ES2895903T3 - Composition and medical device comprising acetylsalicylic acid for the treatment of human papillomavirus skin infections - Google Patents

Abstract

Acetylsalicylic acid for use in the topical treatment of HPV skin infections, wherein the acetylsalicylic acid is contained in a patch or plaster comprising a layer of adhesive material that is oriented towards the skin to be treated and a waterproof layer facing out.

Description

DESCRIPTION

Composition and medical device comprising acetylsalicylic acid for the treatment of human papillomavirus skin infections

field of invention

The object of this invention is a patch or plaster containing acetylsalicylic acid for use in the topical treatment of HPV skin infections, the patch or plaster comprising a layer of adhesive material that is oriented towards the skin to be treated. treated and a waterproof layer that faces out.

The invention is defined by the claims. Any content, disclosure or information outside the scope of the claims is provided by reference.

Background art

Human papillomaviruses (HPV) are small DNA viruses of the papovavirus family. Although not encapsulated, HPVs are very resistant viruses, with a diameter of approximately 55 nm. Its genome consists of a double-stranded circular DNA containing approximately 8,000 nucleotide base pairs, associated with histones to form structures similar to small chromosome bodies.

According to their trophism, HPV can be classified into cutaneous and mucosal. The skin types are differentiated into those commonly disseminated among the population (HPV 1, 2 and 4) and those associated with epidermodysplasia verruciformis, the most important being HPV 5 and HPV 8 due to the strong tendency in relation to malignant transformation. . The mucosal types are generally divided into high-risk and low-risk types. Low-risk types (HPV 6 and 11) are almost always absent in invasive squamous cell carcinomas, while high-risk types are always present (HPV 16 and 18).

Benign HPV skin infections are generally classified as warts, papillomas, and warts. Papillomas affect the oral cavity, while warts affect the genital organs of both men and women.

A wart is a skin formation induced by the human papillomavirus (HPV) and is a benign manifestation composed of a core of inner tissue fed by blood vessels and covered by layers of epithelial tissue. The virus penetrates the epidermis and infects it.

The appearance of the wart changes depending on the location of the viral strain that caused it. Warts are divided into:

1. Common warts: Skin lesions caused by the papillomavirus are generally irregular in shape and often (but not always) develop asymptomatically.

2. Plantar warts: typical of the sole of the foot, these warty lesions caused by HPV are easily transmitted in swimming pools and gyms.

3. Flat warts: slightly raised warty lesions; The papillomavirus, which infects the hands, feet, face, and legs, can cause these skin lesions, which tend to fade quickly. Common warts have a normally rough surface, often wrinkled at the edges and are unattractive in appearance, and usually appear on the hands, elbows and knees.

Warts are a fairly common problem: it is estimated that they affect around 10% of the world's population, with a tendency to increase. The most affected population group are school-age children, youth and young adults. The peak is reached in the age group between 10 and 15 years.

Warts are usually asymptomatic and tend to disappear although, if left untreated, healing times are very long, even several years. Given the unattractive appearance of these skin manifestations, affected subjects often resort to treatments to eliminate them.

Treatments currently used include:

• surgical excision: consists of the total removal of the infected skin. Although this method is effective, it is very invasive and in any case does not eliminate the problem of wart recurrence;

• cryotherapy: this involves freezing the affected area with liquid nitrogen;

• keratolytic preparations: these accelerate the aging cycle of the wart, causing it to rise to the surface and allowing its spontaneous detachment;

• intralesional injections: injections of interferon into the wart itself, to induce apoptosis of virus-infected cells;

• Laser therapy: consists of burning the wart with a laser;

• Application of vitamin E: vitamin E, in oily preparations also used as an anti-irritant skin cream, applied locally leads to the elimination of the wart, probably improving its healing capacity.

These treatments are mostly invasive and have a probability of success of less than or equal to 70%. US2008/0312196 discloses the use of keratolytic compounds including acetylsalicylic acid for the removal of warts and other fibromas and papillomas.

Thus, there is a need for a treatment for HPV skin infections, particularly benign skin infections such as warts and the like, that is effective and mildly or non-invasive.

Acetylsalicylic acid (ASA) belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs). ASA is a derivative of salicylic acid, which differs from it by the presence of an acetyl group in position 2, responsible for the anti-inflammatory activity of the molecule. ASA acts by inhibiting prostaglandin synthesis through serine acetylation at the active site of the enzyme cyclooxygenase (COX). At low doses (75-81 mg/day), the action of ASA is selective at the platelet level, where it irreversibly inhibits serine 530 of COX1, producing an antithrombotic effect. At higher doses (650-4000 mg/day), ASA inhibits COX1 and COX2, blocks prostaglandin synthesis, and has an antipyretic and analgesic effect. Other mechanisms of action of the molecule have been studied or proposed to explain its numerous pharmacological properties, but little is known regarding a possible antiviral activity of ASA. ASA, like other COX2 inhibitors, might be able to act on cytomegalovirus (CMV), a pathogen of the herpes virus family. Scientific evidence has suggested that ASA can block the flu virus.

Summary of the invention

Aspirin for use in the topical treatment of HPV skin infections has now been found to be effective in the treatment of HPV skin infections, particularly benign infections such as warts and similar manifestations, by eliminating, in a few hours, the stratum corneum that characterizes such manifestations.

Without wishing to be bound by any particular theory, although there is no scientific evidence regarding the activity of ASA against HPV, its ability to interfere with the cellular route chosen by the virus to spread in the host could explain its effectiveness in the treatment of HPV. these skin infections.

Another possible mechanism could be attributable to a keratolytic effect exerted by ASA directly on the skin manifestation, with the separation of the epidermal layer from the dermis due to the accelerated loss of cells. ASA inhibits the synthesis of COX1 and influences the prostaglandin pathway, weakening the intercellular bonds of the corneocytes, which disrupt their adhesion to the underlying stratum corneum, causing the upper stratum to separate from the newly formed lower stratum.

Given the observed high effectiveness of the treatment, it is more likely that ASA acts through the concurrence of various mechanisms that work synergistically.

Therefore, an object of this invention is acetylsalicylic acid for use in the treatment of HPV skin infections, in particular benign infections such as warts, papillomas and condylomas, as defined in the claims.

An additional object of the invention is a patch or plaster for topical application, preferably by controlled release, comprising acetylsalicylic acid in solid form or incorporated into a polymeric matrix of various kinds, as defined in the claims.

Brief description of the drawings

Figure 1 represents a schematic cross-sectional view of a first embodiment of the medical device according to the invention;

Figure 2 represents a schematic cross-sectional view of a second embodiment of the medical device according to the invention;

Figure 3 represents a schematic cross-sectional view of a third embodiment of the medical device according to the invention.

Detailed description of the invention

This invention relates to acetylsalicylic acid for use in the treatment of HPV skin infections, in particular benign skin infections such as warts, whether common or plantar or flat, papillomas, condylomas as defined in the claims .

In certain embodiments, the skin infections treated with aspirin according to the invention are so-called genital warts, more often known as warts, which appear as growths or bumps on the skin. These warts are the expression of a sexually transmitted genital HPV infection, although the possibility of infection through other non-sexual routes cannot be ruled out.

In men, warts are preferably found at the level of the gland, urinary meatus, frenulum, penis and groove of the preputial gland; In women, on the other hand, the most affected areas are the vulva, the cervix, and the vagina.

Warts can be raised or flat, large or small; they can sometimes group together and take on a shape similar to a polyp or cauliflower. In some cases, 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 variations cause a burning sensation, itching, and local irritation.

Acetylsalicylic acid (ASA) according to this invention is used for topical administration, in the solid state or incorporated in a polymeric matrix.

In preferred embodiments, the ASA dosage is between 0.3 and 5 g/day, or between 0.3 and 4 or between 0.3 and 1.2 g/day, preferably between 0.5 and 1 g/day. .

In general, the ASA will be contained in a patch or plaster comprising an adhesive layer or material that faces towards the skin to be treated and an impermeable layer that faces outwards.

The waterproof layer is preferably selected from:

• Poly(ethylene terephthalate) (PET) film

• polyethylene film

• polyurethane film

• polyamide film

• ethylene-vinyl alcohol (EVA) copolymer film

• laminated materials comprising two or more layers of film selected from those mentioned above.

In the case of laminated materials, it can be manufactured by adhesion or by co-extrusion.

These films are commercial and well known to those skilled in the art.

The adhesive layer or material may be in the form of strips, arranged along opposite ends of the plaster, for example, or along its perimeter, in a continuous or broken line. In other embodiments, the adhesive layer or material takes the form of square or round pads, or other shapes, disposed in discrete areas of the side of the plaster that faces the skin to be treated.

The adhesive used for the purpose of this invention is an easily removable adhesive. In certain embodiments, a "hot melt" type glue is used which comprises a thermoplastic polymer and contains zinc oxide, preferably in weighted amounts between 5% and 35%, more preferably between 10% and 10%. twenty%.

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

In the preferred embodiment, adhesion promoting agents are added to the thermoplastic polymer. In the preferred embodiment, such agents are selected from: terpenes and modified terpenes, cycloaliphatic resins, aromatic resins, rosin, hydrogenated hydrocarbon resins, terpene-phenol resins, and silicone resins.

In certain embodiments, the ASA is used in the form of a tablet applied to the skin manifestation to be treated by means of a band-aid or patch as discussed above.

In other embodiments, the 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 gelling liquid phase is water.

In preferred embodiments, the gelling substances are selected from:

• poly(acrylic acid) and salts thereof, for example Carbopol-934,

• carboxymethylcellulose,

• hydroxypropylcellulose,

• methylcellulose 400 and 4000 cPs,

• hydroxyethylcellulose,

• hydroxypropylmethylcellulose (HPMC) 25, 100, 4000 and 15000 cPs,

• xanthan gum,

• acacia (gum arabic),

• agar-agar,

• guar gum,

• locust bean gum,

• alginates,

• molasses,

• mannose and galactose polysaccharides,

• chitosan,

• modified starches

or mixtures thereof.

In preferred embodiments, the gelling substances are contained in the gel composition in amounts between 0.5% and 6%, more preferably between 1% and 4%, by weight.

Hydrophobic gels:

Hydrophobic gels are anhydrous systems, in which the dispersing phase consists of a hydrophobic dispersing agent.

In preferred embodiments, the dispersing phase is selected from: vegetable oils (triglycerides), vegetable waxes, eg Simmondsia chinensis oil, liquid paraffin, hydrogenated 1-decene polymers, high molecular weight silicone, eg dimethicone.

Preferred gelling agents are selected from:

• colloidal silica,

• aluminum salts of fatty acids,

• high molecular weight fatty alcohols, preferably between 100 and 450 DA,

• ozokerite,

• vegetable waxes,

• animal waxes.

Hydrophilic, hydrophobic or lipid matrices:

ASA can also be formulated in special hydrophilic, hydrophobic or lipid matrices or matrices that are dry, for example by direct compression of the drug into the polymeric matrix or also by mixing ASA granules and polymeric matrix prior to compression.

The hydrophilic matrices will be those defined above for hydrophilic gels.

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

In these solid forms, ASA is released by the penetration of steam or sweat into the polymeric matrix. The result is a delayed and essentially constant release over time, caused by the slow dissolution and, therefore, the dispersion of the active ingredient through a network of channels that exist between the compacted polymer particles.

Lipid matrices are prepared from waxes and lipids. The active ingredient is released both through the dispersion pores and by erosion. In certain embodiments, carnauba wax is used in combination with stearic acid.

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

Such dosage forms can be prepared using conventional methods and excipients well known to those skilled in the art. Such methods are described, for example, in Remington, The Science and Practice of Pharmacy, edited by Allen, Loyd V., Jr, 22nd edition, 2012.

Acetylsalicylic acid can also be associated with another active ingredient with anti-inflammatory or emollient and soothing activity, also of plant origin, such as, for example , Malva sylvestris, Melaleuca alternifolia and Helianthus annuus.

In preferred embodiments, the ASA is in micronized form.

In the patch or plasters according to this invention, the delayed release of the drug depends on various factors. A first important factor is the porosity of the matrix. For the purposes of this invention, a matrix with macro or microporosity or also a non-porous matrix can be used.

Matrices with macroporosity have pore sizes between 0.1 and 1 micrometer. the drug propagates through said holes.

Microporous matrices have pore sizes between 50 and 200 Angstroms. In this case, the drug also spreads through the pores.

In non-porous matrices, the drug disperses through the lattice mesh and is released more slowly.

Other important factors are:

• the solubility of the ASA, which, being sufficiently high, allows its release through dissolution by erosion of the matrix;

• the hydration/swelling ratio of the polymeric matrix used,

• the viscosity of the polymer, since increasing the molecular weight of the polymer or its viscosity in the gel layer slows down the dissolution of the ASA;

• the polymer concentration, since an increase in its concentration causes an increase in the viscosity of the gel and, therefore, a slower diffusion of the drug;

• the thickness of the polymer and of the hydrodynamic dispersion layer, since an increase in thickness causes a slower release of the drug;

• the area of the scattering surface, since a smaller scattering area speeds up drug release;

• the presence of extenders or additives, as water-soluble extenders such as lactose increase the release rate, while insoluble extenders such as dicalcium phosphate reduce diffusion and increase erosion.

Certain embodiments of a medical device for topical administration according to this invention are shown in Figures 1, 2 and 3. In such embodiments, the polymeric matrix layer, the outer impermeable layer and the adhesive layer are selected from those previously described.

In an embodiment shown in Figure 1, ASA is administered in the form of a patch or plaster 1 applied to the skin area C where HPV infection is present, for example a wart V, to be treated. . Patch 1 comprises a solid dose 2 of ASA, for example a tablet, powder, granulate or other conventional solid form, in which the ASA may be in pure form or added with common excipients, and a layer 3 of adhesive that normally surrounds solid dose 2.

A dose pusher plate 4 is positioned above the solid dose 2. The patch 1 is covered on the outside with a waterproof layer 5 .

In a particular preferred embodiment of the patch 1 of Figure 1, the solid dose 2 of ASA comprises the ASA in a hydrophilic matrix (such as, for example, hydroxyethylcellulose) and/or modified starches.

In other embodiments shown in Figure 2, the patch or band-aid 101 comprises an ASA-containing polymeric matrix 102, in which the ASA is dispersed in a solvent-melt or hot-melt adhesive polymer onto the impermeable layer 105 . . The side of the plaster 101 that faces the surface to be treated comprises a layer 103 of adhesive.

In a particular preferred embodiment of the patch 101 of Figure 2, the polymeric matrix 102 comprises AAS in Vaseline-liquid paraffin (7:3) and 20% by weight urea.

In other embodiments shown in Figure 3, the patch or plaster 201 comprises a polymeric 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 and then dispersing homogeneously disperse such a suspension in a lipophilic polymer to form ASA-containing microspheres 206.

The external face of the patch 201 comprises an impermeable layer 205 while the face of the patch 201 that faces the surface to be treated comprises a border 203 of adhesive surrounding the polymer matrix 202 .

In a particular preferred embodiment of the patch 201 of Figure 3, the polymeric matrix 202 comprises acid acetylsalicylic in about 5% by weight of sodium carboxymethylcellulose, about 12% by weight of ethanol, about 20% by weight of glycerin, about 16% by weight of propylene glycol and distilled water qs 100%.

Claims (12)

1. Acetylsalicylic acid for use in the topical treatment of HPV skin infections, wherein the acetylsalicylic acid is contained in a patch or plaster comprising a layer of adhesive material that is oriented towards the skin to be treated and an impermeable layer that faces outwards. 2. Acetylsalicylic acid for use according to claim 1, wherein the HPV skin infections are of the benign type and are selected from papillomas, warts, warts of the male or female genitalia, or common, plantar, or flat warts. 3. Acetylsalicylic acid for use according to any one of claims 1 to 2, wherein the dosage of acetylsalicylic acid is between 0.3 and 5 g/day or between 0.3 and 4 g/day, or between 0 .3 to 1.2 g/day, or between 0.5 and 1 g/day. 4. Acetylsalicylic acid for use according to any one of claims 1 to 3, wherein the impermeable layer is preferably selected from: - polyethylene terephthalate (PET) film - polyethylene film - polyurethane film - polyamide film - ethylene-vinyl alcohol (EVA) copolymer film - laminated materials comprising two or more layers of film selected from those listed above. 5. Acetylsalicylic acid for its according to claim 4, in which the acetylsalicylic acid is contained in a polymeric matrix and is in the form of hydrophilic or hydrophobic gels, in which the hydrophilic gel comprises gelling substances selected from: - polyacrylic acid salts thereof, for example Carbopol-934, - carboxymethylcellulose, - hydroxypropylcellulose, - methylcellulose 400 and 4000 cPs, - hydroxyethylcellulose, - hydroxypropylmethylcellulose (HPMC) 25, 100, 4000 and 15000 cPs, - xanthan gum, - acacia (gum arabic), - agar-agar, - guar gum, - locust bean gum, - alginates, - molasses, - mannose and galactose polysaccharides, - chitosan, - modified starches or mixtures thereof, and optionally water, and wherein the hydrophobic gel comprises gelling substances selected from: - colloidal silica, - aluminum salts of fatty acids, - high molecular weight fatty alcohols, preferably between 100 and 450 DA, - ozokerite, - vegetable waxes, - animal waxes, and optionally a dispersing phase selected from vegetable oil (triglycerides), vegetable waxes, eg Simmondsia chinensis oil, liquid paraffin, hydrogenated 1-decene polymers, high molecular weight silicone, eg dimethicone. 6. Acetylsalicylic acid for use according to claim 5, wherein the acetylsalicylic acid is contained in hydrophilic, hydrophobic, lipid matrices or matrices that are dry biodegradable by direct compression or after granulation, wherein the hydrophilic matrices are according to Claim 5, the hydrophobic matrices are preferably selected from polyethylene, polyvinyl chloride, ethylcellulose, acrylate polymers or copolymers thereof and the lipid or biodegradable matrices are selected, respectively, from waxes or lipids and proteins, polysaccharides, as such or modified, synthetic polymers such as aliphatic polyesters and polyanhydrides, and matrices derived from seaweed, such as alginic acid. 7. Acetylsalicylic acid for use according to any one of claims 1 to 6, in combination with active ingredients with anti-inflammatory or emollient and soothing activity, Malva sylvestris, Melaleuca alternifolia and Helianthus annuus. 8. Acetylsalicylic acid for use according to any one of claims 1 to 7, wherein the acetylsalicylic acid is in micronized form. 9. Acetylsalicylic acid for use according to any one of claims 1 to 8, wherein the acetylsalicylic acid is in amorphous or crystalline form, or hydrated or as clathrate and is optionally in the form of a cyclodextrin inclusion complex, in the that said cyclodextrin is preferably selected from p-cyclodextrin and hydroxy propyl-p-cyclodextrin. 10. Patch or plaster (1) for use in the topical treatment of HPV skin infections according to claim 1, comprising: - a solid dose (2) of acetylsalicylic acid, selected from a tablet, a powder, a granule and other conventional solid forms, in which the acetylsalicylic acid is in pure form or is added with excipients, in which the dose (2 ) solid preferably comprises acetylsalicylic acid in a hydrophilic matrix such as for example hydroxyethylcellulose and/or modified starches, - a layer (3) of adhesive surrounding the solid dose (2), - a dose pusher plate (4) positioned above the solid dose (2), - an external waterproof layer (5). 11. Patch or plaster (101) for use in the topical treatment of HPV skin infections according to claim 1, comprising a polymeric matrix (102) containing acetylsalicylic acid, in which the acetylsalicylic acid is dispersed in a adhesive polymer, the polymer having been melted by means of a solvent or heat onto an impermeable layer (105), wherein the side of the patch (101) that faces the surface to be treated comprises a layer (103) of adhesive , in which the polymeric matrix (102) preferably includes acetylsalicylic acid in Vaseline-liquid paraffin 7:3 and 20% by weight urea. 12. Patch or band-aid (201) for use in the topical treatment of HPV skin infections according to claim 1, comprising a polymeric matrix (202) containing acetylsalicylic acid in the form of microspheres, since it can be obtained by suspending the acetylsalicylic acid in an aqueous solution of a water-soluble polymer and then homogeneously dispersing such suspension in a lipophilic polymer to form microspheres (206) containing acetylsalicylic acid, wherein the external face of the patch (201) comprises an impermeable layer (205) and the face of the patch (201) that is oriented towards the surface to be treated comprises a border (203) of adhesive that surrounds the polymeric matrix (202), in which the polymeric matrix (202) preferably comprises acetylsalicylic acid in approximately 5% by weight of sodium carboxymethylcellulose, approximately 12% by weight of ethanol, approximately 20% by weight of glycerin, approximately 16% by weight of propylene glycol and distilled water qsp 100%.