Abstract:
The described invention relates to the new compound “sucrose-octosulphate salified with silver” usefully applicable in the prevention and cure of infections by micro-organisms of bacterial, fungal, viral and/or of yeast origins and in the promotion of tissue repair. The silver salts of sucrose octosulphate, subject of the invention have in fact been demonstrated to possess antimicrobial activities even higher than that of known silver compounds. These properties therefore make them particularly appropriate for use in different pathological or paraphysiological conditions of the skin, of the epithelia and of the mucosa both intact and lesioned.

Description:
FIELD OF THE INVENTION  
         [0001]    The present invention relates to the new compound of “sucrose-octosulphate salified with silver” for use in compositions usefully applicable in pathological or paraphysiological conditions of the skin, of the epithelia and of the mucosa in the prevention and cure of infections sustained by different types of microorganisms and in the promotion of tissue repair.  
         STATE OF THE ART  
         [0002]    It is widely known that in the pathologies characterised by lesions of the epidermal and dermal layers, such as for example ulcers and burns, the treatments are essentially for the promotion/acceleration of the processes of tissue repair in aseptic conditions. In fact, infections constitute one of the major problems in the treatment of cutaneous lesions and the appearance of infections resistant to antibiotics represents a serious problem in the clinical treatment of these pathologies, complicated further by the limited choice of antibiotic agents useful for this purpose. For example, infections constitute one of the most serious complications of burns, even of small dimensions; and in the most serious cases, represent the major cause of death and are furthermore involved in the appearance of disfiguring scaring or disabling results.  
           [0003]    For the treatment of these pathologies it is therefore necessary to address attention towards therapeutic agents capable of, on the one hand, promoting tissue repair and also supporting or increasing the physiological processes of tissue repair, and on the other, of blocking, from the beginning and until scar formation has occurred, the colonisation of cutaneous tissues by pathogenic agents.  
           [0004]    For some time silver has been recognised as a therapeutic agent used for the prevention of infections. Silver nitrate at a concentration of 10% has in fact been used in clinical practice for the treatment of cutaneous lesions since the last century, though later abandoned due to its toxicity. Currently, silver nitrate at 0.5% or silver sulphadiazine at 1% constitute the most common and chosen treatments for burns, being capable of controlling Gram-negative infections, not effectively controlled by conventional antibiotics. Also other silver based ionisable compounds are used clinically, amongst these for example silver lactate or picrate. Also available are colloidal forms of silver, the antimicrobial activity of which depends not only on the total silver content, but on the content of free silver ions. The use of silver for the treatment of cutaneous lesions is however limited due to its toxicity, which could also be the cause of delay in tissue repair, as a consequence of its cytotoxic effect on granulated tissue. This effect is moreover shared in general by all disinfecting agents. In addition to this cytotoxic activity, other limitations related to the use of silver as an antimicrobial agent exist: i) the precipitation of silver chloride upon contact of the silver with biological fluids, with consequent reduction of its antimicrobial strength, ii) its possible binding to serum albumin which, in addition to a loss in effectiveness, gives rise also to the possibility of later systemic absorption of the same silver and iii) its photoinstability and the discolouring of the tissues with which it comes into contact (J. M. Schierholz, L. J. Lucas, A. Rump, G. Pulverer,  J. Hospital Infection,  40, 257-262, 1998; in “ The pharmacological basis of therapeutics” , A. Goodman Gilman, T. W. Rall, A. S. Nies, P. Taylor Eds, 4 th  Ed., Maxwell Macmillan Int. Eds., New York, pp. 1049-1050, 1970).  
           [0005]    The use and efficacy of silver derivatives against pathogenic agents of various types, for example bacteria, moulds, yeasts and viruses are also known; for this activity silver has been used as a preservative in cosmetic preparations, demonstrating activity against  Pseudomonas aeruginosa, Candida albicans  and  Staphylococcus aureus  at concentrations of 10 −5  M silver (M. Scalzo, F. Cerretou, C. Orlandi, N. Simonetti,  Int. J. Cosmetic Sci.,  19, 27-35, 1997).  
           [0006]    Sucrose-octosulphate (SOS) is a compound, already known and used, for example in the form of an aluminium salt in sulcralfate, a compound widely used in the therapy of gastro-intestinal ulcers. The protective effect of sulcralfate seems to be linked in part to the buffering effect performed by aluminium hydroxide, as well as the ability of sucrose-octosulphate to protect the gastric epithelium, an effect which probably arises, from its ability to form a protective barrier on the area of the lesion. Sulcralfate is in fact an insoluble compound which, in acid environment, polymerises forming a viscous substance capable of adhering to the gastric epithelium.  
           [0007]    Data from the literature lead one to hypothesise that sucrose octosulphate can favour the bioavailability of trophic factors released locally. These would be capable of favouring the re-epithelialisation of the lesioned area. This mechanism, described at the gastric epithelium level, could have a functional effect also at the cutaneous level (J. Folkman, S. Szabo, M. Strovoff, P. McNeill, W. Li, Y Shing,  Ann. Surg.,  214, 414-427, 1991; H. Paimela, P. J. Goddard, K. Carter, R. Khakee, P. L. McNeill, S. Ito, W Silen,  Gastroenter.,  104, 1337-1345, 1993).  
         SUMMARY OF THE INVENTION  
         [0008]    Now the applicant has surprisingly found that silver salts of sucrose-octosulphate (SOS-Ag) can be advantageously used for the prevention and the therapy of infections sustained by microorganisms of different types (bacterial, fungal, viral and/or by yeasts) and for the promotion/acceleration of tissue repair in pathologies of the cuteus (skin), of the mucosa and of epithelia both intact and lesioned, characterised by potential or actual infections sustained by pathogens of various types, such as for example fungal infections or ulcers.  
           [0009]    The subject of the present invention is therefore the compound of formula (I)  
                         
 
           [0010]    wherein R is SO 3   − Ag +   
           [0011]    A further subject of the invention relates to the synthetic processes characterised by: a) preparation of sucrose-octosulphate in acid form (SOS-H) and its successive salification either by neutralisation in solution with Ag ion bases to pH 7.2, or by passing through a column of ion exchange resin derivatised with Ag ions; b) direct exchange between sucrose-octosulphate salts and silver salts. Still another subject of the invention is the use of compounds for treatment in the prevention and/or the therapy of bacterial, fungal, viral and/or yeast infections and in the promotion/acceleration of tissue repair in pathologies of the skin, the mucosa and of the epithelia, both intact and characterised by lesions of the epidermal and/or dermal layers. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0012]    The aims and the advantages of the present invention, will be better understood throughout the course of the following invention in detail.  
         [0013]    The Compound SOS-Ag of Formula (I)  
                         
 
         [0014]    wherein R is SO 3   − Ag +   
         [0015]    can be obtained according to known methods which usually involve the direct exchange of sodium salts of SOS, or salts of other alkaline metals, with other counterions of interest. These processes have however the disadvantage of almost never corresponding to a stoichiometric exchange, with a significant effect on the yields and the Ag titre of the final product. A further limitation connected with this method is the achievement of unstable products, as a consequence of the high acidity due to the possible formation of sulphuric acid.  
         [0016]    The first synthetic process devised with the aim of overcoming the above mentioned problems is characterised by two distinct steps which consist of: a) preparation of SOS-H starting from a salt of SOS with for example monovalent cations such as Na and K; b) neutralisation, under controlled conditions to pH 7.2, of the SOS-H with Ag ion bases (for example oxides, hydroxides, bicarbonates and carbonates).  
         [0017]    The second synthetic process is characterised by: a) preparation of SOS-H starting from a salt of SOS with for example monovalent cations such as Na and K; b) preparation of resins derivatised with Ag ions through activation with strong bases and later exchange with salts or oxides of Ag and c) passing the acid form product obtained in step a) through the columns obtained in step b).  
         [0018]    The third synthetic process is instead characterised by the direct exchange between sodium or potassium salts of sucrose-octosulphate with Ag salts selected for example from AgBF 4 , AgClO 4 , AgNO 3  and Ag 2 CO 3 . The exchange reaction between monovalent salts of SOS and AgBF 4  results as being the preferred, in that it gives a final product with a high Ag titre and has a good yield.  
         [0019]    The exchange reaction must however be carried out in suitable conditions to overcome the above mentioned problems; in particular it appears to be essential that the exchange reaction be carried out in the dark, in an aqueous environment and in the absence of solvents, as it is also essential that the tetrafluoroborate salt with the starting sucrose-octosulphate monovalent ion, obtained as a product of the exchange reaction, be eliminated.  
         [0020]    Herein, examples of the preparation of SOS-Ag are described, with the purpose of non-limiting illustration of the present invention, enabling one skilled in the field to introduce all the modifications and the improvements suggested through normal experience and by the natural evolution of the technique.  
       EXAMPLE 1  
     Method of Synthesis of SOS-Ag  
       [0021]    Commercial SOS-K has been purified with the aim of reducing the amounts of impurities present and in particular the chloride and sulphate content, obtaining SOS-K containing less than 0.1% chloride and sulphate. 10 g of SOS-K have been therefore solubilised in 150 ml of double distilled water. The solution thus obtained has been percolated through Amberlite IR 120H ion exchange resin, collecting the acid-nature eluted fractions. The resin has then been washed twice with 35 ml of double distilled water. The acid solution (pH 1.5) collected after passage through the ion exchange resin has been stored in an ice bath to avoid possible desulphatisation of the product. All of the subsequent operations have been carried out by working in the absence of light, natural or artificial, and can also be conveniently carried out in a dark room.  
         [0022]    The SOS-H solution has then been subjected to stirring, constantly monitoring the pH with a pH meter. 6.4 g of Ag 2 O have been added, to reach a pH of 7.2 (Ag 2 O theoretical=7.2 g). The solution of SOS-Ag obtained has been kept stirring for 4-5 hours and then filtered under reduced pressure through a porous septum coated with Celite HSS. Following filtration an opalescent solution has been obtained which has been again filtered through Celite until a clear solution was obtained. The final solution has been taken to dryness in a rotary evaporator in a thermostated water bath at 60-65° C. under reduced pressure. The residue, constituted by a spongy-glasslike solid, has been treated with 50 ml of acetone and again evaporated to dryness under reduced pressure. The solid residue, obtained in the form of shiny off-white flakes, has been collected and washed twice with 70 ml of acetone and, after brief stirring, has been decanted eliminating the overlying acetone. The solid has been finally purified from the residual acetone by evaporation of the latter in a rotating evaporator in a thermostated water bath at 60-65° C. under reduced pressure. All the final manipulations of the solid have been carried out in the absence of light.  
         [0023]    Yield 13.3 g SOS-Ag (93%) Ag titre: 45.7%, equal to 97.2% of the theoretical value (47%)  
         [0024]    Appearance: shiny, almost white flakes  
         [0025]    Solubility: very soluble in water; particularly insoluble in organic solvents.  
       EXAMPLE 2  
     Method of Synthesis of SOS-Ag  
       [0026]    2 g of commercial SOS-K, previously purified as reported in example 1, has been solubilised in 30 ml of double distilled water and the solution thus obtained has been percolated through Amberlite IR 120H ion exchange resin, collecting the acid nature eluted fractions. The resin has then been washed twice with 10 ml of double distilled water. The collected acid solution (pH 1.5) following passage through ion exchange resin has been stored in an ice bath. All the following operations have been carried out by working in the absence of light, natural or artificial, and can also be conveniently carried out in a dark room.  
         [0027]    A solution of 7.8 g of Silver nitrate in 100 ml of double distilled water has been eluted through a second column of Amberlite IRC 50 resin previously activated with a solution of 0.5 N KOH. This way one obtains a column of resin derivatised with Ag ions. Following a wash with water, the acid form SOS-H product obtained previously has been eluted through the second column, derivatised with Ag ions, obtaining an eluate constituted by SOS-Ag. The eluate has been collected and, kept in the dark, taken to dryness. The resulting solid has been washed twice with acetone and then decanted. The compound obtained, constituted by a white solid, has been subsequently dissolved in double distilled water and re-crystallised.  
         [0028]    Yield 2.2 g SOS-Ag (77%);  
         [0029]    The characteristics of the product correspond with these reported in example 1.  
       EXAMPLE 3  
     Method of Synthesis of SOS-Ag  
       [0030]    KSOS (7.13 g corresponding to 1 eq) is dissolved in 5 volumes of distilled H 2 O (35.6 ml) at T=40° C. in a dark, screw-topped beaker. The solution is left to cool to room temperature.  
         [0031]    Solid AgBF 4  (8.37 g=0.97 eq) is added, whilst working in a dark room. Immediately, a suspension of a fine precipitate is formed. It is left stirring for 2 hours and the KBF 4  precipitate (4 g) is filtered using a Buchner funnel fitted with a paper filter (Whatman filter papers 5; 55 mm Ø).  
         [0032]    The clear solution is then filtered through a nylon membrane with a porosity of 0.45 μm (Superchrom syringe filters 25 mm Ø).  
         [0033]    The clear filtrate is collected (43 ml) and the water is completely removed by distillation at a temperature of between 20° C. and 40° C.  
         [0034]    The product is washed with acetone (20 ml). The solvent is removed and another aliquot (20 ml) added and left stirring for 10 minutes. The white solid obtained is filtered with a Pyrex glass filter funnel (cylindrical with a porous septum of porosity 3) and it is washed on the filter with a further aliquot of acetone (30 ml), paying attention not to allow the product to dry for an overlong time. Being highly hygroscopic it tends in fact to become adhesive.  
         [0035]    The solid obtained is transferred to vials and dried at room temperature in a crystalliser under vacuum.  
         [0036]    Yield: 9.84 g (93%); Ag titre: 93%;  
         [0037]    Appearance: white crystalline, fine powder.  
         [0038]    The results obtained from the synthesis and the stability data indicate that, unexpectedly, from the salification reaction between SOS-H and Ag bases one obtains compounds which are stable in aqueous solution at neutral or slightly acidic pH, whilst it is known that Ag salts are stable in solution only in very acidic environments. Also, the SOS-Ag obtained according to example 3 results as having good stability, both in the solid state and in aqueous solution, whilst it is a particular industrial advantage, having a single step method.  
         [0039]    The methods of synthesis outlined, other than the attainment of a stable product, present also other advantages with regard to industrial applicability, in particular for the high yield of product and for the high Ag titre.  
         [0040]    Antimicrobial Activity of SOS-Ag  
         [0041]    The antimicrobial activity of the compound, subject of the present invention, SOS-Ag, having a Ag titre of 42.51%, has been verified through comparison of the same with equimolar concentrations of the commercial product Katoxyn powder, having a Ag titre of 4.25%.  
         [0042]    The antimicrobial activity has been evaluated according to the experimental regimen described below.  
         [0043]    1. Bacterial Growth Inhibition Test in Culture Broth  
         [0044]    Serial dilutions of known titre of the two products SOS-Ag and Katoxyn, the latter containing Ag in the form of metallic silver (silver Katadyn® colloidal chemical), have been placed directly in contact with the test microorganism ( Staphylococcus Aureus  ATCC 6538) for incubation in culture broth with agitation. The effect of the substances on cellular growth has been measured by evaluating the absence of turbidity in the culture medium. Confirmation of the anti bacterial activity has been verified by the seeding of 1 ml of culture broth in an agarised medium, with observations at 7, 14, 21, 28 days from the beginning of the experiment (tables 1 and 2).  
         [0045]    2. Bacterial Growth Inhibition Test by Diffusion in Agar  
         [0046]    The inhibition of bacterial growth has been, in this case, evaluated on a confluent bacterial culture of  Staphylococcus aureus  ATCC 6538 obtained on solid medium, according to the seeding method for inclusion. Serial dilutions of the test products, of known Ag titre, have been deposited inside 8 mm diameter wells formed in the medium, in this way coming into direct contact with the bacteria  Staphylococcus aureus  ATCC 6538. The antibacterial activity of the products under test have been evaluated, after appropriate incubations, by measuring the halos of inhibition around each well (tables 3 and 4).  
         [0047]    The results obtained are reported in the following tables, summarised according to the different experimental methods used:  
                                                       TABLE 1                           inhibition of the growth of  S. aureus  ATCC 6538 through       the action of SOS-Ag: growth method in culture broth                Incubation times                    Ag titre   7 days   14 days   21 days   28 days                       1 × 10 −2  M   +   +   +   +           1 × 10 −3  M   +   +   +   +           5 × 10 −4  M   −   −   −   −           1 × 10 −4  M   −   −   −   −           1 × 10 −5  M   −   −   −   −           Positive   +   +   +   +           control:           ampicillin                                              
 
         [0048]    [0048]                                                       TABLE 2                           inhibition of the growth of  S. aureus  ATCC 6538 through       the action of the product Katoxyn: growth method in culture broth                Incubation times                    Ag titre   7 days   14 days   21 days   28 days                       1 × 10 −1  M   +   +   +   +           1 × 10 −2  M   +   +   +   +           5 × 10 −3  M   −   −   −   −           1 × 10 −3  M   −   −   −   −           1 × 10 −4  M   −   −   −   −           Positive   +   +   +   +           control:           ampicillin                                                
         [0049]    [0049]                                                                                   TABLE 3                       inhibition of the growth of  S. aureus  ATCC 6538 through       the action of the product SOS-Ag: method of diffusion in       agar (seeded by inclusion)                                    Ag titre                SOS-Ag   1 × 10 −3  M   5 × 10 −4  M   1 × 10 −4  M                       Halo of   13    0    0           inhibition           (mm)                            Positive               control:   Concentration (I.U./ml)                ampicillin   20   10   5                       Halo of   39   20   11           inhibition           (mm)                                    
         [0050]    [0050]                                                                                   TABLE 4                       inhibition of the growth of  S. aureus  ATCC 6538       through the action of the product Katoxyn: method of       diffusion in agar (seeded by inclusion)                                    Ag titre                Katoxyn   1 × 10 −2  M   5 × 10 −3  M   1 × 10 −3  M                       Halo of   12    0    0           inhibition           (mm)                            Positive               control:   Concentration (I.U./ml)                ampicillin   20   10   5                       Halo of   39   20   11           inhibition           (mm)                                    
         [0051]    From the experimental results shown above one can conclude that the product SOS-Ag results as being more active than Katoxyn having demonstrated in the experimental conditions used as being active at a concentration of Ag of 1×10 −3  M, whilst Katoxyn in the same experimental conditions has been demonstrated to be active at a concentration of Ag of 1×10 −2  M.  
         [0052]    On the basis of the results shown above, the product SOS-Ag, characterised by a Ag titre of 44.7%, has been further tested in comparison with the known antimicrobial agent silver sulphadiazine, using concentrations of the two compounds equimolar in Ag.  
         [0053]    We report below the results obtained in the evaluation of the effect of inhibition of growth of  S. aureus  ATCC 6538 through the action of the two products under test. The characterisation of the antibacterial activity has been carried out using the method of diffusion in agar, placing the substances in contact with confluent bacterial cultures on solid medium. The experiments have been carried out according to two distinct methods: 1) wetting sterile cellulose disks, 13 mm in diameter with 100 μl of solutions at serial dilutions of the product of known Ag titre. The disks have been placed in direct contact with the seeded solid medium and the appearance of halos of inhibition around the same disks after 72 hours of incubation at a 37° C. was observed, in comparison with a control constituted of just the solvent used to dissolve the products. The results obtained are reported in table 5. These results have been confirmed also by diffusion tests in agar according to the method of seeding by inclusion, in which on the medium supporting the confluent culture of the microorganism have been created wells having diameters of 8 mm using a sterile biopsy punch. 100 μl of the solutions containing the products at known concentrations of Ag are placed on the base of the wells, and the bacteriocidal activity is observed after 72 hours of incubation at 37° C. against a blank constituted of just the solvent used for the solubilisation of the products. (table 6).  
                                                   TABLE 5                           inhibition of the growth of  S. aureus  ATCC 6538 in the       presence of SOS-Ag or silver sulphadiazine: diffusion method       in agar (disks of 13 mm)                Compound   Ag titre (M)   Halo of inhibition (mm)                            SOS-Ag   10 −2     15.3               10 −3     12               10 −4     0               10 −5     0           Silver sulphadiazine   10 −2     14               10 −3     11.4               10 −4     0               10 −5     0           Negative control   —   0                      
 
         [0054]    [0054]                                                   TABLE 6                           inhibition of the growth of  S. aureus  ATCC 6538 in the       presence of SOS-Ag or silver sulphadiazine: diffusion method       in agar (seeded by inclusion)                Compound   Ag titre (M)   Halo of inhibition (mm)                            SOS-Ag   10 −2     14.5               10 −3     14               10 −4     0               10 −5     0           Silver sulphadiazine   10 −2     14               10 −3     13.0               10 −4     0               10 −5     0           Negative control   —   0                        
         [0055]    The results obtained, reported for exemplification, but not exhaustively, of the antimicrobial properties of the compound subject of the invention, demonstrate that at parity in Ag titre the same has activity equal or greater with respect to the known silver compounds normally used in therapy.  
         [0056]    The compound SOS-Ag can therefore have an antimicrobial activity typical of the silver salts and in particular towards numerous bacterial strains (both Gram positive and Gram negative), on fungi, on viruses and on yeasts. We cite for example the bacteria:  Staphylococcus  sp.,  Enterobacter  sp.,  Clostridium  sp.,  Acinetobacter  sp.,  Yersinia  sp.,  Pasturella  sp.,  Pseudomonas aeruginosa, Klebsiella pneumoniae, Bacillus subtilis, Escherichia coli, Streptococcus  sp.,  Micrococcus luteus, Chlamydia  sp.,  Mycobacterium  sp.; the yeasts  Candida albicans, Candida tropicalis  and  Saccharomyces cerevisiae ; the fungi  Trichophyton rubrum, Aspergillus  sp.,  Borrelia  sp.; the viruses: Herpes simplex virus, and Human papilloma virus. The above cited microorganisms are intended for exemplification, but not exhaustively, of the range of microorganisms on which the product SOS-Ag can exercise its antimicrobial action, being known as silver, that is, active on many different pathogenic microorganisms, amongst which many strains resistant to normal antibiotics (N. Grier, “ Silver and its Compounds” , in:  Disinfection Sterilisation and Preservation,  3 rd  Ed., SS Block Ed., Lea &amp; Febiger, Philadelpia, Ch. 20, p. 395, 1983). Other examples and characteristics of the invention appear for this reason obvious to the export operator in the art; the examples reported are not intended therefore to define the limits or the aims of the applicability of the product SOS-Ag.  
         [0057]    The Ag salts of sucrose-octosulphate subject of the invention possess therefore, with respect to known products, a series of advantages from the point of view of therapeutic application, inherent essentially in their stability in solutions of neutral or slightly acidic pH and their high ionic content. This confers on these Ag salts a prolonged antimicrobial action, whilst it is known that the brief duration of the therapeutic effect of the Ag salts available is one of the major restraints to the clinical use of these compounds. It is further known that the antimicrobial activity of silver depends not so much on the total quantity of metal present, but on the quantity of free ions.  
         [0058]    The stabilisation of the Ag ions through the formation of salts with sucrose derivatives determines an improvement in the therapeutic coefficient, because it can, through a slower and more gradual release of the Ag ions, bring about a more prolonged effective duration in time without the appearance of the cytolesive effects, inhibition of the formation of granulated tissue and therefore a slowing down of the processes of tissue repair, due to the same. Furthermore the effects on tissue repair can be further potentiated by sucrose-octosulphate, of which the stimulating effects on proliferation of epithelial cells have already been mentioned. The complexive effect of the molecule can therefore result in an improvement of the process of tissue repair, with a probable concomitant reduction in the wound healing times. An additional advantage is furthermore connected to the possibility of avoiding the repeated daily medication necessary with the products currently in use.  
         [0059]    On the basis of the results obtained and of the brief considerations shown above, the compound, subject of the present invention can be used in all these pathological conditions in which it is necessary to control or eradicate the development in situ of infective pathogenic agents of whichever type, guaranteeing therefore a condition of relative asepticity in the treated tissue, and at the same time promote the processes of tissue repair. On the basis of the data reported above one can deduce that the product SOS-Ag can be usefully employed in all the pathological conditions of epithelial and dermal tissues both intact and lesioned characterised by potential or actual infections sustained by pathogens such as the skin, the mucosa of the oral cavity and internal and external genitals and ocular epithelia. In particular the compound SOS-Ag can be used as a therapeutic agent with disinfectant activity for the prevention and/or profilaxy of the following pathologies:  
         [0060]    infections of the skin both intact and lesioned, of the oral mucosa, and external and internal genitals and ocular epithelia, brought about by bacteria, fungi, yeasts or viruses (for example candidiasis, acne, herpes, papilloma virus pathologies);  
         [0061]    superficial and deep wounds, internal and external, grazes and abrasions, lacerated/contused wounds, wounds with soft tissue loss, strongly exudating wounds both chronic and acute, surgical wounds, traumatic wounds;  
         [0062]    superficial and deep burns;  
         [0063]    vascular trophic lesions, ischemic ulcers, vascular ulcers, diabetic ulcers, stasis ulcers, corneal ulcers;  
         [0064]    bedsores;  
         [0065]    athletes foot;  
         [0066]    abscesses.  
         [0067]    According to the pathology and its degree of seriousness for the aims of the present invention the compounds can be used in concentrations comprised of between 10 −5  M and 10 −2  M Ag, in topical formulations and in combination with appropriate excipients or diluents compatible with the uses envisaged.  
         [0068]    Other than the more literal therapeutic pharmaceutical uses, in conditions of straightforward pathology, the compound can have in addition a useful application in paraphysiological conditions or with preventive aims in dermoprotective, lenitive or also cosmetic parapharmaceutical compositions.  
         [0069]    These topical formulations can be more varied; the compositions can in fact contain, according to the application aims, the compound of the invention as it is or encapsulated in nanospheres and/or microspheres based on known or new materials. The compositions can be presented in the form of liquids, semi-solids or solids, containing excipients and/or diluents of pharmaceutical or cosmetic grade (for example solutions and aqueous, non aqueous, hydroalcoholic suspensions, drops, gels, emulsions, creams, ovules, powder sprays, sprays with or without propellants, foams). Furthermore the compound, as it is or encapsulated in nanospheres and/or microspheres constituted by known or new materials, can be supported upon inert biocompatibile materials such as films, membranes, patches and dressings, also with a slow release, or can be incorporated into biomaterials, such as for example hydrogels, membranes, sponges, or into materials dissolving rapidly in aqueous environments.