Antimicrobial composition comprising zinc and a biguanide or quaternary ammonium cationic surface active agent

Abstract

The invention concerns an insoluble salt composition having antimicrobial activity, said composition containing zinc and a cation of a cationic surface-active agent, wherein the cationic surface-active agent is preferably selected from benzalkonium, didecyldimethylammonium, octenidine and chlorhexidine. The invention further relates to an insoluble compound having antimicrobial activity, said compound having a structure represented by the general formula (W"1+)n[Zn2+(L2-)2], wherein W is a cationic surface active agent, preferably selected from benzalkonium, didecyldimethylammonium, octenidine and chlorhexidine and L is a bridging ligand capable of coordinating the zinc cation and capable of binding through an ionic bond the cation of a cationic surface active agent, preferably selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3-mercapto-1-propansulfonate, and mixtures thereof. The invention further relates to an antimicrobial powder composition or a functionalized antimicrobial powder comprising the insoluble salt composition according to the invention and a silica powder, such as silicon dioxide or silicon dioxide amorphous, wherein the salt composition is adsorbed to the surface of the silica powder. The composition and compound of the invention may be included in alcoholic solutions or may be formulated as gel, cream or powder. The composition and compound of the invention may be used in antimicrobial treatment, antiviral treatment and / or antifungal treatment

Description

[0001] ANTIMICROBIAL COMPOSITION COMPRISING ZINC AND A BIGUANIDE OR QUATERNARY AMMONIUM CATIONIC SURFACE ACTIVE AGENT

[0002] FIELD OF THE INVENTION

[0003] The invention relates to an insoluble salt containing zinc and a cation of a cationic surfaceactive agent. The invention further relates to an insoluble compound containing zinc, a cation of a cationic surface-active agent and a bridging ligand. The invention further relates to antimicrobial formulations in the form of a gel, cream or powder and the use thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] Chronic wounds, such as venous or arterial ulcers, diabetic foot ulcers, pressure sores, and non-healing surgical wounds, have a significant impact on a patient’s quality of life, and are an important economic burden. Chronic wounds are associated with chronic mono- or polymicrobial biofilm infections and are characterized by tolerance and resistance to antimicrobials.

[0006] Wound surgical or chemical debridement and the topical application of antibiotics or other antimicrobial substances are the conventional methods usually considered to eradicate wound infection.

[0007] Zinc compounds are used in wound care and can be assimilated orally or included in formulations for topical use. Their popularity in medicine is associated with the antiinflammatory properties of the Zn2+ion and in part also with the antimicrobial properties.

[0008] Zinc ions also have an anti-inflammatory and preservative action on cellular vitality (Acta Derm Venereol, 75 (1): 19-23. 1995) and have an antioxidant action and healing (Journal of the American College of Nutrition, 18 (2): 152-158. 1999), zinc is in fact one of the main astringent and antiseptic constituents in cosmetics and it is often used in the form of zinc gluconate.

[0009] International Journal of Nanomedicine, 18 (13): 2217-2263. 2018 discloses hydrogel providing antimicrobial effects. Zinc oxide nanoparticles (ZnO NP) have been disclosed to be embedded as antimicrobial agents in alginate hydrogel and CMC / ZnO nanocomposite hydrogels.

[0010] Finally, it must be emphasized the important antiviral action that zinc exerts by altering the cellular capacity to support viral replication (Antimicrobial Agents and Chemotherapy, Mar. 2004, p. 783-790. American Journal of Biomedical Science and Research, 2019. Adv Nutr 2019, 10: 696-710. Patents: US 5,785,054, 1998, and US 6,321,750 Bl, 2001). It has also been observed that zinc ions and pyrithione ions, even at low concentrations, are able to inhibit the replication of Coronavirus (Pios Pathogens, November 2010, Volume 6, Issue 11, elOOl 176).

[0011] Cationic surface-active agents are mainly used as detergents and cleaning agents, but are also known to poses antibacterial and antifungal properties. Some of the popular cationic surface-active agents include octenidine, chlorhexidine, benzalkonium and didecyldimethylammonium.

[0012] Octenidine dihydrochloride (abbreviates as octenidine or OCT) was introduced for the antisepsis of the skin, mucous membranes and wounds more than 30 years ago. Much knowledge has been gained on efficacy, tolerance, safety and clinical experience from both case reports and controlled prospective studies. Nowadays, octenidine is an established antiseptic in a wide range of applications and represents an alternative to older substances such as chlorhexidine, iodine-povidone or triclosan (Skin Pharmacol Physiol 2010; 23: 244-258).

[0013] It is noteworthy that octenidine is not absorbed either through the skin or through the mucous membranes and does not cross the placental barrier.

[0014] Since 1987, octenidine has been used in Europe as an antiseptic, in concentrations from 0.1 to 2.0% and no resistance to its application has been observed. (J Antimicrob Chemother 2007; 59: 1280-1). Octenidine is active against Gram-positive and Gram-negative bacteria (Antimicrob Agents Chemother. 1985; 28: 786-90). In vitro suspension tests with exposure times of 5 minutes have shown that octenidine requires lower effective concentrations three to eight times compared to chlorhexidine to eliminate common bacteria such as Staphylococcus aureus, Escherichia coli, Proteus mirabilis and Candida albicans yeast. A study in 17 intensive care units on thousands of cases, treated with octenidine, demonstrated a decrease in nosocomial infection rates (J Antimicrob Chemother. 2016,71 (9 ), 2569-76).

[0015] Octenidine is one of the most successfully used skin antiseptics (Klinische Padiatrie. 228 (4): 208-12. BMJ Open 2017; 7: e016251 . doi: 10.1136 / bmj open-2017-016251. J Hosp Infect. 2019 Mar; 101 (3): 264). In addition, it has recently been shown that octenidine exhibits antiviral activity against enveloped viruses such as SARC-COV-2 (European Journal of Dermatology vol. 30, 613, 2020.)

[0016] Chlorhexidine (CHL), commonly known by the salt forms chlorhexidine digluconate, chlorhexidine acetate or chlorhexidine chloride, is a disinfectant and antiseptic that is used for mouth and skin disinfection before surgery and to sterilize surgical instruments (Minerva Stomatologica. 61 (9): 399-4192, WHO Model Formulary 2008. World Health Organization. Pp. 321-22.) It may be used both to disinfect the skin of the patient and the hands of the healthcare providers. It is also used for cleaning wounds, preventing dental plaque, treating yeast infections of the mouth, and to keep urinary catheters from blocking. It is used as a liquid or powder. CHG is active against Gram-positive and Gram-negative organisms, facultative anaerobes, aerobes, and yeasts (Leikin, Jerrold B.; Paloucek, Frank P., eds. (2008). Poisoning and Toxicology Handbook (4thed.), Informa, pp. 183-8417). It is particularly effective against Gram-positive bacteria (in concentrations > 1 pg / L). Significantly higher concentrations (10 to more than 73 pg / mL) are required for Gram-negative bacteria and fungi.

[0017] Benzalkonium chloride (abbreviates as benzalkonium or BZ) is in general a mixture of quaternary ammonium salts. More precisely, it is a mixture of alkyl-benzyl- dimethylammonium chlorides, in which the alkyl group varies from octyl (CsHn-) to octadecyl (C18H37-). It is mainly used as a bactericide and spermicide in numerous preparations intended for daily use: disinfectants, eye drops, mouthwashes, spermicidal creams. Its antimicrobial action has been attributed to the denaturation of cellular proteins and the rupture of the cell membrane. Its antiviral action has been widely demonstrated in the literature (J. Antimicrobial Chemotherapy, 2000, 46, 685-693. Antiviral Res. 1998 Jul; 39 (1): 55-61. Journal of Hospital Infection, 1998 38, 283-295) and recently it has been proven its activity against SARS COV-2 in inactivating one million viral units in a counting time of 5 min (ACS Appl. Mater. Interfaces. 2021 Nov 24; 13 (46): 54648-54655.)

[0018] Didecyldimethylammonium Chloride (abbreviated as didecyldimethylammonium or DDAC) is a quaternary ammonium compound used as antiseptic / disinfectant. Analogously to benzalkonium it causes the disruption of intermolecular interactions and the dissociation of lipid bilayers (Antiseptic Stewardship. Cham.: Springer, pp. 371-394), it is a broad spectrum biocidal against bacteria and fungi and can be used as disinfectant cleaner recommended for use in hospitals, hotels and industries. It is also used in gynaecology, surgery, ophthalmology and for the sterilization of surgical instruments and endoscopes.

[0019] There are several disadvantages of the conventional antimicrobial therapies. Whereas for chemical debridement, once the biofilm has been eliminated, the problem arises of avoiding recontamination of the wound.

[0020] Therefore, there is a need for new and improved therapeutic agents and compositions for avoiding recontamination of wounds.

[0021] Accordingly, it is an object of the invention to provide a new therapeutic agent which improves one or more of the following objectives, including antimicrobial, immunomodulatory, and regenerative effects and is suitable for topical wound applications.

[0022] SUMMARY OF THE INVENTION The inventors have unexpectedly established that water insoluble salt products according to the invention containing zinc and a cationic surface-active agent exhibit an extraordinary antimicrobial activity and are particularly effective in accelerating wound healing, avoiding microbial colonization and biofilm formation.

[0023] It is uniquely and remarkably that these salts maintain the antimicrobial activity and do not release the active species in presence of water and aqueous environments, similar to those present in wounds or on the gingival or vaginal mucous membranes (in presence of aqueous solutions containing amino acids or sodium chloride in concentration isotonic with blood plasma).

[0024] The composition of the present description contains water insoluble salt products. In particular, the solid salt composition according to the invention is further insoluble in presence of water, aqueous environments and / or aqueous solution, similar to those present in wounds or on the gingival or vaginal mucous membranes (in presence of aqueous solutions containing amino acids or sodium chloride in concentration isotonic with blood plasma) in such a way as to preserve a barrier effect against microbial attacks on the wound to which they are applied. Additionally, as said salt composition is insoluble and solid, it remains intact (preferably without releasing the ions of the solid salt) during therapeutic use. Said composition is further described for use in the treatment of wounds.

[0025] The composition encompassed herein includes gel, cream and spray compositions, the application of which to the wounds, exhibit a barrier effect. This barrier function contributes to wound protection and supports the therapeutic efficacy of the preparations.

[0026] This allows for the realization of medical devices based on antimicrobial compositions comprising these salts or these compounds, for topical, dental or vaginal use, which provides that the active component behaves as a barrier against the bacterial, fungal or viral contaminating species, without release, in the wound or in the mucous, of the active ingredients (such as the salt ingredients or the functionalized antimicrobial powder) that have a specific antimicrobial activity.

[0027] Without wishing to be bound to any theory, the inventors believe that the remarkable antimicrobial and skin regenerative activity found for these antimicrobial compositions is caused by the lack of release of the active ingredients (such as the salt ingredients or the functionalized antimicrobial powder) allowing the compositions to provide an improved barrier against microbial contaminations.

[0028] Accordingly, in a first aspect, the invention provides: A salt composition comprising a zinc cation, a cation of a cationic surface-active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent, wherein:

[0029] - the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof, and

[0030] - the second anion moiety is a selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof, or wherein

[0031] - the first and second anion moieties are part of a bridging ligand, which has the following general structure: wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1- propansulfonate, and mixtures thereof.

[0032] According to one embodiment, preferably wherein said salt composition is insoluble in water or under physiological conditions. Said salt composition is present as a solid, when applied in the antimicrobial compositions according to the invention. Preferably said salt composition is finely and / or homogeneously dispersed within the antimicrobial compositions according to the invention. The inventors have, further, unexpectedly found that the water insoluble salt containing a zinc cation and a cationic surface-active agent, which forms the basis of the general inventive concept of this disclosure, can also be provided as a single molecule (or single salt compound) through the use of a bridging ligand.

[0033] Therefore, in a second aspect, a compound is provided:

[0034] A compound having a structure represented by formula (I):

[0035] (I) (Wm+)n[Zn2+(L2-)2] wherein: W is a cationic surface-active agent; m is the positive charge of the cationic surface-active agent; when m is 2, n is 1 or when m is 1, n is 2; and

[0036] L is a bridging ligand with the following general structure wherein R1is an aryl or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate (MBS) and 3-mercapto-l- propansulfonate (MPS) , and mixtures thereof.

[0037] According to one embodiment, preferably wherein the said compound is insoluble in water or under physiological conditions. Said compound is present as a solid, when applied in the antimicrobial compositions according to the invention. Preferably said compound is finely and / or homogeneously dispersed within the antimicrobial compositions according to the invention.

[0038] In one embodiment, wherein the zinc cation together with the first anion moiety associated therewith and the cation of a cationic surface-active agent together with the second anion moiety associated therewith are insoluble under physiological conditions.

[0039] In another aspect, the present disclosure relates to an antimicrobial composition comprising:

[0040] (i) a solid salt composition comprising a zinc cation, a cation of a cationic surface-active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent; wherein

[0041] - the cation of a cationic surface active agent is selected from the group consisting of biguanide and quaternary ammonium cationic surface active agent and mixtures thereof, preferably selected from the group consisting of polybiguanide and quaternary ammonium cationic surface active agent and mixtures thereof, more preferably selected from the group consisting of benzalkonium, didecyldimethylammonium, octenidine and chlorhexidine, and mixtures thereof, most preferably selected from the group consisting of chlorhexidine, benzalkonium, octenidine, and mixtures thereof; the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof; - the second anion moiety is selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof; or wherein

[0042] - the first and second anion moieties are part of a bridging ligand, which has the following general structure: wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3-mercapto-l- propansulfonate, and mixtures thereof; and

[0043] (ii) preferably one or more components selected from the group consisting of water, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, polyvinylpyrrolidone, glycerin, a hyaluronate, dimethicone, silica powder (silicon dioxide, silicon dioxide amorphous), soluble starch, carboxymethyl chitosan and chitosan, preferably low molecular weight chitosan.

[0044] In another aspect, the present disclosure relates to an antimicrobial powder composition comprising:

[0045] (i) a salt composition comprising a zinc cation, a cation of a cationic surface -active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent; wherein

[0046] - the cation of a cationic surface active agent is selected from the group consisting of benzalkonium, octenidine, chlorhexidine and mixtures thereof;

[0047] - the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof;

[0048] - the second anion moiety is selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof; or wherein the first and second anion moieties are part of a bridging ligand, which has the following general structure: wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1- propansulfonate, and mixtures thereof; and

[0049] (ii) silica powder, such as silicon dioxide or silicon dioxide amorphous, wherein the salt composition (i) is adsorbed to the surface of the silica powder.

[0050] In yet another aspect, the antimicrobial powder composition is a functionalized antimicrobial powder.

[0051] In one aspect, the present disclosure relates to an antimicrobial gel composition comprising:

[0052] (i) a solid salt composition comprising a zinc cation, a cation of a cationic surface-active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent; wherein

[0053] - the cation of a cationic surface active agent is selected from the group consisting of benzalkonium, octenidine, and mixtures thereof;

[0054] - the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof;

[0055] - the second anion moiety is selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof; or wherein

[0056] - the first and second anion moieties are part of a bridging ligand, which has the following general structure: wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3-mercapto-l- propansulfonate, and mixtures thereof; and

[0057] (ii) one or more components selected from the group consisting of water, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, polyvinylpyrrolidone, glycerin, a hyaluronate, dimethicone, silica powder (silicon dioxide, silicon dioxide amorphous), soluble starch, carboxymethyl chitosan and chitosan, preferably low molecular weight chitosan.

[0058] DEFINITIONS

[0059] The term ‘bridging ligand’ as used herein relates to a molecule comprising more than one anion moiety.

[0060] The term ‘complex’ as used herein relates to a molecular entity formed by a coordination bond involving two or more molecular components, such as the [Zn2+(L2')2]2' species.

[0061] The term ‘salt’ as used herein relates to a molecular entity consisting of an ionic assembly of cations and anions. A salt within the scope of this definition may also be a double salt, which is a salt containing two or more different cations and / or anions or may be a combination of two or more distinct cation-anion pairs.

[0062] The term ‘insoluble’ as used herein refers to products with a solubility lower than 0.2g / l preferably 0.02g / l, more preferably 0.002g / l .

[0063] The term ‘physiological conditions’ as used herein refers to conditions of the external or internal of animal body environment, which is usually aqueous in nature with the presence of 0.9% sodium chloride aqueous solution at a temperature range of 20-40 degrees Celsius, atmospheric pressure of 1, pH of 6-8, glucose concentration of 1-20 mM, atmospheric oxygen concentration.

[0064] The term ‘associated with’ as used herein refers to the association wherein ions of opposite electric charge come together to form a distinct chemical entity.

[0065] BRIEF DESCRIPTION OF THE FIGURES

[0066] Figure 1 depicts the EDS spectrum of (OCT)[Zn2+(MBS2)2]

[0067] Figure 2 depicts the EDS spectrum of (CHL)[Zn2+(MBS2)2]

[0068] Figure 3 depicts the EDS spectrum of (BZ)2[Zn2+(MBS2')2] Figure 4 depicts the development of microbial colonies in Petri dishes containing Example 2.1 (A), Example 2.2 (B), Example 2.3 (C), Example 2.4 (D) and a control (E).

[0069] Figure 5 depicts the development of microbial colonies in Petri dishes containing antimicrobial silica powder compositions example 3.1 (A) and example 3.3 (B).

[0070] Figure 6 depicts a chronic leg ulcer (left) and the same ulcer after 6 weeks of treatment showing complete healing (right).

[0071] Figure 7 depicts an acute post traumatic ulcer in the leg (left) and the same ulcer after 8 weeks of treatment showing complete healing (right).

[0072] Figures 8A and 8B depicts the development of microbial colonies in Petri dishes containing example 5.2.

[0073] Figure 9 depicts the development of microbial colonies in Petri dishes containing example

[0074] 5.4.

[0075] Figure 10 depicts the development of microbial colonies in Petri dishes containing example 5.5.

[0076] Figure 11 depicts the development of microbial colonies in Petri dishes containing example 5.6.

[0077] Figure 12 depicts the development of microbial colonies in Petri dishes containing example 5.7.

[0078] Figure 13 depicts the development of microbial colonies in Petri dishes containing example 5.8.

[0079] Figure 14 depicts the development of microbial colonies in Petri dishes containing example 5.9.

[0080] Figure 15 depicts the development of microbial colonies in Petri dishes containing example 5.11.

[0081] Figure 16 depicts the development of microbial colonies in Petri dishes containing example 5.12.

[0082] DETAILED DESCRIPTION

[0083] A salt composition

[0084] In a first aspect, the invention concerns salt compositions comprising a zinc cation, a cation of a cationic surface-active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent, wherein: - the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof, and

[0085] - the second anion moiety is a selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof, or wherein

[0086] - the first and second anion moieties are part of a bridging ligand, which has the following general structure: wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3-mercapto-l- propansulfonate, and mixtures thereof.

[0087] In an embodiment, the first anion moiety associated with the zinc cation is selected from the group consisting of inorganic phosphate and thiolate and mixtures thereof, preferably selected from the group consisting of inorganic phosphate and thiolate according to general structure (a),

[0088] (a) wherein R2is selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12 membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl, optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of halo, hydroxy, oxo, imino and C1-C4 alkyl, optionally substituted with one to three substituents at each occurrence independently selected from the group consisting of halo, hydroxy, oxo and imino, more preferably the first anion moiety is inorganic phosphate; and the second anion moiety associated with the cation of a cationic surface-active agent is a selected from the group consisting of organosulfonate and sulfonylazanide, preferably selected from the group consisting organosulfonate according to general structure (b) and sulfonylazanide according to general structure (c)

[0089] (b) (c) wherein R3is selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12 membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl, and wherein R4and R5are each independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12 membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl or R4and R5, taken together with the sulfur and nitrogen atoms to which they are attached, form a 4- to 12-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, wherein each R3, R4and R5is optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of halo, hydroxy, oxo, imino and C1-C4 alkyl, optionally substituted with one to three substituents at each occurrence independently selected from the group consisting of halo, hydroxy, oxo and imino, more preferably the second anion moiety associated with the cation of a cationic surface-active agent is selected from the group consisting of para-toluenesulfonate, 2, 3 -dihydro-3 - oxobenzisosulfonazole, and mixtures thereof.

[0090] In a preferred embodiment, the first and second anion moieties are part of a bridging ligand, which has the following general structure: wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3-mercapto-l- propansulfonate, and mixtures thereof.

[0091] As will be appreciated by the person skilled in the art, this bridging ligand is capable of coordinating the zinc cation and capable of binding through an ionic bond the cation of a cationic surface-active agent.

[0092] In a preferred embodiment, the cationic surface-active agent is selected from the group consisting of biguanide and quaternary ammonium cationic surface-active agent and mixtures thereof, preferably selected from the group consisting of polybiguanide and quaternary ammonium cationic surface-active agent and mixtures thereof, more preferably selected from the group consisting of benzalkonium, didecyldimethylammonium, octenidine and chlorhexidine, and mixtures thereof, most preferably selected from the group consisting of chlorhexidine, benzalkonium, octenidine, and mixtures thereof.

[0093] In an embodiment, the salt composition is a salt mixture comprising a first salt containing the zinc cation and the first anion moiety and a second salt containing the cation of a cationic surface-active agent and the second anion moiety.

[0094] In an embodiment, the zinc cation and the first anion moiety associated therewith and the cation of a cationic surface-active agent and the second anion moiety associated therewith are both water insoluble.

[0095] In a preferred embodiment, the zinc cation and the first anion moiety associated therewith and the cation of a cationic surface-active agent and the second anion moiety associated therewith are both insoluble under physiological conditions.

[0096] In an embodiment, the zinc cation and the first anion moiety associated therewith has a solubility in water below 0.2g / l, preferably below 0.02g / l, more preferably below 0.002g / l.

[0097] In a preferred embodiment, the zinc cation and the first anion moiety associated therewith has a solubility under physiological conditions below 0.2g / l, preferably below 0.02g / l, more preferably below 0.002g / l.

[0098] In an embodiment, the cation of a cationic surface-active agent and the second anion moiety associated therewith has a solubility in water below 0.2g / l, preferably below 0.02g / l, more preferably below 0.002g / l.

[0099] In a preferred embodiment, the cation of a cationic surface-active agent and the second anion moiety associated therewith has a solubility under physiological conditions below 0.2g / l, preferably below 0.02g / l, more preferably below 0.002g / l.

[0100] In one embodiment, the said salt composition is solid salt composition, preferably insoluble in water and physiological conditions.

[0101] Bridging salt compound

[0102] As will be appreciated by those skilled in the art, the use of a bridging ligand capable of coordinating the zinc cation and simultaneously forming an electrostatic interaction with the cation of a cationic surface-active agent results in a single complex compound or single complex salt. Therefore, in a second aspect, the invention concerns a compound having a structure represented by formula (I):

[0103] (Wm+)n[Zn2+(L2-)2] wherein:

[0104] W is a cationic surface-active agent or sodium, preferably a cationic surface-active agent; m+ is the positive charge of the cationic surface-active agent or sodium; when m is 2, n is 1 or when m is 1, n is 2; and

[0105] L is a bridging ligand with the following general structure wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand comprising the first and second anion moiety is selected from the group consisting of 2-mercapto-5- benzimidazole sulfonate and 3 -mercapto- 1-propansulfonate, and mixtures thereof.

[0106] In a preferred embodiment, the cationic surface active agent is selected from the group consisting of biguanide and quaternary ammonium cationic surface active agent and mixtures thereof, preferably selected from the group consisting of polybiguanide and quaternary ammonium cationic surface active agent and mixtures thereof, more preferably selected from the group consisting of benzalkonium, didecyldimethylammonium, octenidine and chlorhexidine, and mixtures thereof, most preferably selected from the group consisting of chlorhexidine, benzalkonium, octenidine, and mixtures thereof.

[0107] In an embodiment, the compound of formula (I) is water insoluble.

[0108] In a preferred embodiment, the compound of formula (I) is insoluble under physiological conditions.

[0109] In an embodiment, the compound of formula (I) has a solubility in water below 0.2g / l, preferably below 0.02g / l, more preferably below 0.002g / l.

[0110] In a preferred embodiment, the compound of formula (I) has a solubility under physiological conditions below 0.2g / l, preferably below 0.02g / l, more preferably below 0.002g / l.

[0111] In an embodiment, the molar ratio between the zinc cation and the cationic surface-active agent cation in the salt composition or in the compound of formula (I) according to the invention is in the range 5: 1 to 1 :5, preferably 3:1 to 1 :3, more preferably 2: 1 to 1 :2, most preferably about 1 : 1. Antimicrobial composition

[0112] A third aspect, the invention concerns an antimicrobial composition comprising the salt composition of the first aspect or comprising the compound of the second aspect, wherein preferably the composition is a tablet, a capsule, a gel, a cream, a powder or a spray, more preferably a gel, a cream, a powder or a spray, such as a spray containing the powder of the invention. In an alternate embodiment, the composition is not suitable for oral administration and / or application.

[0113] In one aspect, the invention concerns an antimicrobial composition comprising:

[0114] (i) a salt composition comprising a zinc cation, a cation of a cationic surface-active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent, wherein:

[0115] - the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof, and

[0116] - the second anion moiety is a selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof, or wherein

[0117] - the first and second anion moieties are part of a bridging ligand, which has the following general structure: wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1-propansulfonate, and mixtures thereof; or

[0118] (ii) a compound having a structure represented by formula (I):

[0119] (Wm+)n[Zn2+(L2-)2] wherein:

[0120] W is a cationic surface-active agent or sodium, preferably a cationic surface-active agent; m+ is the positive charge of the cationic surface-active agent or sodium; when m is 2, n is 1 or when m is 1, n is 2; and

[0121] L is a bridging ligand with the following general structure wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand comprising the first and second anion moiety is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1-propansulfonate, and mixtures thereof; wherein the composition is a gel, a cream, a powder or a spray, such as a spray containing the powder of the invention.

[0122] In an embodiment, the first anion moiety associated with the zinc cation is selected from the group consisting of inorganic phosphate and thiolate and mixtures thereof, preferably selected from the group consisting of inorganic phosphate and thiolate according to general structure (a),

[0123] S2

[0124] R2

[0125] (a) wherein R2is selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12 membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl, optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of halo, hydroxy, oxo, imino and C1-C4 alkyl, optionally substituted with one to three substituents at each occurrence independently selected from the group consisting of halo, hydroxy, oxo and imino, more preferably the first anion moiety is inorganic phosphate.

[0126] In another embodiment, the second anion moiety associated with the cation of a cationic surface-active agent is a selected from the group consisting of organosulfonate and sulfonylazanide, preferably selected from the group consisting organosulfonate according to general structure (b) and sulfonylazanide according to general structure (c)

[0127] (b) (C) wherein R3is selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12 membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl, and wherein R4and R5are each independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12 membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl or R4and R5, taken together with the sulfur and nitrogen atoms to which they are attached, form a 4- to 12-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, wherein each R3, R4and R5is optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of halo, hydroxy, oxo, imino and C1-C4 alkyl, optionally substituted with one to three substituents at each occurrence independently selected from the group consisting of halo, hydroxy, oxo and imino, more preferably the second anion moiety associated with the cation of a cationic surface-active agent is selected from the group consisting of paratoluenesulfonate, 2,3-dihydro-3-oxobenzisosulfonazole, and mixtures thereof.

[0128] In a preferred embodiment, the cationic surface-active agent is selected from the group consisting of biguanide and quaternary ammonium cationic surface-active agent and mixtures thereof, preferably selected from the group consisting of polybiguanide and quaternary ammonium cationic surface-active agent and mixtures thereof, more preferably selected from the group consisting of benzalkonium, didecyldimethylammonium, octenidine and chlorhexidine, and mixtures thereof, most preferably selected from the group consisting of chlorhexidine, benzalkonium, octenidine, and mixtures thereof.

[0129] In an embodiment, the antimicrobial composition comprises a salt composition, which is a salt mixture comprising a first salt containing the zinc cation and the first anion moiety and a second salt containing the cation of a cationic surface-active agent and the second anion moiety.

[0130] In another embodiment, the molar ratio between the zinc cation and the cationic surfaceactive agent cation in the salt composition or in the compound of formula (I) according to the invention is in the range 5: 1 to 1 :5, preferably 3: 1 to 1 :3, more preferably 2: 1 to 1 :2, most preferably about 1 :1.

[0131] In an embodiment, the antimicrobial composition is pharmaceutical composition.

[0132] In an embodiment, wherein the salt composition is insoluble in water or under physiological conditions, preferably the salt composition is a solid composition. Preferably said salt composition is finely and / or homogeneously dispersed within the antimicrobial compositions according to the invention.

[0133] In an embodiment, the antimicrobial composition further comprises one or more components selected from the group consisting of water, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, polyvinylpyrrolidone, glycerin, a hyaluronate, dimethicone, silica powder (SiCh, silicon dioxide, silicon dioxide amorphous), soluble starch, carboxymethyl chitosan and chitosan, preferably a low molecular weight chitosan.

[0134] In a preferred, the antimicrobial composition further comprises one or more components selected from the group consisting of carboxymethyl chitosan and low molecular weight chitosan, wherein the low molecular weight chitosan is the chitosan having molecular weight of about <10 kDa, and / or further characterized to have higher water solubility at pH values ranging from 3.0 to 8.5, compared to that of the high-molecular-weight (>100 kDa) chitosan.

[0135] In another embodiment, the antimicrobial composition comprises soluble starch, wherein the said soluble starch (CAS NO: 9005-84-9) is a modified starch that is water soluble, preferably soluble in hot water. Preferably the starch is modified by one or more of physical modifications such as exposing the starch to heat, pressure, electricity or radiation; chemical modifications such as oxidation, esterification or etherification; enzymatic modifications. More preferably, the starch is modified by hydrolyzing with an acid to make it soluble in water.

[0136] In an embodiment, the antimicrobial composition further comprises one or more fragrances, preferably selected from the group consisting of essence or mentha piperita.

[0137] In an embodiment, the one or more fragrances are present in an amount between 0.3 - 0.9 wt.%.

[0138] In an embodiment, the antimicrobial composition has antimicrobial activity.

[0139] Examples of antimicrobial cream-gel compositions

[0140] In an embodiment, antimicrobial gel compositions is formed by using the following components and provided by the following compositions

[0141] In an alternative embodiment, antimicrobial cream compositions is formed by using the following components and provided by the above compositions. It has been observed that by providing Gel formulation A and Gel formulation B, an insoluble salt composition according to the invention is formed within the resulting antimicrobial gel composition as a homogeneously dispersion.

[0142] In an embodiment, antimicrobial gel compositions is provided with the following compositions: It has been observed that by providing Gel formulation A and Gel formulation B, an insoluble salt composition according to the invention is formed within the resulting antimicrobial gel composition as a homogeneously dispersion.

[0143] In an alternative embodiment, antimicrobial cream compositions is formed by using these components and provided by the above compositions. It has been observed that by providing formulation A and formulation B, an insoluble salt composition according to the invention is formed within the resulting antimicrobial cream composition as a homogeneously dispersion.

[0144] In an embodiment, an antimicrobial (cream or gel) composition is provided further comprising chitosan, preferably low molecular weight chitosan, or carboxymethyl chitosan. Chitosan products are family of linear polysaccharides, with different molecular weights, composed of varying amounts of residues of N-acetyl-2 amino-2-deoxy- D-glucose (glucosamine, GlcN) and 2-amino-2-deoxy-D-glucose (N-acetyl-glucosamine, GlcNAc) residues. Chitosan is soluble in aqueous acidic media via primary amine protonation. One of the factors that determine the biological, mechanical, and physicochemical properties of chitosan is its molecular weight. For example, a high molecular weight chitosan (HMW chitosan) are characterized to have molecular weight of about >100 kDa, while a low molecular weight chitosan (LMW chitosan) are characterized to have molecular weight of about <10 kDa.

[0145] Chitosan has a number of interesting properties for application in the pharmaceutical field which have been documented in several publications. For a review on this subject see Chitosan: An Overview of Its Properties and Applications, Polymers 2021, 13, 3256. Properties of particular interest are the mucoadhesive, the anti-inflammatory and antioxidant properties which makes this polymer very useful for topical applications.

[0146] During the formulation of topical use creams or gel, it has been observed that powder composed by high molecular weight chitosan (CAS N: 9012-76-4) can be quicky jellified by addition of gluconic acid. The obtained gel has ideal properties for trapping the previously described insoluble zinc and surfactant components. Examples of compositions comprising chitosan are described in the following sections.

[0147] In one embodiment, the antimicrobial composition is a topical compositions, preferably selected from a cream or a gel composition, further comprises a low molecular weight chitosan, a carboxymethyl chitosan or a mixture thereof. It has been found that the presence of the low molecular weight chitosan, carboxymethyl chitosan or a mixture thereof keeps the said topical composition stable by avoiding the phase separation and further allows the formation of a film over the wound, which protect the wound like an artificial skin. In an embodiment, an antimicrobial (cream or gel) composition is provided further comprising Hyaluronic acid (HYA) or its sodium salt (NaYA).

[0148] Hyaluronic acid (HYA) or its sodium salt (NaYA) is a linear polysaccharide with repeating disaccharide units composed of glucuronic acid and N-acetyl glucosamine.

[0149] HYA is one of the major matrix substances in which cells and fibrous constituents of the matrix such as collagen and elastin are embedded. Another unique characteristic of HYA is its enormously high-water binding capacity. In solutions HYA exists in a flexible, coiled configuration that contains approximately 1000- fold more water than polymer (Biopolymers. 1970;9:799-810). This special feature enables HYA to contribute largely to the maintenance of the extracellular space and to control tissue hydration.

[0150] It has been surprisingly observed that the addition of benzalkonium chloride or chlorhexidine di-gluconate to hyaluronate gel containing Na+2[Zn2+(MBS2')2]2-result in the instantaneous formation of white creams in which the (BZ)2[Zn2+(MBS2')2] or (CHL)[Zn2+(MBS2')2] complexes are homogeneously dispersed, i.e. as solids.

[0151] In an embodiment, an antimicrobial gel compositions is provided with the following compositions:

[0152] It has been observed that by providing Gel formulation A and Gel formulation B, an insoluble salt composition according to the invention is formed within the resulting antimicrobial gel composition as a homogeneously dispersion.

[0153] In an alternative embodiment, antimicrobial cream compositions is provided with the above compositions. In an embodiment, an antimicrobial gel compositions is provided with the following compositions:

[0154] It has been observed that by providing Gel formulation A and Gel formulation B, an insoluble salt composition according to the invention is formed within the resulting antimicrobial gel composition as a homogeneously dispersion.

[0155] In an alternative embodiment, antimicrobial cream compositions is provided with the above compositions.

[0156] Antimicrobial powder composition

[0157] In an embodiment, an antimicrobial powder composition is provided with the following compositions:

[0158] In an embodiment, an antimicrobial powder composition is provided with the following compositions:

[0159] In an embodiment, the amorphous silica in the antimicrobial powder compositions is a silica having a particle diameter in the 0.2-1 micron range, preferably in the 0.2-0.3 micron range.

[0160] In one embodiment, the antimicrobial powder composition comprises the solid salt composition according to any of the present description, which is coupled to the silica particles. In a preferred embodiment, the antimicrobial powder composition comprises the solid salt composition of zinc phosphate and one or more of benzalkonium saccharide, chlorhexidine saccharide or octenidine saccharide, coupled to the silica particles, preferably the silica particles having diameter in the 0.2-0.3 micron range.

[0161] In an additional embodiment, the antimicrobial powder composition comprises a first salt comprising the zinc cation with the first anion; and a second salt comprising the cation selected from cationic surface-active agent and the second anion, wherein the said first and second salts are coupled to the silica particles. In a preferred embodiment, the antimicrobial powder composition comprises a first salt selected from zinc phosphate and a second salt selected from one or more of benzalkonium saccharide, chlorhexidine saccharide and octenidine saccharide, wherein the said first and second salts are coupled to the silica particles.

[0162] In one embodiment, the said antimicrobial powder composition is also termed as a functionalized antimicrobial powder.

[0163] In another embodiment, the antimicrobial powder composition or the functionalized antimicrobial powder is dried (antimicrobial dry powder). In an alternate embodiment, the antimicrobial powder composition or the functionalized antimicrobial powder is hydrated (antimicrobial wet powder). In preferable embodiments, the antimicrobial powder composition or the functionalized antimicrobial powder is hydrated (antimicrobial wet powder).

[0164] In an additional embodiment, the antimicrobial powder composition or the functionalized antimicrobial powder is used for the preparation of an antimicrobial composition, preferably a topical composition such as one or more of gel composition, cream composition, spray composition. In an embodiment, an alcoholic solution comprising a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein.

[0165] In an embodiment, a coating for medical devices comprising a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein.

[0166] In one embodiment, a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein, is / are suitable for topical application, preferably the topical application is selected from: powder spray or cream / gel application.

[0167] In an embodiment, the present disclosure relates to a spray can comprising a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein and a propellant, preferably n-butane as the propellant.

[0168] In one embodiment, a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein, wherein a source of the zinc cation is provided as a zinc salt, preferably the zinc salt is selected from the group containing zinc digluconate, zinc sulphate, zinc chloride, zinc acetate, zinc citrate, and mixtures thereof, more preferably the zinc salt is zinc di gluconate.

[0169] In one embodiment, a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein, wherein a source of the cation of a cationic surface-active agent is provided as salt of a cationic surface-active agent, preferably the salt of a cationic surface-active agent is selected from the group containing octenidine hydrochloride, octenidine dihydrochloride, chlorhexidine digluconate, chlorhexidine chlorhexidine acetate, chlorhexidine chloride, benzalkonium chloride, and mixtures thereof.

[0170] In one embodiment, a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein, wherein a source of the first anion moiety is provided as a phosphate salt, preferably the phosphate salt is selected from the group containing sodium mono-hydrogen phosphate dodecahydratye or sodium phosphate dodecahydratye.

[0171] In one embodiment, a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein, wherein a source of the second anion moiety is provided as a sulfonate or sulfonamide salt, preferably the sulfonate or sulfonamide salt is selected from the group containing sodium paratoluene sulfonate and saccharin sodium salt.

[0172] Uses

[0173] In a fourth aspect, the use of the salt composition as described herein, the compound of formula (I) as described herein, the antimicrobial composition as described herein, the antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein and the antimicrobial gel composition as described herein is disclosed.

[0174] In one embodiment, a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein, for use as a medicament or for use as a medicine or for use as a therapy.

[0175] In an embodiment, a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein for use in the treatment of wounds and / or for treatment of inflammation. In an embodiment, the present disclosure relates to a method for the treatment of wounds and / or a method for the treatment of inflammation, comprising the use of or administration of or application of a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein.

[0176] In an embodiment, the present disclosure relates to a use of a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein, in the manufacture of a medicament for the treatment of wounds and / or for treatment of inflammation.

[0177] In an embodiment, the wounds are chronic wounds, acute wounds, skin wounds, including burn wounds, and / or oral wounds.

[0178] In an embodiment, a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder or a functionalized antimicrobial powder composition as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein for use in antimicrobial treatment, antiviral treatment or antifungal treatment, preferably antimicrobial treatment.

[0179] In an embodiment, the present disclosure relates to a method of antimicrobial treatment, antiviral treatment or antifungal treatment, comprising the use of or administration of or application of a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein.

[0180] In an embodiment, the present disclosure relates to a use of a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein, in the manufacture of a medicament for antimicrobial treatment, antiviral treatment or antifungal treatment, preferably antimicrobial treatment.

[0181] In an embodiment, the treatment comprises topical use, oral use, pain reduction, wound healing, gynecological topical (vaginal) treatments, and / or antiseptic treatment.

[0182] In an embodiment, the treatment does not comprise oral use. In an embodiment, use of a salt composition as described herein, a compound of formula (I) as described herein, an antimicrobial composition as described herein, an antimicrobial powder composition or a functionalized antimicrobial powder as described herein, an antimicrobial cream composition as described herein or an antimicrobial gel composition as described herein, as antimicrobial agent.

[0183] The antimicrobial powder compositions or the functionalized antimicrobial powder of the embodiments above are suitable for use in sprays, in vaginal capsules or in a cream for topical applications, preferably for use in spray can.

[0184] In an embodiment, a spray formulation comprising the antimicrobial powder compositions or the functionalized antimicrobial powder, preferably a spray formulation comprising the antimicrobial powder compositions or the functionalized antimicrobial powder in an amount between 2-20 wt.% based on the total contents of the spray formulation.

[0185] In an embodiment, the spray formulation can further comprise one or more excipients, preferably one or more selected from the group comprising Kaolin, Zeolites and suitable propellant.

[0186] In an embodiment, vaginal capsule comprising the antimicrobial powder compositions or the functionalized antimicrobial powder.

[0187] In an embodiment, cream for topical application comprising the antimicrobial powder compositions or the functionalized antimicrobial powder.

[0188] In an embodiment, the salt composition as described herein, the compound of formula (I) as described herein, the antimicrobial composition as described herein, the antimicrobial powder composition or the functionalized antimicrobial powder as described herein, the antimicrobial cream composition as described herein or the antimicrobial gel composition as described herein, is / are suitable for topical application, preferably the topical application is selected from: powder spray or cream / gel application.

[0189] In one embodiment, wherein the treatment comprises topical application or gynaecological topical (vaginal) application, preferably for pain reduction, wound healing, and / or antiseptic treatment.

[0190] Method for preparing the salt, the compound, the antimicrobial composition and the antimicrobial powder composition

[0191] A fifth aspect, concerns a method for preparing the salt composition as described herein, the compound as described herein, the antimicrobial composition as described herein, the antimicrobial powder composition as described herein, the antimicrobial cream composition as described herein and the antimicrobial gel composition as described herein.

[0192] In an embodiment, the invention concerns a method for preparing the salt composition of the first aspect, the method comprising the steps: a) providing the following cations:

[0193] (I) a fist cation selected from a zinc cation

[0194] (II) at least one second cation selected from cationic surface-active agent; b) providing the following anions:

[0195] (III) at least one first anion moiety selected from phosphate and thiolate, and

[0196] (IV) at least one second anion moiety selected from organosulfonate and sulfonamide, preferably selected from the group consisting of a paratoluenesulfonate, and a 2,3 -dihydro-3 -oxobenzisosulfonazole salt (saccharin), or

[0197] (V) providing a bridging ligand comprising the first and second anion moiety, which has the following general structure: wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1-propansulfonate, and mixtures thereof. c) preparation of a mixture comprising a solvent, the zinc cation (I), the cationic surface-active agent (II), the first anion moiety (III) and the second anion moiety (IV), comprising dissolving the components (I - IV) in the solvent or a mixture comprising a solvent, the zinc cation (I), the cationic surface-active agent (II) and the bridging ligand (V), comprising dissolving the components (I, II and V) in the solvent; or c’) preparation of a mixture comprising components (I - IV) in the solvent, comprising: mixing a first mixture comprising a solvent, the zinc cation (I) and the first anion moiety (III) in the solvent, and a second mixture comprising the cationic surface-active agent (II) and the second anion moiety (IV) in the solvent; d) allowing the precipitation of the zinc cation (I) and the first anion moiety (III) and the cation of the cationic surface-active agent (II) and the second anion moiety (IV) or the precipitation of the zinc cation (I), the cation of the cationic surface-active agent (II) and the bridging ligand (V).

[0198] By using the method as described above the salt composition according to the invention or the compound according to the invention of Formula (I) can be formed as a solid, preferably thereby forming a homogeneous dispersion of the solid.

[0199] In a preferred embodiment, the cationic surface active agent is selected from the group consisting of biguanide and quaternary ammonium cationic surface active agent and mixtures thereof, preferably selected from the group consisting of polybiguanide and quaternary ammonium cationic surface active agent and mixtures thereof, more preferably selected from the group consisting of benzalkonium, didecyldimethylammonium, octenidine and chlorhexidine, and mixtures thereof, most preferably selected from the group consisting of chlorhexidine, benzalkonium, octenidine, and mixtures thereof.

[0200] In an embodiment, the cations, being the zinc cation (I) and the cation of a cationic surface-active agent (II) and the anions, being the first anion moiety (III) and the second anion moiety (IV), are provided as a corresponding salt or as a corresponding acid.

[0201] As will be understood by the skilled person, the cations and anions are generated through the dissolution of the corresponding salt or the deprotonation of the corresponding acid.

[0202] In a preferred embodiment, the zinc cation (I) is provided as a water-soluble zinc salt, preferably a zinc salt selected from the group containing zinc (di)gluconate, zinc sulphate, zinc chloride, zinc acetate, zinc citrate, and mixtures thereof, more preferably the zinc salt is zinc (di)gluconate.

[0203] In a preferred embodiment, the first anion moiety (III) is provided as a water-soluble phosphate salt, preferably a phosphate salt selected from the group containing sodium monohydrogen phosphate (ISfeHPCU) or sodium phosphate (NasPCk) or sodium mono-hydrogen phosphate dodecahydrate or sodium phosphate dodecahydrate.

[0204] In a preferred embodiment, the cation of a cationic surface-active agent (II) is provided as a water-soluble salt of a cationic surface-active agent, preferably a salt of a cationic surfaceactive agent selected from the group containing, octenidine hydrochloride octenidine dihydrochloride, chlorhexidine digluconate, chlorhexidine chlorhexidine acetate, chlorhexidine chloride, benzalkonium chloride, didecyldimethylammonium chloride, and mixtures thereof. In a preferred embodiment, the second anion moiety (IV) is provided as a water-soluble sulfonate or sulfonamide salt, preferably a water-soluble sulfonate or sulfonamide salt selected from the group containing sodium para-toluene sulfonate and saccharin sodium salt.

[0205] In an embodiment, the solvent used in step c) comprises at least 50% water, preferably at least 75% water, more preferably at least 90% water, even more preferably at least 95% water, most preferably the solvent used in step c) consists essentially of water.

[0206] In an embodiment, the preparation of the mixture in step c) is performed under constant stirring.

[0207] The precipitation, as used herein is achieved by the association of zinc cation with the first anion, and also by the association of the cation of a cationic surface-active agent and the second anion. The precipitation of zinc salt occurs following the addition of the first anion, and similarly, the precipitation of the salt of cationic surface-active agent occurs following the addition of the second anion. With regards to the complex salt of a compound having a structure represented by general formula (I): (Wm+)n[Zn2+(L2')2], as described herein, which is insoluble in the water, preferably the compound of formula (I) or the bridging ligand L or the complex zinc anion contained with the bridging ligand are insolubilized / precipitated by the addition of the cation of a cationic surface-active agent. In these preferable embodiments of the invention, the advantage is that the precipitation is achieved directly (in situ). This is obtained without an additional use of changing solvent conditions (such as temperature change or solvent mixture modification).

[0208] In an alternate embodiment, the precipitation can be achieved by the methods known to the skilled person, including but not limited to: allowing to stir, cooling, saturation under vacuum and / or temperature, seeding or addition of a solvent, preferably an anti-solvent or any combination thereof. In a preferred embodiment, the precipitation step d) is carried out by addition of a solvent, preferably an organic solvent miscible with water, more preferably selected from acetone, ethanol, methanol, acetonitrile or mixture thereof followed by optionally allowing the mixture to stir. In another embodiment, the precipitation step d) is carried out by addition of acetone followed by optionally stirring the mixture.

[0209] In an embodiment, step d) optionally comprises stirring the mixture obtained in step c) for at least 1-12 hrs.

[0210] In an embodiment, each of the cations, being the zinc cation (I) and the cation of a cationic surface-active agent (II), and each of the anions, being first anion moiety (III) and the second anion moiety (IV), are separately mixed in the solvent after which the resulting solutions are mixed with each other. In an embodiment, the cations, being the zinc cation (I) and the cation of a cationic surface-active agent (II), and each of the anions, being the first anion moiety (III) and the second anion moiety (IV), are each separately mixed in the solvent after which the resulting solutions comprising the cations and the resulting solution comprising the anions are mixed with each other.

[0211] In a highly preferred embodiment, a bridging ligand (V) is provided comprising both the first anion moiety and second anion moiety with the following general structure:

[0212] Wherein R1is an aryl or alkyl moiety, preferably R1is benzimidazole or propyl, preferably the bridging ligand is selected from 2-mercapto-5-benzimidazole sulfonate and 3- mercapto-l-propansulfonate, and mixtures thereof.

[0213] As will be appreciated by those skilled in the art, the bridging ligand can be provided as a corresponding salt or as a corresponding acid and the use of such a bridging ligand result in the precipitation of the first complex and the second complex from the mixture as a single complex salt of a compound having a structure represented by general formula (I): (Wm+)n[Zn2+(L2-)2], wherein:

[0214] W is a cationic surface-active agent, preferably a cationic surface-active agent; m+ is the positive charge of the cationic surface-active agent or sodium; when m is 2, n is 1 or when m is 1, n is 2; and

[0215] L is a bridging ligand with the following general structure wherein R1is an aryl or alkyl moiety, preferably the bridging ligand comprising the first and second anion moiety is selected from the group consisting of 2-mercapto-5- benzimidazole sulfonate and 3 -mercapto- 1-propansulfonate, and mixtures thereof.

[0216] In an embodiment, each of the cations, being the zinc cation (I) and the cation of a cationic surface-active agent (II), and each of the anions, being the first anion moiety (III) and the second anion moiety (IV), or the bridging ligand (V) containing both the first and second anion moiety, are separately mixed in the solvent after which the resulting solutions are mixed with each other. In an embodiment, the cations, being the zinc cation (I) and the cation of a cationic surface-active agent (II), and the bridging ligand (V), are each separately mixed in the solvent after which the resulting solutions comprising the cations and the resulting solution comprising the bridging ligand are mixed with each other.

[0217] In an embodiment, in step c) each of the cations, being the zinc cation (I) and the cation of a cationic surface-active agent (II), and the bridging ligand (V), are separately mixed in the solvent, after which:

[0218] 1. the solution containing the zinc cation (I) and the solution containing the bridging ligand are mixed with each other; and

[0219] 2. the solution containing and the cation of a cationic surface-active agent (II) and the solution resulting from the previous step are mixed with each other.

[0220] In an embodiment, the mixture provided in step c) comprises at least one further ingredient selected from the group containing ascorbyl phosphate, hyaluronate, chitosan, low molecular weight chitosan, carboxymethyl chitosan, glycerine, and mixtures thereof.

[0221] In an embodiment, the first anion (III) and the first cation (I) are provided in a molar ratio between 5: 1 to 1 :5 based on the stoichiometric ratio, preferably 2: 1 to 1 :2.

[0222] In an embodiment, the second anion (IV) and the second cation (II) are provided in a molar ratio between 5: 1 to 1 :5 based on the stoichiometric ratio, preferably 2: 1 to 1 :2.

[0223] In a specific embodiment, a method for the preparation of an antimicrobial gel composition is described, the method comprising the following steps: a) providing the following cations:

[0224] (I) a fist cation selected from a zinc cation

[0225] (II) at least one second cation selected from cationic surface-active agent; b) providing the following anions:

[0226] (III) at least one first anion moiety selected from phosphate and thiolate, and

[0227] (IV) at least one second anion moiety selected from organosulfonate and sulfonamide, preferably selected from the group consisting of a paratoluenesulfonate and a 2,3-dihydro-3-oxobenzisosulfonazole salt, c) providing one of more gel forming additives; d) preparation of a mixture comprising a solvent, the first cation (I), the second cation (II), the first anion (III), the second anion (IV) and the one or more gel forming additives, comprising dissolving the cations and anions in the solvent; e) allowing the formation of a gel-cream from the mixture obtained in step d). In an embodiment, the gel formed in step e) is homogenized by mixing for a time interval between 12 and 24 hours.

[0228] In a preferred embodiment, the one of more gel forming additives are selected from the group containing pharmaceutically acceptable gel forming additive, preferably gel forming additives are selected from the group containing high molecular weight acrylic acid polymer crosslinked with divinyl glycol (such as Noveon® AA-1 Polycarbophil), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) hydroxyethylcellulose, polyvinylpyrrolidone, hyaluronic acid, sodium hyaluronate, soluble starch, chitosan, low molecular weight chitosan, carboxymethyl chitosan and mixtures thereof. The gel forming additives can also be used to form a cream formulation instead of a gel formulation. The skilled person can use common skills to form the cream formulation using these gel forming additives.

[0229] In a preferred embodiment, the mixture provided in step d) further comprises one or more further ingredient selected from the group consisting of sodium ascorbyl phosphate, betaine, dimethicone, glycerine, essence, such as essence of mentha piperita, and mixtures thereof.

[0230] In a preferred embodiment, the first anion moiety and second anion moiety are part of a single molecule being a bridging ligand with the following general structure: wherein R1is an aryl or alkyl moiety, preferably the bridging ligand comprising the first and second anion moiety is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1-propansulfonate, and mixtures thereof.

[0231] In an embodiment, the preparation of the mixture of step d) comprises following intermediate steps:

[0232] • preparation of a first mixture (gel A) comprising a solvent and the one or more gel forming additives, optionally homogenized the first mixture for a time interval between 4 and 12 hours;

[0233] • preparation of a second mixture (gel B) comprising a solvent and each of the cations, being the zinc cation (I) and the cation of a cationic surface-active agent (II), and each of the anions, being the first anion (III) and the second anion (IV), or the bridging ligand (V) containing both the first and second anion, and optionally the one or more gel forming additives, optionally homogenized the second mixture for a time interval between 4 and 12 hours; and

[0234] • mixing the first mixture with the second mixture, optionally homogenized the resulting mixture for a time interval between 12 and 24 hours.

[0235] Exemplary compositions of the first mixture (gel A) and second mixture (gel B) are disclosed in the embodiments above disclosing suitable compositions of the antimicrobial gel compositions.

[0236] In a specific embodiment, a method for the preparation of an antimicrobial powder composition is described, the method comprising the following steps: a) treating an amorphous silica powder with an aqueous solution comprising a zinc cation and a cation of a cationic surface-active agent; the treating step preferably comprising mixing for at least 30 minutes; b) adding to the treated silica powder of step a):

[0237] • at least one first anion moiety selected from the group consisting of: phosphate and thiol ate, and

[0238] • at least one second anion moiety selected from the group consisting of: organosulfonate and sulfonamide, preferably selected from the group consisting of paratoluenesulfonate and 2,3-dihydro-3-oxobenzisosulfonazole, and mixtures thereof, or

[0239] • adding at least one bridging ligand comprising a first and second anion moiety, which has the following general structure: wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1- propansulfonate, and mixtures thereof; and

[0240] • optionally mixing for at least 30 minutes; c) filtering the mixture of step b) to form a solid phase comprising the treated silica powder; d) optionally drying the solid phase obtained by step c), preferably at a temperature of at least 40°C for at least 16 hrs. In a preferred embodiment, the first anion moiety and second anion moiety are part of a single molecule being a bridging ligand with the following general structure: wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1-propansulfonate, and mixtures thereof.

[0241] In a preferred embodiment, in step b) the at least one first anion moiety is added to the treated silica powder, and thereafter the at least one second anion moiety is added to the treated silica powder.

[0242] The compositions of the different formulations in gels or creams and the results of antimicrobial tests are reported in the next section.

[0243] EXAMPLES

[0244] Example 1 Preparation of (Wm+)n[Zn2+(L2)2]

[0245] Preparation of Na+21Zn2+(MBS2~)2l2~

[0246] A 4 g amount of 2-mercapto-5-benzimidazole sulfonic acid sodium salt was dissolved in 46 g of an aqueous solution containing 14 g of 1 M NaOH. To this solution, 2 g of ZnSCU x 7 H2O, dissolved in 40 g of water, was added. Stirring was continued for 15 min and the solid product was precipitated by addition of an excess of acetone, filtered and dried at 50°C.

[0247] Elemental analysis was consistent with the stoichiometry of the zinc complex.

[0248] Calculated for Na2ZnCi4H8O6S4N4 (MW 567.87): C 29.61 %; H 1.42 %; N 9.87 % S 22.59 %.

[0249] Experimentally found: C 28.91 %; H 1.60 %; N 9.54 %; S 21.87 %.

[0250] Preparation of Na+21Zn2+(MPS2~)2l2~

[0251] A 2.5 g amount of 3 -mercapto- 1-propansulfonate sodium salt was dissolved in 46 g of an aqueous solution containing 14 g of 1 M NaOH. To this solution, 2 g of ZnSO4 x 7 H2O, dissolved in 40 g of water, was added. Stirring was continued for 15 min and the solid product was precipitated by addition of an excess of acetone, filtered and dried at 50°C.

[0252] Elemental analysis was consistent with the stoichiometry of the zinc complex.

[0253] Calculated for Na2ZnC6Hi2O6S4 (MW 419.79): C 17.17 %; H 2.88 %; S 30.55 %. Experimentally found: C 16.89 %; H 3.02 %; S 28.75 %.

[0254] Preparation of Complex Salts of Compound of General Formula (I): Wm+)nrZn2+2l

[0255] All complex salts were prepared by mixing aqueous solutions containing dissolved the Na+2[Zn2+(MBS2')2]2' or Na+2[Zn2+(MPS2')2]2' complexes with aqueous solution containing stoichiometric amounts of octenidine (OCT) x 2 HCL, or chlorhexidine (CHL) Di-gluconate or benzalkonium (BZ) Cl or didecyldimethylammonium (DDA) Cl.

[0256] The precipitated neutral complex salts were collected by filtration, washed with water and dried at 50°C.

[0257] Energy -Dispersive X-ray Spectroscopy (EDS) analysis of the powders through Electronic Microscopy confirm, inside a maximum error of 15%, the presence of Zinc ions in the amount foreseen for:

[0258] EDS spectrum of (OCT)[Zn2+(MBS2)2] can be found in figure 1 (Calculated Zn, 6.9%, Experimentally found Zn, 6.5%)

[0259] EDS spectrum of (CHL)[Zn2+(MBS2)2] can be found in figure 2 (Calculated Zn: 5.8%, Experimentally found Zn: 5.2%).

[0260] EDS spectrum of (BZ)2[Zn2+(MBS2')2] can be found in figure 3 (Calculated Zn: 5%, Experimentally found Zn: 4.2%).

[0261] Example 2: antimicrobial gel compositions

[0262] Example 2.1 : an antimicrobial gel compositions is provided with the following composition:

[0263] The gel contains moisturizing and antimicrobial components, useful for gynaecological applications and is obtained by mixing two gelled phases, called A and B. Gel A is obtained by mixing in water the following raw materials: sodium ascorbyl phosphate, betaine, sodium hyaluronate, noveon ® a-a-1 polycarbophil, glycerine, dimethicone, essence distilled water. The percentages of the different components are expressed as weight / weight relative to the final product, obtained by mixing the two phases A and B. The homogenization of the different components can be obtained in a time interval of 12-24 hours, depending by the mixing apparatus.

[0264] Gel B is obtained by mixing the following raw materials in water: Zinc digluconate, octenidine hydrochloride, hydroxypropylcellulose, polyvinylpyrrolidone, glycerine, distilled water. Mix for 8-12 hours and then add sodium-mono hydrogen phosphate or sodium phosphate and sodium para-toluene-sulfonate or saccharin sodium salt, distilled water up to 100%. Mix for additional 2 hours and add gel B to gel A. Mix the final product for 12 h until completely homogenized. It has been observed that by providing Gel formulation A and Gel formulation B, an insoluble salt composition according to the invention is formed within the resulting antimicrobial gel composition as a homogeneously dispersion.

[0265] Example 2.2: an antimicrobial gel composition is provided with the following compositions:

[0266] The gel contains moisturizing and antimicrobial components, useful for gynaecological applications and is obtained by mixing two gelled phases, called A and B.

[0267] Gel A is obtained by mixing in water the following raw materials: sodium ascorbyl phosphate, betaine, sodium hyaluronate, noveon ® a-a-1 polycarbophil, glycerine, dimethicone, essence, distilled water. The percentages of the different components are expressed as weight / weight relative to the final product, obtained by mixing the two phases A and B. The homogenization of the different components can be obtained in a time interval of 12-24 hours, depending by the mixing apparatus.

[0268] Gel B is obtained by mixing the following raw materials in water: Zinc digluconate, benzalkonium chloride, hydroxypropylcellulose, polyvinylpyrrolidone, glycerine, distilled water. Mix for 8-12 hours and then add sodium-mono hydrogen phosphate dodecahydrate or sodium phosphate dodecahydrate and sodium-para-toluen sulfonate or saccharin sodium salt, distilled water up to 100%. Mix for additional 2 hours and add gel B to gel A. Mix the final product for 12 h until completely homogenized. It has been observed that by providing Gel formulation A and Gel formulation B, an insoluble salt composition according to the invention is formed within the resulting antimicrobial gel composition as a homogeneously dispersion.

[0269] Example 2.3: an antimicrobial gel composition is provided with the following composition:

[0270] The gel for topical use contains antimicrobial moisturizing components and is obtained by mixing two gel phases A and B.

[0271] Gel A is prepared by mixing in distilled water solution chitosan; with gluconic acid. Stirring is continued for 4-6 h until formation of a homogeneous gel. Gel B is prepared by mixing in distilled water, benzalkonium chloride, zinc gluconate, sodium-p-toluene sulfonate or saccharin, sodium-mono-hydrogen phosphate dodecahydrate or sodium phosphate dodecahydrate, natrosol and sodium hyaluronate, water up to 100%.

[0272] Mix for additional 2 hours and add gel B to gel A. Mix the final product for 12 h until completely homogenized. It has been observed that by providing Gel formulation A and Gel formulation B, an insoluble salt composition according to the invention is formed within the resulting antimicrobial gel composition as a homogeneously dispersion.

[0273] Example 2.4: an antimicrobial gel compositions is provided with the following compositions:

[0274] The gel for topical use contains antimicrobial moisturizing components and is obtained by mixing two gel phases A and B.

[0275] Gel A is prepared by mixing in distilled water solution chitosan; with gluconic acid. Stirring is continued for 4-6 h until formation of a homogeneous gel.

[0276] Gel B is prepared by mixing in distilled water, octenidine hydro-chloride, Zinc gluconate, sodium-p-toluene sulfonate or saccharin, sodium-mono-hydrogen phosphate dodecahydrate or sodium phosphate dodecahydrate, natrosol and sodium hyaluronate, water up to 100%.

[0277] Mix for additional 2 hours and add gel B to gel A. Mix the final product for 12 h until completely homogenized. It has been observed that by providing Gel formulation A and Gel formulation B, an insoluble salt composition according to the invention is formed within the resulting antimicrobial gel composition as a homogeneously dispersion.

[0278] Example 3: antimicrobial silica powder compositions

[0279] Example 3.1 : an antimicrobial silica powder compositions is provided with the following composition:

[0280] Fumed silica, or more generally a silica having a particle diameter in the 0.2-1 micron range, are treated with an aqueous solution containing dissolved zinc di-gluconate and octenidine hydrochloride. After mixing and homogenizing for 30-60 min, sodium phosphate dodecahydrate and saccharin sodium salt dissolved in distilled water are added. Addition of the anion results in the precipitation over the silica particles of the corresponding zinc salt. Analogously addition of the saccharinate anion cause the precipitation of the organic cation. The mixture is kept under stirring for 30-60 min and filtered on the G3 filter. The solid is finally dried in an oven at 70 ° C for 16 -24 h. Example 3.2: an antimicrobial silica powder compositions is provided with the following composition:

[0281] Fumed silica, or more generally a silica having a particle diameter in the 0.2-1 micron range, are treated with an aqueous solution containing dissolved zinc di-gluconate and chi orhexi dine di gluconate. After mixing and homogenizing for 30-60 min, sodium phosphate dodecahydrate and saccharin sodium salt dissolved in distilled water are added. The mixture is kept under stirring for 30-60 min and filtered on the G3 filter. The solid is finally dried in an oven at 70 ° C for 16 -24 h.

[0282] Example 3.3: an antimicrobial silica powder compositions is provided with the following composition: range, preferably in 0.2-0.3 micron range, are treated with an aqueous solution containing benzalkonium chloride and zinc di-gluconate. After about 30-60 min of mixing, sodium phosphate and saccharin sodium salt are added in sequence. After mixing for about 60 min, the mixture is filtered and the solid is dried in an oven at 50 ° C for 24 h.

[0283] Example 4: Antimicrobial tests

[0284] Example 4,1 : test of antimicrobial activity of active powders

[0285] With the aim of evaluating the relative effectiveness of the powders functionalized with the described actives, comparative tests of antimicrobial activity were performed on 10 g samples of silica powders coated with saccharinate salts of the active organic compounds and with zinc phosphate. Equimolecular amounts (2.7 x 10'4Mol) of the saccharinate salts of BZ or CHL or OCT and of Zns(PO4)2 (2.7 x 10'4Mol) were loaded on different 10 g silica samples according to the procedure of example 3.1-3.3. In these tests, the equimolar amounts of the different species correspond to the following cationic weight percentages: BZ = 0.9%, CHL = 1.3%; OCT = 1.5%, Zn = 0.18% which approximately represent those present in the spray formulations where the actives are mixed with excipients such as zeolites or kaolin and with the propellant.

[0286] The antimicrobial activity exhibited by the powders, was tested against the following strains of microorganisms (purchased from Diagnostic International Distribution S.p.A.): Pseudomonas aeruginosa ATCC 15442, Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 10536, Enterococcus hire ATCC 10541, Candida albicans ATCC 10231. Mixtures of the different microorganisms were prepared, having concentrations expressed in colony forming units (CFU) ranging from 1.5 x 109- 5.5 x 109for each species. 100 pl of the mixtures were seeded in Petri dishes containing TSA solid culture medium (Tryptone Soya Agar). Sowing was carried out according to a known and standardized analytical method, that is, by depositing the liquid sample on the surface of the agar using a micro pipette and distributing the liquid sample on the surface of the agar using sterile glass balls. Subsequently, samples of the different silica powders were placed in a central area of the agar of each of the Petri dishes. The Petri dishes were then incubated at 37 ° C for 24 h. In all tests the microorganisms were identified with ChromaticTM Detection © (Liofilchem®). After incubation, the capsules were examined to assess microbial proliferation (colony formation) and the width of the halo of inhibition (i.e., the width of the portion of medium in which microbial proliferation was inhibited), surrounding the agar zone on which the various gels were deposited. Analogous tests were performed on solid samples of the pure complex salts of general formula (Wm+)n[Zn2+(L2‘ h] where L is the MBS or MPS ligand synthesized according to example 1. The width of the inhibition halo observed are reported in Table 1.

[0287] Table 1. Comparison of antimicrobial activity of the active powders. It can be noted that powders based on Benzalkonium and Chlorhexidine with Saccharine as counter-anion show superior antimicrobial activity with respect to analogous sample containing Octenidine. The trend is confirmed also for (Wm+)n[Zn2+(L2')2] pure complex salts showing a much higher antimicrobial activity when W is CHL or BZ.

[0288] Example 4.2: Antimicrobial activity test on gel formulations

[0289] The antimicrobial activity, of the above described gel formulations (example 2.1-2.4), containing phosphate and saccharin sodium salts as precipitating counter anions was tested against the following strains of microorganisms (purchased from Diagnostic International Distribution S.p.A.): Pseudomonas aeruginosa ATCC 15442, Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 10536, Enterococcus hirae ATCC 10541, Candida albicans ATCC 10231. Mixtures of the different microorganisms were prepared, having concentrations expressed in colony forming units (CFU) ranging from 1.5 x 1010- 5.5 x 1010for each species. 100 pl of the mixtures were seeded in Petri dishes containing TSA solid culture medium (Tryptone Soya Agar). Sowing was carried out according to a known and standardized analytical method, that is, by depositing the liquid sample on the surface of the agar using a micro pipette and distributing the liquid sample on the surface of the agar using sterile glass balls. Subsequently, 100 pl of the various gels were deposited in a central area of the agar of each of the Petri dishes. The Petri dishes were then incubated at 37 ° C for 24 h. In all tests the microorganisms were identified with ChromaticTM Detection © (Liofilchem®). After incubation, the capsules were examined to assess microbial proliferation (colony formation) and the width of the halo of inhibition (i.e., the width of the portion of medium in which microbial proliferation was inhibited), surrounding the agar zone on which the various gels were deposited. As shown in Figure 4, while the control plate shows a confluent development of microbial colonies, in all other cases evident zones of inhibition surrounding the deposit zones of the different gels were observed. The analytical result obtained indicates that the gel formulations are able to inhibit the growth of 109CFUs of gram-positive bacteria, gramnegative bacteria and of the fungal species Candida albicans.

[0290] All formulations were observed to show a very high antimicrobial activity. As examples are reported those containing Zinc in association with Octenidine or Benzalkonium cations.

[0291] Example 4.3: Antimicrobial activity test on powder formulations

[0292] The tests were carried out on the silica powders functionalized with Zinc - Octenidine (example 3.1) and Zinc-Benzalkonium (example 3.3). In these tests, the active powders were diluted at 1.5% in the same type of amorphous silica. The solid samples were mixed and homogenized for 30 min in a powder milling machine The tests were conducted in the presence of a microbial pool consisting of: Staphilococcus aureus (ATCC 6538), Enterococcus hirae (ATCC 10541), Pseudomonas aeruginosa (ATCC 15442), Escherichia coli (ATCC 10536) and Candida albicans (ATCC 10231), Diagnostic International Distribution S.p.A, with concentrations ranging from 1-5 x 1010cfu / ml. Samples of the diluted active powders powderswere randomly distributed on the plates which were then incubated at 37 ° C for 24 h. In all tests the microorganisms were identified with ChromaticTM Detection © (Liofilchem®)

[0293] In Figure 5, the inhibition rings surrounding the crystals demonstrate the activity of the powders in eliminating from 109-5 x 109microbial species Gram positive, Gram negative and Candida albicans.

[0294] Example 4.4: Antimicrobial activity test on patients

[0295] Tests have been performed on the gel formulations of examples 2.1, 2.3 and 2.4, containing phosphate and saccharin sodium salts as precipitating counter anions, as well as on spray powders prepared as described in example 3.3, using propane-buthane as propellant. Both gel formulation and spray powders, based on the coupling of Zinc and Octenidine or Zinc and Benzalkonium ions, were applied on wounds. In all cases, the indications for use are the dressing of both acute and chronic skin wounds.

[0296] The gel formulation is best suited for the treatment of excavated lesions; the spray formulation is suitable for the treatment of flat lesions as well as for lesions present in sites difficult to be reached.

[0297] The clinical objectives to be achieved with the use of these products are the following: creating a physical barrier and thus preventing contamination of the wound; destroying any microorganisms present at the bottom of the lesion; maintaining a properly hydrated environment at the bottom of the wound to promote a physiological healing process; contrast any inflammatory processes; pain reduction; obtainment of wound healing with as little scar as possible.

[0298] The products have been applied with the following protocol:

[0299] Cleanse with saline the bottom of the wound, acute or chronic, possibly removing non- vital tissues; Completely dry the bottom of the ulcer with sterile gauze;

[0300] In cases of bleeding, wait for the haemostasis to occur

[0301] Apply the product on the bottom of the ulcer and on the surrounding skin for about 2 or more cm beyond the edge of the ulcer;

[0302] Cover the lesion with greasy gauze or sterile gauze.

[0303] Swaddle and / or bandage as needed.

[0304] At the next dressing, after having tom apart and removed the gauze, wash thoroughly with sterile physiological solution and then dry thoroughly. The products can then be reapplied as above described.

[0305] These operations should be repeated at time intervals depending by the extent of the exudate until the ulcer has healed.

[0306] Clinical results

[0307] The compositions according to the invention were tested on over 60 volunteer patients, applying the above mentioned protocol. In all treated patients, the treatments were associated with pain relief and were effective in the dressing of both acute and chronic skin wounds without any observation of systemic, local or perilesional skin complications and / or side effects. Formulations based on the different associations zinc-octenidine or Zinc Benzalkonium showed analogous activity.

[0308] In all treated patients, the skin wound evolved towards the progressive re-epithelialization of the lesion. No (re)appearance of bacterial infection of the wound base was observed in any patient.

[0309] The application of the compositions, according to the invention, produced in all cases a complete restoration of the tissues in the lesions, favoring their healing.

[0310] The protocol described above can be applied to all patients affected by chronic wounds and is also optimal for home treatment by the patient himself or his family.

[0311] Examples of effectiveness of the treatments are reported in Figures 6 and 7.

[0312] Example 5: Preparation of Test Formulations

[0313] 5.1 : A dry benzalkonium saccharin antimicrobial silica

[0314] 20 g of fumed silica (with particle diameters of 0.2-0.3 microns) were treated with a solution containing 16 g (0.021 moles) of Benzalkonium Chloride (BzCl) at 50% (MW 365 g) in 250 g of distilled water. After mixing and homogenization for 20 minutes, a solution consisting of 4.5 g of Sodium Saccharin (MW = 205.2 g; 0.022 moles) in 70 g of water was added. Following another mixing and homogenization for 20 minutes, an aqueous solution containing 14 g of hydrated Zinc Gluconate in 160 g of distilled water (MW 473.7 g, 0.03 moles) was added. After mixing and homogenizing for another 20 minutes, 7.6 g of NasPCE I2H2O (MW 380.12 g, 0.02 moles) dissolved in 70 g of water was added. The mixture is maintained for an additional 20 minutes, and the solid is then filtered using a G3 filter and washed with 300 g of distilled water. Finally, the solid is dried at 70 °C.

[0315] Final Weight: 35 g

[0316] Composition: Zns(PO4)2, 11% (Zn2+, 5.5%); Bz Saccharin 33%; SiCE, 56%.

[0317] Example 5.2: A spray composition in spray can / aerosol can

[0318] 2.3 g of active silica + 0.2 g of Sodium Hyaluronate + 7.5 g of Zeolite in a 125 g can containing n-Butane as the propellant.

[0319] The 125 g can contains 2.3 g of active silica, which includes the following quantities: 0.25 g of Zns(PO4)2 (Zn2+, 0.13 g) and BZ Saccharin, 0.74 g.

[0320] Example 5.3: A hydrated benzalkonium saccharin antimicrobial silica powder composition 20 g of fumed silica (with particle diameters of 0.2-0.3 microns) were treated with a solution containing 16 g (0.021 moles) of Benzalkonium Chloride at 50% (MW 365 g) in 250 g of distilled water. After mixing and homogenization for 20 minutes, a solution consisting of 4.5 g of Sodium Saccharin (MW = 205.2 g; 0.022 moles) in 70 g of water was added. Following another mixing and homogenization for 20 minutes, an aqueous solution containing 14 g of hydrated Zinc Gluconate in 160 g of distilled water (MW 473.7 g, 0.03 moles) was added. After mixing and homogenizing for another 20 minutes, 7.6 g of NasPCE I2H2O (MW 380.12 g, 0.02 moles) dissolved in 70 g of water was added. The mixture was maintained for an additional 20 minutes, and the solid was then filtered using a G3 filter and washed with 300 g of distilled water.

[0321] The weight of the hydrated solid is 235 g.

[0322] Composition: Benzalkonium Saccharin, 4.9%; Zm PCE 1.6% ; SiCE, 8.5%; H2O, 85%.

[0323] To 411 g of water, 50 g of the hydrated benzalkonium saccharin antimicrobial silica powder composition, 15 g of Glycerin, 12.5 g of Betaine, and 5 g of Dimethicone were added. The solid suspension was subjected to turbo-emulsification for a few minutes until a homogeneous dispersion of the silica particles was achieved. Finally, 6.5 g of high molecular weight Sodium Hyaluronate (in the range of 1,500,000-2,000,000 g) was added, and agitation was maintained for approximately 6-8 hours until complete swelling of the Sodium Hyaluronate is reached. Composition: BZ Saccharin 0.49%; Zns(PO4)2 0.16%; SiCE 0.85%; Sodium Hyaluronate 1.3%; Glycerine 3%; Betaine 2.5%; Dimethicone 1%; Water up to 100%.

[0324] Further, by adding a 30% tartaric acid solution to the above gel in a ratio of 1 : 10-15, an extremely viscous adhesive gel can be obtained, with a pH in the range of 4 - 5.5.

[0325] Example 5.5: Antimicrobial HPMC gel composition- 1

[0326] To 486 g of water, 60 g of the hydrated benzalkonium saccharin antimicrobial silica powder composition, 18 g of Glycerin, 15 g of Betaine, and 6 g of Dimethicone were added. The solid suspension was subjected to turbo-emulsification until a homogeneous dispersion of the silica particles was achieved. Then, 15 g of Hydroxypropyl Methylcellulose (HPMC) was added, and the suspension was maintained under agitation for approximately 6-8 hours until complete swelling of the HPMC was reached.

[0327] Composition: BZ Saccharin 0.49%; Z PCE)? 0.16%; SiCE 0.85%; HPMC 2.5%; Glycerine 3%; Betaine 2.5%; Dimethicone 1%; Water up to 100%.

[0328] Example 5.6: Antimicrobial HPMC gel composition-2

[0329] To 501 g of water, 60 g of hydrated benzalkonium saccharin antimicrobial silica powder composition, 18 g di Xilitol and 6 g of Mint were added. The solid suspension was subjected to turbo-emulsification for a few minutes until a homogeneous dispersion of the silica particles was achieved. Then, 15 g of Hydroxypropyl Methylcellulose (HPMC) was added, and the suspension was maintained under agitation for approximately 6-8 hours until complete swelling of the HPMC was reached.

[0330] Composition: Benzalkonium Saccharin, 0. 49%; Z PCE)?, 0. 16%; SiO2 0. 85%; HPMC, 2.5%. Xilitol 3%; Mint 1%; Water up to 100 %.

[0331] Example 5.7: Antimicrobial hyaluronate gel composition

[0332] To 420.5 g of water, add 25 g of hydrated benzalkonium saccharin antimicrobial silica powder composition, 15 g of Glycerin, 20 g of Betaine, 10 g of Dimethicone, and 2.5 g of Essence. The suspension was subjected to turbo emulsification until complete homogenization was achieved, which can be verified by the uniform dispersion of the silica particles. Finally, add 6 g of oralgrade high molecular weight hyaluronic acid, and maintain mixing for about 6 hours until complete homogenization. Composition: Benzalkonium Saccharin 0.25%; Zns(PO4)2, 0.08%; Sodium Hyaluronate 1.2%;

[0333] Glycerine 3%; Betaine 4%; Dimethicone 2%; Essence 0.5%. Water up to 100 %.

[0334] Example 5.8: Antimicrobial chitosan gel composition

[0335] To 190 g of water, 25 g of the hydrated benzalkonium saccharin antimicrobial silica powder containing silica functionalized with Zinc Phosphate and benzalkonium saccharin, 8 g of Glycerin, 8.5 g of Betaine, 2.5 Allantoin, 3.5 g of Dimethicone, and 2.5 g of low molecular weight (LMW) Chitosan were added. The suspension was subjected to turbo emulsion until complete homogenization, and 10 g of HPC were added with stirring which was maintained for 6 hours until complete swelling.

[0336] Composition: Benzalkonium Saccharin, 0. 49%; Zns(PO4)2, 0. 16% (Zn2+, 0.08%); SiCh 0. 85%; HPC 4 %; LMW Chitosan 1%; Glycerin 3%, Betaina, 3.4%, Allantoina 1%; Dimeticone, 1.4% ; water up to 100.

[0337] Example 5.9: Antimicrobial carboxymethyl chitosan gel composition

[0338] To 362.5 g of distilled water, 50 g of the hydrated benzalkonium saccharin antimicrobial silica powder containing silica functionalized with zinc phosphate and benzalkonium saccharinate, 25 g of Glycerin, 15 g of Betaine, 25 g of Dimethicone, 5 g of Allantoin and 5 g of Carboxymethyl Chitosan, CMC, were added. The suspension was subjected to turbo emulsification until complete homogenization, verified by the homogeneous dispersion of the particles. Finally, 12.5 g of hydroxy-propyl cellulose, HPC, were added and stirring was maintained for 6 h until complete swelling.

[0339] Composition: Benzalkonium Saccharin, 0.49%; Zn3(PO4)2, 0. 16% (Zn2+, 0.08%); SiO2 0. 85%; HPC 2.5 %; CMCHT 1 %; Glycerine 5%, Betaine, 3%, Dimeticone, 5% ; Allantoin 1%, water up to 100.

[0340] Example 5.10: A hydrated chlorhexidine saccharinate antimicrobial silica powder composition 20 g of fumed silica was treated with 300 ml of an aqueous solution containing 50 ml of 20% Chlorhexidine Digluconate (CHL Glu MW = 898 g) (0.011 moles). After mixing and homogenizing for 20 minutes, a solution consisting of 4.6 g of Sodium Saccharinate (MW = 205.2 g; 0.022 moles) in 100 g of water was added. After mixing and homogenizing for another 20 minutes, an aqueous solution containing 186 g of distilled water + 14 g of hydrated Zinc gluconate (MW 473.7 g, 0.03 moles) was added. After homogenization for 20 minutes, 7.6 g of Na3PO4 dodecahydrate (MW 380.12 g, 0.02 moles) dissolved in 100 g of water was added. The mixture was then stirred for another 20 minutes and filtered through G3. The solid was filtered and washed with approximately 300 g of water.

[0341] The final weight of the hydrated solid is 219 g.

[0342] Composition: Chlorhexidine bis-Saccharinate, 4.3%; Zn3(PO4)2, 1.7%; SiO2 9.1%; water 84.9%.

[0343] Example 5.11 : chlorhexidine saccharinate antimicrobial gel composition

[0344] To 433 g of water, add 25 g of the hydrated chlorhexidine saccharinate antimicrobial silica powder composition, 15 g of glycerin, 12.5 g of betaine, and 5 g of dimethicone. The suspension was subjected to turbo emulsification until complete homogenization was achieved, which can be verified by the uniform dispersion of the silica particles. Finally, add 6.5 g of high molecular weight sodium hyaluronate and 3 g of HPMC, and maintain agitation for about 6 hours until complete swelling of the sodium hyaluronate and HPMC.

[0345] Composition: Chlorhexidine bis-Saccharinate, 0.21%; Zn3(PO4)2 0.085%; SiO2 0.45%; Sodium Hyaluronate 1.3%; Glycerin 3%; Betaine 2.5%; Dimethicone 1%; Water up to 100%.

[0346] 5.12: chlorhexidine saccharinate antimicrobial carboxymethyl chitosan gel

[0347] To 209 g of water, 12.5 g of the hydrated chlorhexidine saccharinate antimicrobial silica powder containing silica functionalized with Zinc phosphate and Chlorhexidine bis- Saccharinate, 7.5 g of Glycerin, 7.5 g of Betaine, 2.5 g of Dimethicone, 3.75 g of Carboxymethylchitosan and 2.5 g of Allantoin were added. The suspension was subjected to turbo emulsion until complete homogenization of the silica particles. Finally, 4.75 g of HPC were added and stirring is maintained for ca 6 hours until completely swelling of HPC.

[0348] Composition: Hydrated Chlorazion Silica 5%, Chl(Sacc)2, 0. 21%; Zn3(PO4)2, 0. 085% (Zn2+, 0.042%); SiO20. 45 %CMCHT 1.5%; HPC 1.9%; Glycerine 3%, Betain, 3%, Dimeticone, 1%; Allantoin 1%; water up to 100.

[0349] Example 6: Antimicrobial tests

[0350] Example 6.1 : Antimicrobial activity test on dry powder formulations

[0351] The tests were carried out on the Silica powders functionalized with Zinc-Benzalkonium (Test formulation according to Examples 5.1, 5.2 and 5.3). The tests were conducted in the presence of a microbial pool consisting of: Staphilococcus aureus (ATCC 6538), Enterococcus hirae (ATCC 10541), Pseudomonas aeruginosa (ATCC 15442), Escherichia coli (ATCC 10536) and Candida albicans (ATCC 10231), Diagnostic International Distribution S.p.A, with concentrations ranging from 1-5 x IO10cfu / ml. 100 pl of the mixtures were seeded in Petri dishes containing TSA solid culture medium (Tryptone Soya Agar). Sowing was carried out according to a known and standardized analytical method, that is, by depositing the liquid sample on the surface of the agar using a micro pipette and distributing the liquid sample on the surface of the agar using sterile glass balls. In these tests, the solid product was sprayed on a Petri dish for 2 seconds. The Petri dishes were then incubated at 37 ° C for 24 h. In the tests the microorganisms were identified with ChromaticTM Detection © (Liofilchem®). After incubation, the capsules were examined to assess microbial proliferation(colony formation) and the width of the halo of inhibition (i.e., the width of the portion of medium in which microbial proliferation was inhibited) surrounding the agar zone on which the various gels were deposited. The total absence of bacteria in the test dish demonstrate the activity of the powders in eliminating 109microbial species.

[0352] Examples of effectiveness of the treatment with example 5.2 are reported in Figures 8 A and 8B.

[0353] Example 6.2: Antimicrobial activity test on gel formulations

[0354] The antimicrobial activity, of the above described gel formulations containing phosphate and saccharin sodium salts as precipitating counter anions was tested against the following strains of microorganisms (purchased from Diagnostic International Distribution S.p.A.): Pseudomonas aeruginosa ATCC 15442, Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 10536, Enterococcus hirae ATCC 10541, Candida albicans ATCC 10231. Mixtures of the different microorganisms were prepared, having concentrations expressed in colony forming units (CFU) ranging from 1 x 1010- 5 x 1010for each species. 100 pl of the mixtures were seeded in Petri dishes containing TSA solid culture medium (Tryptone Soya Agar). Sowing was carried out according to a known and standardized analytical method, that is, by depositing the liquid sample on the surface of the agar using a micro pipette and distributing the liquid sample on the surface of the agar using sterile glass balls. Subsequently, 100 pl of the various gels were deposited in a central area of the agar of each of the Petri dishes. The Petri dishes were then incubated at 37 ° C for 24 h. In all tests the microorganisms were identified with ChromaticTM Detection © (Liofilchem®). After incubation, the capsules were examined to assess microbial proliferation (colony formation) and the width of the halo of inhibition (i.e., the width of the portion of medium in which microbial proliferation was inhibited) surrounding the agar zone on which the various gels were deposited. As shown in the imagines which follows, evident zones of inhibition surrounding the deposit zones of the different gels were observed. The analytical result obtained indicates that the gel formulations are able to inhibit the growth of 109CFUs of gram -positive bacteria, gram negative bacteria and of the fungal species Candida albicans. Examples of effectiveness of the treatment with example 5.4 is reported in Figure 9;

[0355] Examples of effectiveness of the treatment with example 5.5 is reported in Figure 10;

[0356] Examples of effectiveness of the treatment with example 5.6 is reported in Figure 11;

[0357] Examples of effectiveness of the treatment with example 5.7 is reported in Figure 12;

[0358] Examples of effectiveness of the treatment with example 5.8 is reported in Figure 13; Examples of effectiveness of the treatment with example 5.9 is reported in Figure 14;

[0359] Examples of effectiveness of the treatment with example 5.11 is reported in Figure 15;

[0360] Examples of effectiveness of the treatment with example 5.12 is reported in Figure 16.

Claims

CLAIMS1. An antimicrobial composition comprising:(i) a solid salt composition comprising a zinc cation, a cation of a cationic surface-active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent; wherein- the cation of a cationic surface active agent is selected from the group consisting of biguanide and quaternary ammonium cationic surface active agent and mixtures thereof, preferably selected from the group consisting of polybiguanide and quaternary ammonium cationic surface active agent and mixtures thereof, more preferably selected from the group consisting of benzalkonium, didecyldimethylammonium, octenidine and chlorhexidine, and mixtures thereof, most preferably selected from the group consisting of chlorhexidine, benzalkonium, octenidine, and mixtures thereof;- the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof;- the second anion moiety is selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof; or wherein- the first and second anion moieties are part of a bridging ligand, which has the following general structure:wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3-mercapto-l- propansulfonate, and mixtures thereof; and(ii) preferably one or more components selected from the group consisting of water, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, polyvinylpyrrolidone, glycerin, a hyaluronate, dimethicone, silicapowder (silicon dioxide, silicon dioxide amorphous), soluble starch, carboxymethyl chitosan and chitosan, preferably low molecular weight chitosan.

2. The antimicrobial composition according to claim 1, wherein the composition is selected from a gel, a cream, a powder and a spray, preferably selected from a gel and a spray.

3. The antimicrobial composition according to claim 1 or 2, wherein the solid salt composition is homogenously dispersed within the antimicrobial composition.

4. The antimicrobial composition according to claim 1 or 2, wherein preferably the antimicrobial composition comprises one or more components selected from the group consisting of water, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, polyvinylpyrrolidone, glycerin, a hyaluronate, dimethicone, silica powder (silicon dioxide, silicon dioxide amorphous), soluble starch, carboxymethyl chitosan and chitosan, preferably low molecular weight chitosan, and wherein the solid salt composition is homogenously dispersed within said one or more components of the antimicrobial composition.

5. An antimicrobial powder composition comprising:(i) a salt composition comprising a zinc cation, a cation of a cationic surface-active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent; wherein- the cation of a cationic surface active agent is selected from the group consisting of benzalkonium, octenidine, chlorhexidine and mixtures thereof;- the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof;- the second anion moiety is selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof; or wherein- the first and second anion moieties are part of a bridging ligand, which has the following general structure:wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1- propansulfonate, and mixtures thereof; and(ii) silica powder, such as silicon dioxide or silicon dioxide amorphous, wherein the salt composition (i) is adsorbed to the surface of the silica powder.

6. A functionalized antimicrobial powder comprising:(i) a salt composition comprising a zinc cation, a cation of a cationic surface -active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent; wherein- the cation of a cationic surface active agent is selected from the group consisting of benzalkonium, octenidine, chlorhexidine and mixtures thereof;- the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof;- the second anion moiety is selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof; or wherein- the first and second anion moieties are part of a bridging ligand, which has the following general structure:wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1- propansulfonate, and mixtures thereof;and(ii) silica powder, such as silicon dioxide or silicon dioxide amorphous, wherein the salt composition (i) is adsorbed to the surface of the silica powder.

7. The antimicrobial powder composition according to claim 5 or the functionalized antimicrobial powder according to claim 6, wherein the silica is having a particle diameter in the 0.2-1 micron range, preferably in the 0.2-0.3 micron range.

8. The antimicrobial powder composition according to claim 5 or the functionalized antimicrobial powder according to claim 6, is dried powder or hydrated powder, preferably hydrated powder.

9. The antimicrobial powder composition according to claim 5 or the functionalized antimicrobial powder according to claim 6, for use in the preparation of an antimicrobial composition according to any one of the claims 1-4.

10. An antimicrobial gel composition comprising:(i) a solid salt composition comprising a zinc cation, a cation of a cationic surface-active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent; wherein- the cation of a cationic surface active agent is selected from the group consisting of benzalkonium, octenidine, and mixtures thereof;- the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof;- the second anion moiety is selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof; or wherein- the first and second anion moieties are part of a bridging ligand, which has the following general structure:wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3-mercapto-l- propansulfonate, and mixtures thereof; and(ii) one or more components selected from the group consisting of water, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, polyvinylpyrrolidone, glycerin, a hyaluronate, dimethicone, silica powder (silicon dioxide, silicon dioxide amorphous), soluble starch, carboxymethyl chitosan and chitosan, preferably low molecular weight chitosan.

11. The antimicrobial composition according to any one of claims 1-4 or the antimicrobial powder composition according to claim 5 or the functionalized antimicrobial powder according to claim 6 or the antimicrobial gel composition according to claim 10, wherein a source of the zinc cation is provided as a zinc salt, preferably the zinc salt is selected from the group containing zinc digluconate, zinc sulphate, zinc chloride, zinc acetate, zinc citrate, and mixtures thereof, more preferably the zinc salt is zinc digluconate.

12. The antimicrobial composition according to any one of claims 1-4 or the antimicrobial powder composition according to claim 5 or the functionalized antimicrobial powder according to claim 6 or the antimicrobial gel composition according to claim 10, wherein a source of the cation of a cationic surface-active agent is provided as salt of a cationic surface-active agent, preferably the salt of a cationic surface-active agent is selected from the group containing octenidine hydrochloride, octenidine dihydrochloride, chlorhexidine digluconate, chlorhexidine chlorhexidine acetate, chlorhexidine chloride, benzalkonium chloride, and mixtures thereof.

13. The antimicrobial composition according to any one of claims 1-4 or the antimicrobial powder composition according to claim 5 or the functionalized antimicrobial powder according to claim 6 or the antimicrobial gel composition according to claim 10, wherein a source of the first anion moiety is provided as a phosphate salt, preferably the phosphate salt is selected from the group containing sodium mono-hydrogen phosphate dodecahydratye or sodium phosphate dodecahydratye.

14. The antimicrobial composition according to any one of claims 1-4 or the antimicrobial powder composition according to claim 5 or the functionalized antimicrobial powder according to claim 6 or the antimicrobial gel composition according to claim 10, wherein a source of the second anion moiety is provided as a sulfonate or sulfonamide salt, preferably the sulfonate or sulfonamide salt is selected from the group containing sodium para-toluene sulfonate and saccharin sodium salt.

15. The antimicrobial composition according to any one of claims 1-4 or the antimicrobial powder composition according to claim 5 or the functionalized antimicrobial powder according to claim 6 or the antimicrobial gel composition according to claim 10, wherein the solid salt composition is a salt mixture comprising a first salt containing the zinc cation and the first anion moiety, preferably inorganic phosphate, and a second salt containing the cation of a cationic surface-active agent and the second anion moiety, preferably saccharinate.

16. The antimicrobial composition according to any one of claims 1-4 or the antimicrobial powder composition according to claim 5 or the functionalized antimicrobial powder according to claim 6 or the antimicrobial gel composition according to claim 10, is / are suitable for oral application or topical application, preferably the topical application is selected from: powder spray or cream / gel application.

17. Coating on medical devices comprising the antimicrobial composition according to any one of claims 1-4 or the antimicrobial powder composition according to claim 5 or the functionalized antimicrobial powder according to claim 6 or the antimicrobial gel composition according to claim 10.

18. An antimicrobial composition according to any one of claims 1-4 or an antimicrobial powder composition according to claim 5 or a functionalized antimicrobial powder according to claim 6 or an antimicrobial gel composition according to claim 10, for use as a medicament.

19. An antimicrobial composition according to any one of claims 1-4 or an antimicrobial powder composition according to claim 5 or a functionalized antimicrobial powderaccording to claim 6 or an antimicrobial gel composition according to claim 10, for use in the treatment of wounds and / or for treatment of inflammation.

20. An antimicrobial composition according to any one of claims 1-4 or an antimicrobial powder composition according to claim 5 or a functionalized antimicrobial powder according to claim 6 or an antimicrobial gel composition according to claim 10, for use in antimicrobial treatment, antiviral treatment or antifungal treatment, preferably antimicrobial treatment.

21. The antimicrobial composition or the antimicrobial powder composition or the functionalized antimicrobial powder or the antimicrobial gel composition for use according to any one of claims 18-20, wherein the treatment comprises topical application or gynaecological topical (vaginal) application, preferably for pain reduction, wound healing, and / or antiseptic treatment.

22. The antimicrobial composition or the antimicrobial powder composition or the functionalized antimicrobial powder or the antimicrobial gel composition for use according to any one of claims 18-21, wherein the wounds are chronic wounds, acute wounds, skin wounds, including bum wounds, and / or oral wounds.

23. A method for the preparation of an antimicrobial powder composition, the method comprising the following steps: a) treating an amorphous silica powder with an aqueous solution comprising a zinc cation and a cation of a cationic surface-active agent; the treating step preferably comprising mixing for at least 30 minutes; b) adding to the treated silica powder of step a):• at least one first anion moiety selected from the group consisting of phosphate and thiol ate, and• at least one second anion moiety selected from the group consisting of organosulfonate and sulfonamide, preferably selected from the group consisting of para-toluenesulfonate and 2,3-dihydro-3-oxobenzisosulfonazole, and mixtures thereof,or adding at least one bridging ligand comprising a first and second anion moiety, which has the following general structure:Wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5 -benzimidazole sulfonate and 3 -mercapto- 1-propansulfonate, and mixtures thereof; and• optionally mixing for at least 30 minutes; c) filtering the mixture of step b) to form a solid phase comprising the treated silica powder; d) optionally drying the solid phase obtained by step c), preferably at a temperature of at least 40°C for at least 16 hrs.

24. The method of claim 23, wherein in step b) the at least one first anion moiety is added to the treated silica powder, and thereafter the at least one second anion moiety is added to the treated silica powder.

25. Antimicrobial powder, preferably obtainable according to the method of any one of claims 23 - 24, comprising the following formulation: at least 60 wt.%, preferably 60 - 70 wt.% of the silica (SiCh); at least 3 wt.%, preferably 6-9 wt.% of the zinc cation, at least 3 wt.%, preferably 9-12wt.% of the cation of the cationic antimicrobial organic component; at least 3wt.%, preferably 6-10wt.% of the at least one second anion moiety; at least 3wt.%, preferably 6-9wt.% of the at least one first anion moiety.

26. A solid salt composition comprising a zinc cation, a cation of a cationic surface-active agent, a first anion moiety associated with the zinc cation and a second anion moiety associated with the cation of a cationic surface-active agent,wherein:- the first anion moiety is selected from the group consisting of inorganic phosphate and thiolate, and mixtures thereof,- the second anion moiety is selected from the group consisting of organosulfonate and sulfonamide, and mixtures thereof, and- wherein the cationic surface active agent is selected from the group consisting of biguanide and quaternary ammonium cationic surface active agent and mixtures thereof, preferably selected from the group consisting of polybiguanide and quaternary ammonium cationic surface active agent and mixtures thereof, more preferably selected from the group consisting of benzalkonium, didecyldimethylammonium, octenidine and chlorhexidine, and mixtures thereof, most preferably selected from the group consisting of chlorhexidine, benzalkonium, octenidine, and mixtures thereof; or wherein- the first and second anion moieties are part of a bridging ligand, which has the following general structure:wherein R1is an aryl and / or alkyl moiety, preferably the bridging ligand is selected from the group consisting of 2-mercapto-5-benzimidazole sulfonate and 3 -mercapto- 1- propansulfonate, and mixtures thereof.

27. A salt composition according to claim 26, wherein the second anion moiety is selected from the group consisting of organosulfonate according to general structure (b) and sulfonamide according to general structure (c)(b) (c) wherein R3is selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12 membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl and R4and R5are each independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12 membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl or R4and R5, taken together with the sulfur and nitrogen atoms to which they are attached, form a 4- to 12-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, wherein each R3, R4and R5is optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of halo, hydroxy, oxo, imino and C1-C4 alkyl, optionally substituted with one to three substituents at each occurrence independently selected from the group consisting of halo, hydroxy, oxo and imino, more preferably the second anion moiety is selected from the group consisting of para-toluenesulfonate, 2,3- dihydro-3-oxobenzisosulfonazole, and mixtures thereof.

28. A salt composition according to any of the previous claims, wherein the zinc cation together with the first anion moiety associated therewith and the cation of a cationic surface-active agent together with the second anion moiety associated therewith are insoluble under physiological conditions.

29. A compound having a structure represented by formula (I):(I) (Wm+)n[Zn2+(L2-)2] wherein:W is a cationic surface-active agent, wherein the cationic surface active agent is selected from the group consisting of biguanide and quaternary ammonium cationic surface active agent and mixtures thereof, preferably selected from the group consisting of polybiguanide and quaternary ammonium cationic surface active agent and mixtures thereof, more preferably selected from the group consisting of benzalkonium,didecyldimethylammonium, octenidine and chlorhexidine, and mixtures thereof, most preferably selected from the group consisting of chlorhexidine, benzalkonium, octenidine, and mixtures thereof; m+ is the positive charge of the cationic surface-active agent; when m is 2, n is 1 or when m is 1, n is 2; andL is a bridging ligand with the following general structurewherein R1is an aryl or alkyl moiety, preferably the bridging ligand comprising the first and second anion moiety is selected from the group consisting of 2-mercapto-5- benzimidazole sulfonate and 3 -mercapto- 1-propansulfonate, and mixtures thereof.

30. An antimicrobial composition comprising the salt according to any of the claims 26-28 or the compound according to claim 29, wherein the composition is a gel, a cream, or a powder.

31. Antimicrobial composition according to claim 30, further comprising one or more components selected from the group consisting of water, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, glycerine, a hyaluronate, dimethicone, silica powder, soluble starch, carboxymethyl chitosan and chitosan, preferably low molecular weight chitosan.

32. Alcoholic solution of the salt composition according to any one of claims 26-28 or a compound according to claim 29 or an antimicrobial composition according to any one of claims 30-31 .

33. Coating on medical devices comprising the salt composition according to any one of claims 26-28 or a compound according to claim 29 or an antimicrobial composition according to any one of the claims 30-31.

34. Salt composition according to any one of claims 26-28 or a compound according to claim 29 or an antimicrobial composition according to any one of the claims 30-31, for use in the treatment of wounds and / or for treatment of inflammation.

35. Salt composition according to any one of claims 26-28 or a compound according to claim 29 or an antimicrobial composition according to any one of the claims 30-31, for use in antimicrobial treatment, antiviral treatment or antifungal treatment, preferably antimicrobial treatment.

36. The use according to claim 34 or 35, wherein the treatment comprises topical use, oral use, pain reduction, wound healing, gynaecological topical (vaginal) treatments, and / or antiseptic treatment.

37. The use according to any one of claims 34-36, wherein the wounds are chronic wounds, acute wounds, skin wounds, including bum wounds, and / or oral wounds.

38. The use of the salt composition according to any one of claims 26-28 or a compound according to claim 29 or an antimicrobial composition according to any one of the claims 30-31, as antimicrobial agent.

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