IT201900006250A1 - MEDICATION FOR THE TREATMENT OF THE INJURED SKIN - Google Patents

Description

Description of the patent for industrial invention entitled:

"MEDICATION FOR THE TREATMENT OF INJURED SKIN"

The invention relates to an adhesive wound dressing which includes a matrix in which a polysaccharide is absorbed.

State of the art

The medical treatment of the wound, both in the case of skin injured by mechanical trauma, by surgical wound and by ulceration or burn, should always allow restitutio ad integrum of the skin: an effective tissue repair (therefore without surgical complications) is possible when the wound is put in a position to best express its biological / biochemical potential with the sole aid of dressings. Dressings can be divided into two categories: traditional dressings and advanced dressings.

By traditional dressing we mean a material placed in direct contact with the wound with the sole function of haemostasis, coverage and protection (tampons or gauze in viscose or cotton), while the advanced dressing is made up of biocompatible material that interacts with the site of the lesion to directly and / or indirectly stimulate a specific reaction and thus achieve a quick recovery.

The "optimal" conditions that these advanced dressings should create for prompt and correct tissue repair are:

- the maintenance of the moist microenvironment at the interface between the wound and the dressing (this microenvironment in fact allows the migration of fibroblastic cells, located at the edges and at the bottom of the wound, to move quickly towards the center of the same thus favoring the regeneration of the injured tissue),

- thermal insulation of the injured skin,

- absorption of excess exudate,

- pain control,

- protection from exogenous infections, as well as

- the greatest possible comfort for the patient (due to less need for dressing changes) and, finally, they must not cause trauma when removing them.

The main classes of advanced dressings are represented by alginates, hydrocolloids, hydro-fibers and polyurethane foams.

Alginates are calcium and / or sodium-based dressings that interact with the exudate of the lesion forming a soft gel which, in this way, keeps the wound healing environment moist.

Hydrocolloids are semi-occlusive dressings comprising adhesives, pastes and powders of various kinds, present with different shapes, sizes and adhesive properties. They are impervious to bacteria and other contaminations and, due to their poor permeability, can promote autolytic debridement.

Hydrofibers are sodium carboxylmethylcellulose (CMC) fibers capable of rapidly absorbing (and therefore retaining) liquids: this dressing immediately interacts with the exudate and, thanks to its transformation into a cohesive gel, creates a moist environment on the wound.

Polyurethane films, on the other hand, are transparent films consisting of an adhesive and semi-permeable polyurethane membrane that varies in thickness and size. They are impermeable to water, bacteria and contaminants in general, however they allow water vapor to cross the skin barrier.

These dressings thus maintain a moist environment, favoring the formation of granulation tissue and the autolysis of necrotic tissue, however they do not possess any absorbent power unlike polyurethane foams which are also absorbent.

Some types of advanced dressings may also have specific antimicrobial properties as they contain a local antiseptic: the most commonly used are iodine and silver, particularly suitable for wounds with moderate or high exudate production.

These dressings very often require a second dressing, defined as secondary, which performs the function of fixing the first dressing as the latter has no adhesive capacity.

As discussed above, the possible alternatives to surgical treatment are represented by advanced dressings designed to maintain the correct degree of humidity in the microenvironment of the lesion as well as, when possible, to favor the greatest number of "optimal" conditions useful for fast and correct healing of the skin. injured; however, these dressings do not contain biologically active agents in favoring the healing process correctly and without scarring, since in this case we are defining a "biomaterial", that is, a biocompatible and bioabsorbable material that actively interfaces with biological systems, be they tissues , microorganisms or organs.

In the biomedical field we speak of a double interaction between the biomaterial and the recipient organism: the biomaterial causes a biological response of the organism, which in turn causes a degradation process in the biomaterial itself, and these interactions occur at different levels: physical- chemical, molecular and cellular. The operating environment of the biomaterial is physiological, characterized by a remarkable chemical activity as these biomaterials are in direct contact with biological fluids, namely water, enzymes, proteins and cells. Hyaluronic acid (HA) and its biocompatible derivatives are among the most important biomaterials, mainly used in the field of wound healing and in the viscosupplementation of osteoarthritis pathology.

HA is a hetero-polysaccharide composed of alternating residues of D-glucuronic acid and N-acetyl-D-glucosamine. It is a linear chain polymer with a molecular weight that can vary between 50,000 and 13 x 10 <6> Da, depending on the source from which it is obtained and the preparation methods used. It is present in the pericellular gels, in the fundamental substance of the connective tissue of vertebrate organisms (of which it is one of the main components), in the synovial fluid of the joints, in the vitreous humor and in the umbilical cord.

HA therefore plays an important role in the biological organism, especially as a mechanical support to the cells of many tissues such as skin, tendons, muscles and cartilage. Furthermore, it is known that HA, through its CD44 membrane receptor, forms many and different processes related to the physiology and biology of the cell such as, for example, cell proliferation, migration and differentiation, angiogenesis.

It was therefore demonstrated that HA plays a fundamental role in the tissue repair process both from a structural point of view (i.e. in the organization of the extracellular matrix and in the regulation of its hydration), and as a stimulating substance for a vast series of biological processes in which directly and indirectly intervenes (neovascularization and re-epithelialization) (Weigel P. et al., J Theoretical Biol, 1986: 219-234; Abatangelo G. et al., J Surg Res, 1983, 35: 410-416; Goa K. et al., Drugs, 1994, 47: 536-566).

Precisely for all these widely recognized properties, HA has long been present in the preparation of biomaterials or pharmaceutical compositions mainly in the form of creams or gels, in the treatment of wounds, ulcers and skin lesions of various origins, however this polysaccharide is also widely used in pharmaceutical and / or dermo-aesthetic compositions for the treatment of skin problems of an inflammatory nature such as, for example, eczema and psoriasis, or in situations of skin relaxation due to its well-known moisturizing properties.

DESCRIPTION OF THE INVENTION

The subject of the present invention is an adhesive dressing that associates the characteristics and benefits of a biomaterial with the characteristics and benefits of a biomaterial, avoiding the need for secondary dressing thanks to the adhesive capacity currently absent for the biomaterials used in healing.

The dressing of the invention comprises as an active agent preferably hyaluronic acid (HA) sodium salt or a derivative thereof with a specific average molecular weight (MW), which is able to create the optimal conditions for the migration of fibroblasts from the margins towards the center of the wound by stimulating its proliferation, to accelerate the macrophage response (the presence of macrophages is essential for correct wound healing), and to exert its well-known moisturizing, anti-inflammatory and anti-pain activity.

The dressing of the invention comprises an absorbent matrix (A) adhered to the central portion of a polyurethane support (B) equipped with an adhesive layer for the skin, the matrix (A) comprising:

to. a transpiring and porous polyethylene film, the surface of which is intended to come into contact with the wound, where this film does not adhere to the wound;

b. an absorbent layer in non-woven fabric adjacent to the film a), said absorbent layer being constituted by:

the. viscose for 60-65%

ii. 25-30% polyester

iii. polypropylene for 5-15%;

c. a layer of adhesive polyethylene interposed between the layer b) and a layer d. of hydrophobic polystyrene, the latter being in contact with the central portion of the polyurethane support (B),

where the matrix (A) is soaked with a solution of one or more possibly salified polysaccharides.

Thanks to its particular structure and its materials, the dressing of the invention is transpiring to water vapor and easy to remove without skin trauma, provided with a support (B) waterproof, resistant and transparent.

The dressing of the invention has the following properties:

• ensures the maintenance of the moist microenvironment at the interface between the wound and the dressing (for as long as it remains in contact with the wound) by stimulating the proliferation of fibroblasts and therefore the correct and fast healing of the wound,

• hinders the adhesion between the new granulation tissue and the matrix placed in direct contact with the lesion (an adhesion that is not kept moist could lead to a "dry" eschar that traps the new granulation tissue),

• adheres exclusively to the non-injured part surrounding the injured tissue and is easy to remove without trauma,

• favors and guarantees:

o thermal insulation of the injured skin ensuring proper skin transpiration,

o absorption of excess exudate,

o pain control,

o protection from exogenous infections,

o greater patient comfort due to the fewer necessary changes compared to known dressings.

Thanks to its specific conformation and the presence of the polysaccharide, the dressing of the invention actively promotes proper skin regeneration, facilitates a fast healing process, protects the wound from microbial contamination, controls pain and avoids the possible formation of hypertrophic scars. The dressing therefore has all the characteristics of a biomaterial without the need for a secondary dressing.

The polysaccharides that can be used for the purposes of the invention include glycosaminoglycans, chitin, chitosan, pectin, pectinic acid, galactans, alginic acid and alginates, glucans, natural gums, fructans, polymannans, carrageenan and derivatives of said polysaccharides.

Examples of glycosaminoglycans include hyaluronic acid and / or its derivatives such as salts, esters, amides, sulfated hyaluronic acid; hybrid complexes of high and low molecular weight hyaluronic acid (described in WO2012 / 032151); chondroitin, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, heparin and heparinoids.

An example of a chitosan derivative is lactose derivatized chitosan (described in WO2007 / 135116 and WO2017 / 211776).

Examples of galactans include agar and agarose. Examples of glucans include dextran, dextrin, trehalose, maltose, starch, cellulose and its derivatives, preferably hydroxyethylcellulose, carboxymethylcellulose, hydroxymethylcellulose and cellulose acetate.

Examples of natural gums include gellan and xanthan. A favorite fructan is inulin.

A preferred polysaccharide is the sodium salt of hyaluronic acid or its derivatives prepared from hyaluronic acid from any source, for example, by extraction from cockscomb (EP138572), by fermentation (from Streptococcus equi or Zooepidemicus, EP716688), or via biosynthetics (from Bacillus, EP2614088). The average molecular weight is between 400 and 3x10 <6> Da, in particular between 1x 10 <5> Da and 1x 10 <6> Da, even more particularly between 150,000 and 250,000 Da and / or between 500,000 and 1x 10 <6> From.

The most preferred polysaccharides are the sodium salt of hyaluronic acid with an average molecular weight between 150 and 250 kDa, the hybrid complexes of low and high molecular weight hyaluronic acids in which the high molecular weight hyaluronic acid is between 1100 and 1400 kDa and the low weight one is between 80 and 100 kDa, and lactose derivatized chitosan.

By average molecular weight we mean the weight average MW calculated with the “intrinsic viscosity” method (Terbojevich et al., Carbohydr Res, 1986, 363-377).

The HA derivatives that can be used in the formation of the matrix of the dressing object of the invention include:

HYAFF <�>: esters of HA with alcohols of the aliphatic, araliphatic, cycloaliphatic, aromatic, cyclic and heterocyclic series, preferably the benzyl ester with an esterification percentage preferably between 1 and 50%, the remaining percentage of Unesterified HA can be salified with sodium (EP216453);

HYADD <®>: amides of HA with amines of the aliphatic, araliphatic, cycloaliphatic, aromatic, cyclic and heterocyclic series, preferably the hexadecyl amide of HA with an amidation percentage from 0.1 to 5% while the remaining percentage of HA not subjected to amidation can be salified with sodium (EP1095064);

O-sulfated derivatives of HA up to the 4th degree of sulfation, preferably grade 1 or grade 3 (EP702699, WO2017085622);

ACP <®>: internal esters of HA with an esterification percentage between 0.05 and 5% while the remaining percentage of non-esterified HA can be salified with sodium (EP341745);

HYOXX ™: HA percarboxylated derivatives obtained from the oxidation of the primary hydroxyl of the N-acetyl-glucosamine fraction with a degree of percarboxylation between 0.1 and 100% and, preferably, between 2 and 5%. All the carboxylic groups of HA can be salified with sodium (EP1339753).

The adhesive layer of the polyurethane support (B) (last external layer) is preferably a layer of polyacrylic glue: this layer ensures both adhesion to the matrix and adhesion to the skin in correspondence with the areas surrounding the matrix (A).

The matrix (A), characterized by a high absorbent capacity, is humid as it is soaked with an aqueous solution comprising the polysaccharide as an active agent, preferably the sodium salt of hyaluronic acid (NaHA) or a derivative thereof, in association with suitable excipients. : the concentration of the polysaccharide or of the HA salt or of its derivative is between 0.1% and 1% w / w and preferably between 0.2% and 0.6% w / w. The solution may comprise other components such as solvents, preservatives, pH correctors. Examples of these components include glycerol, propylene glycol, 2-phenylethanol, ethylhexylglycerin, lactic acid and other excipients suitable for topical application.

The sodium salt of hyaluronic acid, NaHA, prepared from an HA produced by fermentation by Streptococcus, in a concentration between 0.1% and 1% w / w and preferably between 0.2% and 0, is preferred as the active agent. 6% w / w, of average MW preferably between 150,000 and 250,000 Da and / or between 500,000 and 1x10 <6> Da, or a derivative thereof, among which O-sulfated hyaluronic acid, HAS, grade 3 is preferable; as the active agent, NaHA with an average MW between 150,000 and 250,000 Da in a concentration equal to 0.3% w / w is more preferred.

An example of a solution that can be used according to the invention to be absorbed on the matrix (A) has the composition shown in Table A:

Table A

The solutions can optionally contain further pharmacologically / biologically active substances both of vegetable and synthetic nature. Examples of pharmacologically / biologically active substances include topical drugs such as NSAIDs and steroids; antibacterials / antibiotics, preferably iodine, silver sulfadiazine, metallic silver; cytostatics; growth factors; fibrinolytics and anti-edematous; proteolytic enzymes, preferably collagenase, hyaluronidase; anticoagulants; proteins such as collagen or silk proteins such as fibroin; local anesthetics such as lidocaine; Triticum vulgare extract; absorbent polymers such as CMC. The matrix of the dressing of the invention is soaked for 50% of its maximum absorption capacity by homogeneous spraying of the aqueous solution containing the active agent, for example of the solution in table A; this matrix is then imbibed with 65 ± 5 mg / cm <2>. Consequently, a matrix with a size equal to 25 cm <2> contains 1.67 g of said liquid composition.

The matrix typically has an average thickness from 2.5 (± 0.3) to 3.0 (± 0.3) mm, preferably equal to 2.7 ± 0.3 mm, with an absorbency (of liquids) ≥ 20 g / 100 cm <2> in a time ≤ 1 sec.

The preferred composition of the absorbent non-woven fabric layer is 60% viscose, 25% polyester, 15% polypropylene (percentages by weight).

A particularly preferred solution that can be used according to the invention to be absorbed on the absorbent layer of 60% viscose, 25% polyester and 15% polypropylene has the composition shown in Table B:

Table B

The matrix (A), in its preferred form, is adhered to the polyurethane adhesive support with polyacrylic glue, has an average thickness of 2.7 ± 0.3 mm and an absorbency ≥ 20 g / 100 cm <2> in a time ≤ 1 sec; it is imbibed for 50% of its maximum absorption capacity by homogeneous spraying of 65 ± 5 mg / cm <2> of the liquid pharmaceutical composition described in table B.

The dressings of the invention are useful for surgical use in the treatment of wounds, burns, ulcers of various kinds, abrasions, light and medium-sized bruises and all skin lesions that involve the use of an advanced dressing.

The dressings of the invention are also useful for dermatological use for the treatment of local inflammations that can cause skin lesions or micro-lesions such as, for example, psoriasis, forms of inflammatory dermatitis of various kinds, atopic and irritative contact dermatitis, eczema of different exogenous or endogenous origin.

The dressings of the invention are also useful for dermo-aesthetic use for the treatment of skin relaxation with or without lesions or micro-lesions, thanks to the high moisturizing power of the polysaccharide, in particular of the sodium salt of HA, as well as the ability to stimulate all physiological functions fibroblasts that lead (over time) not only to the hydration of the skin, but also to the regeneration of the skin tissue itself which becomes compact due to the increased production of collagen by the treated skin fibroblasts.

Claims (17)

CLAIMS 1. Adhesive wound dressing comprising an absorbent matrix (A) adhered to a central portion of a polyurethane support (B) equipped with an adhesive layer for the skin, the matrix (A) comprising: to. a transpiring and porous polyethylene film at the end intended to come into contact with the wound; b. an absorbent layer in non-woven fabric adjacent to the film a), said absorbent layer being constituted by: the. viscose for 60-65% ii. 25-30% polyester iii. polypropylene for 5-15%; c. a layer of adhesive polyethylene interposed between the layer b) and a layer d. of hydrophobic polystyrene, the latter being in contact with the central portion of the polyurethane support (B); where the matrix (A) is soaked with a solution of one or more polysaccharides, their salts or derivatives. 2. A dressing according to claim 1 wherein the adhesive layer of the support (B) is a layer of polyacrylic glue. 3. Dressing according to claim 1 or 2 wherein the absorbent layer b) consists of: the. viscose for 60%; ii. 25% polyester; iii. 15% polypropylene. 4. A dressing according to any one of claims 1 to 3, wherein the polysaccharide is selected from glycosaminoglycans, chitin, chitosan, pectin, pectinic acid, galactans, alginic acid and alginates, glucans, natural gums, fructans, polymannans, carrageenan and derivatives of called polysaccharides. 5. A dressing according to claim 4 wherein the polysaccharide is the sodium salt of hyaluronic acid or a derivative thereof with an average molecular weight comprised between 400 and 3x10 <6> Da. Dressing according to any one of claims 1 to 5 wherein the concentration of the polysaccharide is between 0.1% and 1% w / w. 7. Dressing according to claim 5 in which the sodium salt of hyaluronic acid has an average molecular weight between 150,000 and 250,000 Da and is present in a concentration equal to 0.3% w / w. 8. Medication according to claims 1 to 8 in which the polysaccharide is a derivative of hyaluronic acid selected from esters, amides, internal esters, O-sulfated derivatives or percarboxylated derivatives. 9. A dressing according to claim 8 wherein the hyaluronic acid derivative is the grade 3 O-sulfated derivative, in a concentration comprised between 0.1% and 1% w / w. Dressing according to any one of claims 1 to 9 wherein the matrix (A) has an average thickness of 2.5 (± 0.3) to 3.0 (± 0.3) mm. 11. Dressing according to claim 10 wherein the matrix (A) is soaked for 50% of its maximum absorption capacity by homogeneous spraying of 65 ± 5 mg / cm <2> of the solution containing the polysaccharide, preferably sodium salt of hyaluronic acid or its derivative. 12. Dressing according to claim 11 wherein the polysaccharide is the sodium salt of hyaluronic acid and the matrix (A) has an average thickness of 2.7 ± 0.3 mm and an absorbency ≥ 20 g / 100 cm <2 > in a time ≤ 1 sec. 13. Dressing according to claims 1-12 wherein the absorbent layer b) consists of 60% viscose, 25% polyester and 15% polypropylene, the matrix (A) has an average thickness of 2 , 7 ± 0.3 mm and an absorbing power ≥ 20 g / 100 cm <2> in a time ≤ 1 sec, and is soaked for 50% of its maximum absorption capacity by homogeneous spraying of 65 ± 5 mg / cm <2> of a solution of sodium salt of hyaluronic acid having an average molecular weight between 150,000 and 250,000 Da in a concentration equal to 0.3% w / w. 14. Medication according to any one of claims 1 to 11 wherein the matrix (A) contains pharmacologically / biologically active substances selected from iodine, silver sulfadiazine, colloidal or micronized metallic silver, topical antibiotics, local anesthetics, NSAIDs, steroids for topical use, cytostatics, growth factors, fibrinolytic and anti-edematous, proteolytic enzymes, collagenase, hyaluronidase, anticoagulants, proteins such as collagen or silk proteins such as fibroin, Triticum vulgare extract, absorbent polymers. 15. Dressing of claims 1 to 14 for surgical use in the treatment of wounds, burns, ulcers of various kinds, abrasions, abrasions of light and medium entity. 16. Dressing of claims 1 to 14 for dermatological use for the treatment of local inflammations which can cause skin lesions or micro-lesions. 17. Dressing of claims 1 to 14 for dermo-aesthetic use for the treatment of skin relaxation with or without lesions or micro-lesions.