer (3) located around the solid dose (2), dosing pressure plate (4) located above the solid dose (2), outer impermeable layer (5 ). 2. Use according to claim 1, wherein HPV skin infections are benign. 3. Use according to any one of claims 1, 2, in which acetylsalicylic acid is in the solid state or is part of a polymer matrix. 4. Use according to any one of claims 1 to 3, wherein the dosage of acetylsalicylic acid is -