SUBSTITUTED CYCLODEXTRIN-METAL COMPLEXES AND USES THEREOF

FIELD OF INVENTION

The present invention relates to complexes of substituted cyclodextrins with metals. The complexes of the present invention are of particular interest as they enhance the aqueous solubility of metals or metal-associated organic compounds. Compositions comprising the substituted cyclodextrin complexes according to the present invention open up new perspectives for the application of metal and metal-associated organic compounds whose use is restrained due to their limited concentration in aqueous media, particularly in the field of therapeutic applications.

BACKGROUND OF INVENTION

Inorganic medicinal chemistry is considered as a promising discipline for enriching the therapeutic armamentarium against a broad range of pathologies ever since the ancient civilizations of Mesopotamia, Egypt, India and China up to Elrich's first arsenic-based treatment against syphilis.

The field of inorganic medicinal chemistry in medicine may usefully be divided into two main categories. On the one hand, metal ions, oxides or salts thereof to be used as such and on the other hand, metal-based drugs and imaging agents where the central metal ion is one of the pharmacological key-features of the drug.

Nowadays, the specific interaction between metals and biomolecules render inorganic medicinal chemistry a promising field for the new drug discovery and the optimization of existing treatments. Current therapeutic strategies involve metal agents in the treatment of bacterial, parasitic and fungal infections, as well as in the treatment of cancer or even diabetes, to name but a few.

Nevertheless, the development of metals or metal-complexes as drugs is a challenging task, namely because of the poor solubility of the metallic therapeutic agents within the aqueous media, such as the biological systems.

As in many solubility enhancement approach strategies, vectorization of the metal-comprising-therapeutic agent seems a promising getaway solution to overcome solubility issues. Such strategies comprise the cyclodextrin vectorization of metallic agents or the use of biphasic formulations such as suspensions or emulsions.

International patent application WO2004071639 discloses biopolymer functionalized (3,6-anhydro)-cyclodextrins for the decontamination of the human body from metals, namely radioactive metals. However, this reference does not teach how to enhance the solubility of an inorganic agent to be administered to the human body, released therein and exerting its pharmacological effects. As generally accepted in the art, a non-reversible and voluminous vectorization hinders the metal agent from reaching its biological target.

Surprisingly, the present invention supplies reversible cyclodextrin-metal complexes that are biocompatible, non-toxic and therapeutically effective.

As previously discussed, current therapeutics use metal-based drugs in a broad spectrum of treatments. For example, silver sulfadiazine is a topical antibiotic used in partial thickness and full thickness burns to prevent infection. Silver sulfadiazine, initially discovered in the 1960s, is currently on the World Health Organization's List of Essential Medicines, considered among the most effective and safe medicines needed in a health system.

Biphasic pharmaceutical formulations cannot be a universal solution to a therapeutic agent's aqueous solubility problems. One the one hand, suspensions and emulsions are restrained to a limited number of administration routes, excluding for example intravenous administration or local application to sensitive tissues. On the other hand, the dispersion of the metallic agent in the non-continuous phase of the biphasic system reduces the bioavailability of the agent. Up to the present invention, the aqueous solubility of silver sulfadiazine was overcome by its formulation into lipid emulsions (such as polysorbate, cetyl alcohol or paraffine based creams) commercialized as Flamazine®, Flamazine® or Silvadene®. In the latter, silver sulfadiazine is dispersed, predominantly in the form of microparticles. However, such formulations not only limit the administration route options and the applicable administration concentration ranges, but also trigger adverse effects to the vulnerable burnt skin. In fact, silver sulfadiazine particles possess abrasive properties, and lipophilic excipients of silver sulfadiazine creams tend to accumulate on the affected skin, further causing irritation and possibly infections of the burn wounds if not thoroughly rinsed.

Advantageously, the cyclodextrin-metal complexes of the present invention can play a dual role, vectorizing at least one metal associated to an organic therapeutic agent. Thus, the Applicant has developed a functionalized-cyclodextrin vector that can solubilize both metal and metal-based drugs. Even more advantageously, the cyclodextrin-metal complexes of the present invention can be formulated into aqueous formulations such as skin, ocular or auricular solutions. Such complexes, give way to further therapeutic applications of metals associated to an organic therapeutic agent whose potential was limited due to their limited aqueous solubility.

Hegazy et al. discloses cyclodextrin-silver sulfadiazine complexes with the aim of enhancing the solubility of silver sulfadiazine. The latter complexes consist of natural beta cyclodextrin complexes, as well as functionalized beta cyclodextrins such as hydroxypropyl-beta-cyclodextrins and carboxymethyl-beta-cyclodextrins (Hegazy et al., 2013. Int J Pharm Pharm Sci. 5(1):461-468). However, the aforementioned complexes do not go beyond the intrinsic solubility of silver sulfadiazine. Furthermore, the simultaneous complexation of both silver and sulfadiazine at the molar ratio of 1:1 is not provided.

Surprisingly, the complexes of the present invention boost the aqueous solubility of silver sulfadiazine by a factor of more than 5×10⁴. Even more surprisingly, the Applicant has demonstrated that the complexes of the present invention maintain the initial ratio between the metal and the organic agent past the preparation of the cyclodextrin-metal-organic agent complexes. This advantageous property of the invention is of particular interest in terms of therapeutic efficacy and stability of the formulations comprising the complexes of the invention.

SUMMARY

The present invention relates to a complex of a metal selected from the group comprising Ag, Zn, Cu, Pt, Au, oxides, hydroxides and salts thereof; with a cyclodextrin of formula (I)

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- wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment,

- p is 7;
- R is —OH or —NH—Z—NHR₁;
- Z is —C═S;
- R₁is methyl;
- with the proviso that at least one cyclodextrin monomer has R=—NH—Z—NHR₁.

In one embodiment, the cyclodextrin of the complex is a beta-cyclodextrin bearing at least one substituent R: —NHC═SNHCH₃.

In one embodiment, the complex of the invention further comprises at least one organic therapeutic agent, said organic therapeutic agent being selected from antibiotic, anti-fungal, antiviral and antiparasitic agents; salts thereof and combinations thereof.

In one embodiment, the complex of the invention comprises:

- a metal being Ag, oxide, hydroxide or salts thereof, and
- an organic therapeutic agent being an antibiotic agent, preferably a sulfamide, even more preferably the organic therapeutic agent is sulfadiazine.

In one embodiment, the complex of the invention comprises:

- a metal being Ag;
- an organic therapeutic agent being a sulfamide, preferably sulfadiazine;
- a cyclodextrin of formula (I), wherein:
  - p is 7;
  - R is —OH or —NH—Z—NHR₁;
  - Z is —C═S; and R₁is methyl;
  - with the proviso that at least one beta-cyclodextrin monomer has R=—NH—Z—NHR₁; and
    
    wherein the molar ratio between the organic therapeutic agent and the metal is ranging from about 200 to about 1, preferably from about 20 to about 2, even more preferably from about 2 to 1.

The present invention also relates to a composition comprising the complex according to the present invention.

In one embodiment, the composition comprises:

- a metal being Ag;
- a cyclodextrin of formula (I), wherein:
  - p is 7;
  - R is —OH or —NH—Z—NHR₁;
  - Z is —C═S;
  - R₁is methyl;
  - with the proviso that at least one beta-cyclodextrin monomer has R=—NH—Z—NHR₁;
    
    wherein:
- when the complex comprises at least one organic therapeutic agent, said organic therapeutic agent is sulfadiazine; and
- the molar ratio between sulfadiazine and Ag is ranging from about 2 to about 1, preferably from about 1.5 to about 1; and
- the concentration of silver sulfadiazine in the composition is ranging from about 1.0 mg/L to about 40 g/L; preferably ranging from about 1.0 to about 20 g/L.

In one embodiment, the composition further comprises at least one active agent selected from antiseptics, antibiotics, anti-inflammatories, and soothing agents.

The present invention also relates to a pharmaceutical composition comprising the composition according to the present invention, and at least one pharmaceutically acceptable excipient.

In one embodiment, the pharmaceutical composition according to the present invention is in a pharmaceutical form selected from aqueous solutions, sprays, gels, hydrogels, liquid soap formulations, eye drops, ear drops and oil-in-water emulsions.

The present invention also relates to the complex, the composition or the pharmaceutical composition according to the present invention, for use as a drug.

In one embodiment, the complex, the composition or the pharmaceutical composition according to the present invention is/are for use in the prevention and/or the treatment of skin infections.

The present invention also relates to a device comprising the complex, the composition or the pharmaceutical composition according to the present invention; preferably the device is a wound dressing; even more preferably the device is a dermal patch.

The present invention also relates to a method for improving the aqueous solubility of a metal selected from the group comprising Ag, Zn, Cu, Pt, Au, Ru, As, Sb, Bi, Ti, V, Ni, Hg, Pb, Co, oxides, hydroxides and salts thereof;

- wherein the method comprises providing a reaction mixture comprising said metal, an aqueous medium and a cyclodextrin of formula (I):

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- wherein:
  - p is 5, 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁
  - X is a single bond or R₂;
  - Z is selected —C═O and —C═S;
  - R₁is selected from H or optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl and propyl; and
  - R₂is selected optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl and propyl;
  - with the proviso that at least one beta-cyclodextrin monomer has R: —X—NH—Z—NHR₁.

In one embodiment, the metal is Ag and the reaction mixture further comprises at least one organic therapeutic agent, wherein the organic therapeutic agent is selected from antibiotic, anti-fungal, antiviral and antiparasitic agents; salts thereof and combinations thereof; preferably the organic therapeutic agent is sulfamide, even more preferably the organic therapeutic agent is sulfadiazine.

Definitions

In the present invention, the following terms have the following meanings:

- “About” is used herein to mean approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.
- “Alkyl” refers to any saturated linear or branched hydrocarbon chain, with 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Short chain alkyl group refer to any saturated linear or branched hydrocarbon chain with 1 to 14 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.
- “Alkylamino” refers to any N-alkyl group. In embodiments of the invention, a substituted alkyl group is an alkylamino group, preferably a methylamino selected from the group comprising or consisting of methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, sec-butylamino, isobutylamino and tert-butylamino.
- “Alkyloxy” refers to any O-alkyl group. In embodiments of the invention, a substituted alkyl group is an alkylamino group, preferably a methylamino selected from the group comprising or consisting of methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, isobutyloxy and tert-butyloxy.
- “Aqueous medium” refers to a medium essentially comprising or consisting of water. An aqueous medium may further comprise sugars, lipids, mineral elements, biopolymers, cells and debris thereof. In one embodiment, the aqueous medium is an aqueous solution. In one embodiment, the aqueous medium is the continuous phase of an oil-in water emulsion. In one embodiment, the aqueous medium is situated in a biological tissue or fluid such as gastrointestinal fluids, blood, blood plasma or wound exudates. In one embodiment, the aqueous medium is situated on the wounded or burnt skin.
- “Complex” refers herein to a molecule binding to a metal ion and/or an organic therapeutic agent. Complexation (also termed vectorization) involves the formation or presence of one or more non-covalent bonds between the complexation agent (vector) with a metal ion and/or an organic therapeutic agent. In one embodiment, the vector is a cyclodextrin. In one embodiment, the complex is a metal-cyclodextrin complex. In one embodiment, the complex is a metal-organic therapeutic agent-cyclodextrin complex.
- “Cyclodextrin” refers to a compound made up of sugar molecules bound together in a ring. Cyclodextrins are composed of 6 or more α-D-glucopyranoside units linked by α-1→4 glucosidic bonds. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shaped polymer. Alpha-cyclodextrins (α-cyclodextrins) comprise 6 α-D-glucopyranoside units. Beta-cyclodextrins (β-cyclodextrins) comprise 7 α-D-glucopyranoside units and gamma-cyclodextrins (γ-cyclodextrins) comprise 8 α-D-glucopyranoside units. In one embodiment, the cyclodextrin according to the invention is a chemically modified cyclodextrin.
- “Intrinsic solubility” is the equilibrium solubility of the free acid or free base form of an ionizable compound at a pH where it is fully un-ionized.
- “Pharmaceutically acceptable excipient” refers to an excipient that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.
- “Subject” refers to an animal, including a human. In the sense of the present invention, a subject may be a patient, i.e., a person receiving medical attention, undergoing or having underwent a medical treatment, or monitored for the development of a disease. In one embodiment, the subject is a burnt-skin patient.
- “Therapeutic agent”, as used herein, describes a molecule or a substance, preferably a chemical entity such as a metal, an organic entity (“Organic therapeutic agent”) or a metal-organic therapeutic agent association, whose administration to a subject slows down or stops the progression, aggravation, or deterioration of one or more symptoms of a disease, or condition; alleviates the symptoms of a disease or condition; cures a disease or condition. In one embodiment, the therapeutic agent is a metal-cyclodextrin complex. In one embodiment, the therapeutic agent is a metal-organic therapeutic agent-cyclodextrin complex.
- “Therapeutically effective amount” refers to the amount of a therapeutic agent necessary and sufficient for slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of the disease, or condition; alleviating the symptoms of the disease or condition; and/or curing the disease or condition.
- “Topical administration” characterizes the delivery, administration or application of a composition directly to the site of interest (e.g., the skin) for a localized effect. Preferably, topical administration is carried out without any significant absorption of components of components of the composition into the subject's blood stream (to avoid a systemic effect).
- “Treatment”, “treating”, “treatment” or “alleviation” refer to both therapeutic treatment and prophylactic or preventative measures (“Prevention”; wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder). Subjects in need of treatment include those already diagnosed with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented. In one embodiment, the treatment according to the present invention refers to an infection treatment and/or prevention. In one embodiment, the treatment according to the present invention refers to a burnt-skin infection treatment and/or prevention. A subject is successfully “treated” for an infection or burnt skin if, after receiving a therapeutically effective amount of a complex, composition, pharmaceutical composition or medicament according to the invention, the subject shows observable and/or measurable reduction in or absence of one or more of the following: reduction in the number of pathogenic cells; reduction in the percent of total cells that are pathogenic; decrease average size of burnt surfaces; reduced redness and/or swelling; and/or relief to some extent, one or more of the symptoms associated with the specific disease or condition; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.

DETAILED DESCRIPTION

The present invention relates to a complex of a metal, oxides, hydroxides and salts thereof, with a substituted cyclodextrin.

The Applicant has developed cyclodextrin-metal complexes using substituted cyclodextrins capable of solubilizing metals, namely metals of therapeutic interest in aqueous media.

According to a first embodiment, the cyclodextrin is a cyclodextrin of formula (I)

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wherein:

- p is 6, 7 or 8;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond or R₂;
- R₂is selected from, short chain alkyls optionally substituted; preferably R₂is selected from methyl, ethyl, propyl and butyl;
- Z is selected from —C═O and —C═S;
- R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the cyclodextrins of the present invention can be α-cyclodextrins, β-cyclodextrins or γ-cyclodextrins. In such embodiment, p is 6, 7 or 8 respectively. In one particular embodiment, the cyclodextrin is a β-cyclodextrin, wherein p=7.

According to the prior art, natural cyclodextrins are not advantageous in the enhancement of the aqueous solubility of metals. Accordingly, the cyclodextrins of the present invention bear at least one R=—X—NH—Z—NHR₁.

According to a first embodiment, the cyclodextrin is a mono-substituted cyclodextrin bearing one R=—X—NH—Z—NHR₁.

According to a second embodiment, the cyclodextrin is a bi-substituted cyclodextrin bearing two R=—X—NH—Z—NHR₁.

According to a third embodiment, the cyclodextrin is a tri-substituted cyclodextrin bearing three R=—X—NH—Z—NHR₁.

In further embodiments, the cyclodextrin is a pluri-substituted cyclodextrin bearing at least four, five or six R=—X—NH—Z—NHR₁.

In one embodiment where β-cyclodextrins are used, the cyclodextrin of formula (I) bears at least one, two, three, four, five, six or seven R=—X—NH—Z—NHR₁.

In a particular embodiment, the cyclodextrin is a mono-substituted β-cyclodextrin bearing one R=—X—NH—Z—NHR₁. In another particular embodiment, the cyclodextrin is a bi-substituted 3-cyclodextrin bearing two R=—X—NH—Z—NHR₁.

In one embodiment, the cyclodextrin substituent R is a thiourea or urea derivative. Accordingly, in one embodiment, Z is from selected from —C═O and —C═S.

According to a first embodiment, Z is —C═O. According to a second embodiment, Z is —C═S.

In one embodiment, the substituent is directly linked to the cyclodextrin. Accordingly, in such embodiment, X represents a single bond.

In one embodiment, the cyclodextrin is a cyclodextrin of formula (I), wherein p=7, bearing at least one R=—X—NH—Z—NHR₁, wherein X represents a single bond, Z is —C═S, and R1 is methyl.

In one embodiment, the cyclodextrin is a mono-substituted cyclodextrin of formula (I), wherein p=7, bearing one R=—X—NH—Z—NHR₁, wherein X represents a single bond, Z is —C═S, and R1 is methyl.

In one embodiment, the cyclodextrin is a bis-substituted cyclodextrin of formula (I), wherein p=7, bearing two R=—X—NH—Z—NHR₁, wherein X represents a single bond, Z is —C═S, and R1 is methyl.

In one embodiment, the cyclodextrin is a tri-substituted cyclodextrin of formula (I), wherein p=7, bearing three R=—X—NH—Z—NHR₁, wherein X represents a single bond, Z is —C═S, and R1 is methyl.

Alternatively, the substituent can be bound to the cyclodextrin via a short alkyl chain R₂. According to such embodiment, the short alkyl chain R₂may optionally be substituted by heteroatoms, preferably selected from O, N and S. According to a first embodiment, R₂is a short alkyl chain selected from the group comprising or consisting of methyl, ethyl propyl and butyl. According to a second embodiment, R₂is a short alkyl chain selected from the group comprising or consisting of methyl, ethyl and propyl. According to a third embodiment, R₂is a short alkyl chain selected from the group comprising or consisting of methyl and ethyl. According to a fourth embodiment, R₂is a methyl group.

According to another embodiment, R₂is a substituted short alkyloxy chain selected from the group comprising or consisting of methyloxy, ethyloxy, propyloxy and butyloxy. According to a second embodiment, R₂is a short alkyloxy chain selected from the group comprising or consisting of methyloxy, ethyloxy and propyloxy. According to a third embodiment, R₂is a short alkyloxy chain selected from the group comprising or consisting of methyloxy and ethyloxy. According to a fourth embodiment, R₂is a methyloxy group.

According to another embodiment, R₂is a substituted short alkylamino chain selected from the group comprising or consisting of methylamino, ethylamino, propylamino and butylamino. According to a second embodiment, R₂is a short alkylamino chain selected from the group comprising or consisting of methylamino, ethylamino and propylamino. According to a third embodiment, R₂is a short alkylamino chain selected from the group comprising or consisting of methylamino and ethylamino. According to a fourth embodiment, R₂is a methylamino group.

In one embodiment, the terminal substituent of the thiourea or urea moiety R₁is selected from the group comprising or consisting of H and optionally substituted short chain alkyls. According to a first embodiment, R₁is H. According to a second embodiment, R₁is a short chain alkyl selected from the group comprising or consisting of methyl, ethyl propyl and butyl. According to a third embodiment, R₁is a short chain alkyl selected from the group comprising or consisting of methyl, ethyl, propyl and butyl. According to a fourth embodiment, R₁is a short chain alkyl selected from the group comprising or consisting of methyl, ethyl and propyl. According to a fifth embodiment, R₁is a short chain alkyl selected from the group comprising or consisting of methyl and ethyl. According to a sixth embodiment, R₁is methyl.

In another embodiment, R₁is a substituted short alkyloxy chain selected from the group comprising or consisting of methyloxy, ethyloxy, propyloxy and butyloxy. According to a second embodiment, R₁is a short alkyloxy chain selected from the group comprising or consisting of methyloxy, ethyloxy and propyloxy. According to a third embodiment, R₁is a short alkyloxy chain selected from the group comprising or consisting of methyloxy and ethyloxy. According to a fourth embodiment, R₁is a methyloxy group.

In another embodiment, R₁is a substituted short alkylamino chain selected from the group comprising or consisting of methylamino, ethylamino, propylamino and butylamino. According to a second embodiment, R₁is a short alkylamino chain selected from the group comprising or consisting of methylamino, ethylamino and propylamino. According to a third embodiment, R₁is a short alkylamino chain selected from the group comprising or consisting of methylamino and ethylamino. According to a fourth embodiment, R₁is a methylamino group.

The substituted cyclodextrins according to the present invention can be manufactured by any process known in the art. In one embodiment, the cyclodextrins of the present invention can be manufactured by the process disclosed in U.S. Pat. No. 6,080,733. In brief, the substituted cyclodextrin is obtained from the adequate amino-cyclodextrin that is subjected to a reaction with an alkyl-isothiocyanate in an organic solvent such as pyridine at room temperature. It is generally known in the art that oxygen and sulphur share equivalent chemical properties. This equivalence can be easily transposed to urea alkyl-isocyanates (R—N═C═O), alkyl-isothiocyanate (R—N═C═S), and respective reactivities thereof. Therefore, in the light of U.S. Pat. No. 6,080,733, one can read the process for preparing ureido-cyclodextrins. Indeed, by minor routine laboratory work, one averagely skilled in the art can prepare ureido-cyclodextrins by replacing the respective alkyl-isothiocyanate by the corresponding alkyl-isocyanate. Furthermore, urea-substituted cyclodextrins have been previously described in the scientific literature (Menuel et al., 2005, Tetrahedron letters, 46, pp 3307-3309).

In one embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of monovalent, bivalent and trivalent metals, oxides, hydroxides and salts thereof.

Without willing to be bound to a theory, the substituent of the cyclodextrins according to the present invention complexes the metal, oxide, hydroxide or salt thereof thanks to the unbound electrons of the aforementioned “R” substituent moieties.

In one embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of monovalent and bivalent metals, oxides, hydroxides and salts thereof. In one embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of monovalent metals, oxides, hydroxides and salts thereof. In one embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of bivalent metals, oxides, hydroxides and salts thereof.

In a preferred embodiment, the metal, oxide, hydroxide or salt thereof, complexed by the cyclodextrins of the present invention, is selected from the group comprising or consisting of metals, oxides, hydroxides or salts thereof used in inorganic medicinal chemistry. The latter comprise metals, oxides, hydroxides and salts thereof already in use, as well as currently developed metals, oxides, hydroxides and salts thereof for use in therapy.

According to a first embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, Ru, As, Sb, Bi, Ti, V, Ni, Hg, Pb, Co, oxides, hydroxides and salts thereof.

According to a second embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, Ru, As, Sb, Bi, oxides, hydroxides and salts thereof.

According to a third embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, Ru, As, oxides, hydroxides and salts thereof.

According to a fourth embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, oxides, hydroxides and salts thereof.

According to a fifth embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of Ag, Zn, Cu, Pt, oxides, hydroxides and salts thereof.

According to a sixth embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of Ag, Zn, Cu, oxides, hydroxides and salts thereof.

According to a seventh embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of Ag, Zn, Cu, oxides, hydroxides and salts thereof.

In one embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of Ag, oxides, hydroxides and salts thereof. In one embodiment, the metal is Ag.

In one embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of Zn, oxides, hydroxides and salts thereof. In one embodiment, the metal is Zn.

In one embodiment, the metal, oxide, hydroxide or salt thereof is selected from the group comprising or consisting of Cu, oxides, hydroxides and salts thereof. In one embodiment, the metal is Cu.

In one embodiment, the invention relates to a complex of a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, Ru, As, Sb, Bi, Ti, V, Ni, Hg, Pb, Co, oxides, hydroxides and salts thereof; and a cyclodextrin of formula (I)

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wherein:

- p is 6, 7 or 8;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond or R₂;
- Z is selected from —C═O and —C═S;
- R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
- R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, Ru, As, Sb, Bi, Ti, V, Ni, Hg, Pb, Co, oxides, hydroxides and salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
- with the proviso one, two, three R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, As, oxides, hydroxides and salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6, 7 or 8;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond or R₂;
- Z is selected from —C═O and —C═S;
- R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
- R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of Ag, oxides, hydroxides or salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6, 7 or 8;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond or R₂;
- Z is selected from —C═O and —C═S;
- R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
- R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of Zn, oxides, hydroxides or salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6, 7 or 8;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond or R₂;
- Z is selected from —C═O and —C═S;
- R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
- R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, As, oxides, hydroxides and salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond or R₂;
- Z is —C═S;
- R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
- R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, As, oxides, hydroxides and salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of a metal selected from the group comprising or consisting of Ag, Zn, oxides, hydroxides and salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of Ag, oxides, hydroxides or salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of Ag, oxides, hydroxides or salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of Ag salts; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of AgNO₃; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7, preferably p is 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of Zn, oxides, hydroxides or salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of Zn, oxides, hydroxides or salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that two R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of Zn, oxides, hydroxides or salts thereof; and a cyclodextrin of formula (I), wherein:

- p is 6 or 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, As, oxides, hydroxides and salts thereof; and a β-cyclodextrin of formula (I), wherein:

- p is 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond or R₂;
- Z is —C═S;
- R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
- R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, As, oxides, hydroxides and salts thereof; and a β-cyclodextrin of formula (I), wherein:

- p is 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is selected from H and methyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, As, oxides, hydroxides and salts thereof; and a β-cyclodextrin of formula (I), wherein:

- p is 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of Ag, oxides, hydroxides or salts thereof; and a β-cyclodextrin of formula (I), wherein:

- p is 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complex according to the present invention is a complex of Zn, oxides, hydroxides or salts thereof; and a β-cyclodextrin of formula (I), wherein:

- p is 7;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond;
- Z is —C═S;
- R₁is methyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁.

In one embodiment, the metal-cyclodextrin complexes of the present invention can further comprise at least one therapeutic agent. The present invention can be implemented with any therapeutic agent known in the art.

In a preferred embodiment, the at least one therapeutic agent is an organic therapeutic agent. Therefore, in one embodiment, the metal-cyclodextrin complexes of the present invention can further comprise at least one organic therapeutic agent.

In one embodiment, the at least one organic therapeutic agent is selected from antibiotic, anti-fungal, antiparasitic, antiviral, anti-ulcer, anticancer, antidiabetic, anti-depressive and immune-modulating agents; salts thereof and combinations thereof.

In one embodiment, the at least one organic therapeutic agent is selected from antibiotic, anti-fungal, antiparasitic and antiviral agents; salts thereof and combinations thereof.

In one embodiment, the at least one organic therapeutic agent is selected from antibiotic agents, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is selected from anti-fungal agents, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is selected from antiviral agents, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is selected from antiparasitic agents, salts thereof and combinations thereof.

According to a first embodiment, the at least one organic therapeutic agent is selected from antibiotic agents, salts thereof and combinations thereof.

In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of sulfamides, aminoglycosides, tetracyclines, oxazolidinones, amphenicols, pleuromutilins, macrolides, lincosamides, streptogramins, fusidic acid, fosfomycin, cycloserine, bacitracin; vancomycin; oritavancin, telavancin, teicoplanin; dalbavancin; ramoplanin, penicillins, penems, carbapenems, cephalosporins, monobactams, beta-lactamase inhibitors, polymyxins, diaminopyridines, dapsone, quinolones, nitro-imidazoles, nitrofurans, rifamycins, salts thereof and combinations thereof.

In one embodiment, the antibiotic agent is selected from the group comprising or consisting of

- sulfamides, selected from sulfadiazine, sulfaisodimidine, sulfamethizole, sulfadimidine, sulfapyridine, sulfafurazole, sulfanilamide, sulfathiazole, sulfathiourea, sulfamethoxazole, sulfamoxole, sulfadimethoxine, sulfadoxine, sulfalene, sulfametomidine, sulfametoxydiazine, sulfamethoxypyridazine, sulfaperin, sulfamerazine, sulfaphenazole, sulfamazone, sulfacetamide, sulfadicramide, sulfametrole and sulfanitran;
- aminoglycosides, selected from streptomycin, dihydrostreptomycin, neomycin, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin B, paromomycin, gentamicin, verdamicin and astromicin;
- tetracyclines selected from doxycycline, chlortetracycline, clomocycline, demeclocycline, lymecycline, meclocycline, metacycline, minocycline, omadacycline, oxytetracycline, penimepicycline, rolitetracycline, sarecycline and tetracycline;
- oxazolidinones selected from eperezolid, linezolid, posizolid, radezolid, ranbezolid, sutezolid and tedizolid;
- amphenicols selected from, chloramphenicol, azidamfenicol, thiamphenicol and florfenicol;
- pleuromutilins selected from retapamulin, tiamulin and valnemulin;
- macrolides selected from azithromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, midecamycin, miocamycin, oleandomycin, rokitamycin, roxithromycin, spiramycin, troleandomycin, tylosin, telithromycin, cethromycin and solithromycin;
- lincosamides selected from clindamycin, lincomycin and pirlimycin;
- streptogramins selected from pristinamycin, quinupristin, dalfopristin and virginiamycin;
- fusidic acid;
- fosfomycin;
- cycloserine;
- bacitracin;
- vancomycin;
- oritavancin;
- telavancin;
- teicoplanin;
- dalbavancin;
- ramoplanin;
- penicillins selected from benzylpenicillin G, benzathine benzylpenicillin, procaine benzylpenicillin, phenoxymethylpenicillin V, propicillin, pheneticillin, azidocillin, clometocillin, penamecillin, cloxacillin, dicloxacillin, flucloxacillin, oxacillin, nafcillin, methicillin, amoxicillin, pivampicillin, ampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, ppicillin, ticarcillin, carbenicillin, carindacillin, temocillin, piperacillin, azlocillin, mezlocillin, mecillinam, pivmecillinam and sulbenicillin;
- penems selected from faropenem and ritipenem;
- carbapenems selected from ertapenem, doripenem, imipenem, meropenem, biapenem and panipenem;
- cephalosporins selected from cefazolin, cefalexin cefadroxil, cefapirin, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaloglycin, cefacetrile, cefalonium, cefaloridine, cefalotin, cefatrizine, cefaclor, cefotetan, cephamycin, cefoxitin, cefprozil, cefuroxime, cefuroxime axetil, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefbuperazone, cefuzonam, cefmetazole, carbacephem, cefixime, ceftriaxone, ceftazidime, cefoperazone, cefdinir, cefcapene, cefdaloxime, ceftizoxime, cefmenoxime, cefotaxime, cefpiramide, cefpodoxime, ceftibuten, cefditoren, cefetamet, cefodizime, cefpimizole, cefsulodin, cefteram, ceftiolene, oxacephem, fomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftaroline, fosamil, ceftolozane, ceftobiprole, ceftiofur, cefquinome and cefovecin;
- monobactams selected from aztreonam, tigemonam, carumonam and nocardicin A;
- beta-lactamase inhibitors selected from sulbactam, tazobactam, clavulanic acid, avibactam and vaborbactam;
- polymyxins selected from polysporin and neosporin;
- daptomycin;
- tyrothricin;
- gramicidin tyrocidine;
- isoniazid;
- teixobactin;
- 2,4-diaminopyridines selected from trimethoprim, brodimoprim, tetroxoprim, iclaprim and ormetoprim;
- dapsone;
- quinolones selected from cinoxacin, flumequine, nalidixic acid, oxolinic acid, pipemidic acid, piromidic acid, rosoxacin, ciprofloxacin, ofloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, pefloxacin, rufloxacin, levofloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, delafloxacin, gatifloxacin, finafloxacin, gemifloxacin, moxifloxacin, clinafloxacin, garenoxacin, prulifloxacin, sitafloxacin, trovafloxacin, alatrofloxacin, danofloxacin difloxacin, enrofloxacin, ibafloxacin, marbofloxacin, orbifloxacin, pradofloxacin, sarafloxacin, nemonoxacin and novobiocin;
- nitro-imidazoles selected from metronidazole, tinidazole, mebendazole, ornidazole;
- nitrofurans selected from nitrofurantoin, furazolidone and nifurtoinol;
- rifamycins selected from rifampicin, rifabutin, rifapentine, rifaximin rifalazil;
- mupirocin;
- clofoctol;
- xibornol;
- nitroxoline;
- salts thereof;
- and combinations thereof.

In one embodiment, the antibiotic agent is selected from the group comprising or consisting of sulfamides, aminoglycosides, tetracyclines, oxazolidinones, amphenicols, pleuromutilins, macrolides, lincosamides, streptogramins, fusidic acid, fosfomycin, cycloserine, bacitracin, vancomycin, oritavancin, telavancin, teicoplanin, dalbavancin, ramoplanin, penicillins, penems, carbapenems, cephalosporins, monobactams, beta-lactamase inhibitors, salts thereof and combinations thereof.

In one embodiment, the antibiotic agent is selected from the group comprising or consisting of sulfamides, aminoglycosides, tetracyclines, amphenicols, macrolides, fusidic acid, bacitracin, penicillins, penems, carbapenems, cephalosporins, beta-lactamase inhibitors, diaminopyridines, quinolones, nitro-imidazoles, nitrofurans, rifamycins, salts thereof and combinations thereof.

In one embodiment, the antibiotic agent is selected from the group comprising or consisting of sulfamides, salts thereof and combinations thereof.

In one embodiment, the antibiotic agent is a sulfamide selected from the group comprising or consisting of sulfadiazine, sulfaisodimidine, sulfamethizole, sulfadimidine, sulfapyridine, sulfafurazole, sulfanilamide, sulfathiazole, sulfathiourea, sulfamethoxazole, sulfamoxole, sulfadimethoxine, sulfadoxine, sulfalene, sulfametomidine, sulfametoxydiazine, sulfamethoxypyridazine, sulfaperin, sulfamerazine, sulfaphenazole, sulfamazone, sulfacetamide, sulfadicramide, sulfametrole and sulfanitran, salts thereof and combinations thereof.

In one embodiment, the antibiotic is sulfadiazine, salts thereof or combinations thereof.

In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of aminoglycosides, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of tetracyclines, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of amphenicols, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of macrolides, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of fusidic acid, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of bacitracin, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of penicillins, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of penems and carbapenems, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of cephalosporins, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of beta-lactamase inhibitors, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of diaminopyridines, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of quinolones, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of nitro-imidazoles, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an antibiotic agent selected from the group comprising or consisting of nitrofurans, salts thereof and combinations thereof. In one embodiment, the at least one organic therapeutic agent is an rifamycins, salts thereof and combinations thereof.

According to a second embodiment, the at least one organic therapeutic agent is selected from antifungal agents, salts thereof and combinations thereof.

In one embodiment, the at least one organic therapeutic agent is an antifungal agent selected from the group comprising or consisting of

- pyrithione;
- imidazoles selected from bifonazole, butoconazole, chlormidazole, clotrimazole, croconazole, eberconazole, econazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, luliconazole, miconazole, neticonazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole;
- triazoles selected from efinaconazole, fluconazole, fosfluconazole, terconazole, hexaconazole, isavuconazole, itraconazole, posaconazole, voriconazole, albaconazole, ravuconazole;
- abafungin;
- polyenes selected from natamycin, nystatin, amphotericin B and hamycin;
- allylamines selected from naftifine and terbinafine;
- amorfoline;
- echinocandins selected from anidulafungin, biafungin, caspofungin, cilofungin and micafungin;
- frucytosine;
- griseofluvin;
- tavaborole;
- bromochlorosalicylanilide;
- chlorophetanol;
- chlorphenesin; ciclopirox; dimazole;
- ethylparaben;
- haloprogin;
- polynoxylin;
- salicylic acid;
- salicylic acid methyl-ester;
- sulbentine;
- taurolidine;
- ticlatone;
- tolciclate;
- tolnaftate;
- tribromometacresol;
- undecylenic acid;
- atovaquone;
- dapsone;
- pentamidine;
- fumagillin;
- essential oils selected from citronella oil, lemongrass oil, lemon myrtle oil, orange peel oil, patchouli oil and tea tree oil;
- salts thereof; and
- combinations thereof.

In one embodiment, the at least one antifungal agent is selected from the group comprising or consisting of pyrithione, imidazoles, triazoles, polyenes, griseofluvin, bromochlorosalicylanilide, chlorophetanol, ciclopirox, dimazole, salicylic acid methyl-ester, tolnaftate, tribromometacresol, undecylenic acid, atovaquone, dapsone, fumagillin, essential oils, salts thereof and combinations thereof. In one embodiment, the at least one antifungal agent is selected from the group comprising or consisting of pyrithione, imidazoles, triazoles, polyenes, griseofluvin, chlorophetanol, ciclopirox, dimazole, salicylic acid methyl-ester, tolnaftate, tribromometacresol, atovaquone, dapsone, essential oils, salts thereof and combinations thereof.

In one embodiment, the at least one antifungal agent is pyrithione, salts thereof or combinations thereof.

In one embodiment, the at least one antifungal agent is selected from the group comprising or consisting of imidazoles, salts thereof and combinations thereof.

In one embodiment, the at least one antifungal agent is selected from the group comprising or consisting of triazoles, salts thereof and combinations thereof.

According to a third embodiment, the at least one organic therapeutic agent is selected from antiviral agents, salts thereof and combinations thereof.

In one embodiment, the at least one organic therapeutic agent is an antiviral agent selected from the group comprising or consisting of acyclovir, docosanol, ganciclovir, imiquimod, penciclovir, podofilox and podophyllin resin.

According to a fourth embodiment, the at least one organic therapeutic agent is selected from antiparasitic agents, salts thereof and combinations thereof.

In one embodiment, the at least one organic therapeutic agent is an antiparasitic agent selected from the group comprising or consisting of

- nitro-imidazoles selected from metronidazole, tinidazole, mebendazole and ornidazole;
- eflornithine;
- furazolidone;
- melarsoprol;
- nifursemizone;
- nitazoxanide;
- ornidazole;
- paromomycin;
- pentamidine;
- pyrimethamine;
- chloroquine;
- clotrimazole;
- crotamiton;
- benzyl benzoate;
- ivermectin;
- thiabendazole;
- diethylcarbamazine;
- niclosamide;
- praziquantel;
- miltefosine;
- salts thereof; and
- combinations thereof.

In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of nitro-imidazoles selected from metronidazole, tinidazole, mebendazole and ornidazole; eflornithine; furazolidone; melarsoprol; nifursemizone; nitazoxanide; ornidazole; paromomycin; pentamidine; pyrimethamine; chloroquine; clotrimazole; crotamiton; benzyl benzoate; ivermectin; thiabendazole, diethylcarbamazine; niclosamide; praziquantel; miltefosine; salts thereof, and combinations thereof. In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of eflornithine, salts thereof and combinations thereof. In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of furazolidone, salts thereof and combinations thereof. In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of melarsoprol, salts thereof, and combinations thereof. In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of nifursemizone, salts thereof, and combinations thereof. In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of nitazoxanide, salts thereof, and combinations thereof. In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of pyrimethamine salts thereof, and combinations thereof. In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of chloroquine, salts thereof, and combinations thereof. In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of clotrimazole, salts thereof, and combinations thereof. In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of crotamiton, salts thereof, and combinations thereof. In one embodiment, the at least one antiparasitic agent is benzyl benzoate.

In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of ivermectin, salts thereof, and combinations thereof.

In one embodiment, the at least one antiparasitic agent is selected from the group comprising or consisting of diethylcarbamazine, niclosamide, praziquantel, miltefosine, salts thereof, and combinations thereof.

Metal-organic therapeutic agent association consist in an effective therapeutic approach in a broad spectrum of pathologies comprising depression, circulatory disorders, hypercalcemia, hyperphosphatemia, arthrosis, gastric ulcer, cancer, microbial infections, fungal infections and parasitic infections (Farrell N., CCC II, 2013; 9:809-840). Lack of sufficient aqueous solubility is one of the major obstacles impeding the wide use of existing and promising metal-organic therapeutic agent associations. The present invention offers the technology to overcome the obstacle of aqueous solubility.

Indicative embodiments of the invention consist in the association of any metal, as previously detailed, with at least one organic therapeutic agents, as previously detailed.

In one embodiment, the metal-organic therapeutic agent association comprises a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, Ru, As, Sb, Bi, Ti, V, Ni, Hg, Pb, Co, oxides, hydroxides and salts thereof; and an organic therapeutic agent selected from the group comprising or consisting of antibiotic, anti-fungal, antiviral, antiparasitic, anti-ulcer, anticancer, antidiabetic, anti-depressive, immune-modulating agents, salts thereof and combinations thereof.

Indicative and non-limitative embodiments of the present invention comprise:

- Ag oxides, hydroxides and salts thereof; with at least one antibiotic agent;
- Ag, oxides, hydroxides and salts thereof; with at least one antifungal agent;
- Zn, oxides, hydroxides and salts thereof; with at least one antibiotic agent;
- Zn, oxides, hydroxides and salts thereof; with at least one antifungal agent;
- Zn, oxides, hydroxides and salts thereof; with at least one antiviral agent;
- Cu, oxides, hydroxides and salts thereof; with at least one antibiotic agent;
- Cu, oxides, hydroxides and salts thereof; with at least one antifungal agent;
- Cu, oxides, hydroxides and salts thereof; with at least one antiviral agent;
- Pt, oxides, hydroxides and salts thereof; with at least one antiviral agent;
- Pt, oxides, hydroxides and salts thereof; with at least one anticancer agent;
- Au, oxides, hydroxides and salts thereof; with at least one immune-modulating agent;
- Au, oxides, hydroxides and salts thereof; with at least one antiarthritic agent;
- Ru, oxides, hydroxides and salts thereof; with at least one antiviral agent;
- As, oxides, hydroxides and salts thereof; with at least one antiparasitic agent;
- Sb, oxides, hydroxides and salts thereof; with at least one antiparasitic agent;
- Bi, oxides, hydroxides and salts thereof; with at least one antibiotic agent;
- Bi, oxides, hydroxides and salts thereof; with at least one anti-ulcer agent;
- V, oxides, hydroxides and salts thereof; with at least one antidiabetic agent;
- Ni, oxides, hydroxides and salts thereof; with at least one antiviral agent; and
- Co, oxides, hydroxides and salts thereof; with at least one antiviral agent.

In one embodiment, the metal-organic therapeutic agent association comprises a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, Ru, As, Sb, Bi, oxides, hydroxides and salts thereof; and an organic therapeutic agent selected from antibiotic, anti-fungal, antiviral and antiparasitic, agents, salts thereof and combinations thereof.

In one embodiment, the metal-organic therapeutic agent association comprises a metal selected from the group comprising or consisting of Ag, Zn, Cu, oxides, hydroxides and salts thereof and an organic therapeutic agent selected from antibiotic, anti-fungal, antiviral and antiparasitic agents and combinations thereof.

In one embodiment, the metal-organic therapeutic agent association comprises a metal selected from the group comprising or consisting of Ag, Zn, Cu, oxides, hydroxides and salts thereof; and an organic therapeutic agent selected from antibiotic agents, salts thereof and combinations thereof.

In one embodiment, the metal-organic therapeutic agent association comprises a metal selected from the group comprising or consisting of Ag, Zn, Cu, oxides, hydroxides and salts thereof; and an organic therapeutic agent selected from anti-fungal, antiviral and antiparasitic agents, salts thereof and combinations thereof.

In one embodiment, the metal-organic therapeutic agent association comprises a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, Ru, As, Sb, Bi, Ti, V, Ni, Hg, Pb, Co, oxides, hydroxides and salts thereof; and an organic therapeutic agent selected from antibiotic, anti-fungal, antiviral, antiparasitic, anti-ulcer, anticancer, antidiabetic, anti-depressive, immune-modulating agents, salts thereof and combinations thereof.

In one embodiment, the metal-organic therapeutic agent association comprises a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, oxides, hydroxides and salts thereof; and an organic therapeutic agent selected from antibiotic, anti-fungal, antiviral, antiparasitic, anti-ulcer, anticancer, antidiabetic, anti-depressive, immune-modulating agents, salts thereof and combinations thereof.

Metals and their dissolved ions, such as, e.g., silver, attacks bacterial cells by rendering the bacterial cell membrane more permeable, and interferes with the bacterial cell's metabolism, leading to the overproduction of reactive, toxic chemical species (Owens B. Nature News, Jun. 19, 2013). Such pharmacodynamic properties of metals can be implemented to make current antibiotics or antibiotics in development more effective against resistant bacteria.

According to a preferred embodiment, the metal-organic therapeutic agent association comprises or consists of Ag as a metal and an antibiotic agent as organic therapeutic agent, preferably the antibiotic agent is selected from sulfamides, more preferably the antibiotic agent is sulfadiazine.

According to a preferred embodiment, the metal-organic therapeutic agent association comprises or consists of Zn as a metal and an antifungal agent as organic therapeutic agent, preferably the antifungal agent is pyrithione.

As previously discussed, the metal-cyclodextrin complexes of the present invention can further comprise at least one therapeutic agent.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, Ru, As, Sb, Bi, Ti, V, Ni, Hg, Pb, Co, oxides, hydroxides and salts thereof;
- (ii) a cyclodextrin of formula (I)

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wherein:

- p is 6, 7 or 8;
- R is —OH or —X—NH—Z—NHR₁;
- X is a single bond or R₂;
- Z is selected from —C═O and —C═S;
- R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
- R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
- with the proviso that at least one R=—X—NH—Z—NHR₁; and
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of antibiotic, anti-fungal, antiviral, antiparasitic, anti-ulcer, anticancer, antidiabetic, anti-depressive, immune-modulating agents, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, Ru, As, Sb, Bi, Ti, V, Ni, Hg, Pb, Co, oxides, hydroxides and salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6 or 7;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond;
  - Z is —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁; and
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of antibiotic, anti-fungal, antiviral, antiparasitic, anti-ulcer, anticancer, antidiabetic, anti-depressive, immune-modulating agents, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, As, oxides, hydroxides and salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁; and
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of antibiotic, anti-fungal, antiviral, antiparasitic agents, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) a metal selected from the group comprising or consisting of Ag, Zn, Cu, Pt, Au, oxides, hydroxides and salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁; and
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of antibiotic, anti-fungal, antiviral, antiparasitic agents, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Ag, oxides, hydroxides or salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁; and
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of antibiotic, anti-fungal, antiviral, antiparasitic agents, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Ag, oxides, hydroxides and salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁; and
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of antibiotic agents, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Ag, oxides, hydroxides or salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁; and
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of sulfonamides, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Ag, oxides, hydroxides or salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁; and
- (iii) sulfadiazine.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Zn, oxides, hydroxides and salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁;
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of antibiotic, anti-fungal, antiviral, antiparasitic agents, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Zn, oxides, hydroxides and salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁;
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of antibiotic, anti-fungal, antiviral, antiparasitic agents, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Ag, oxides, hydroxides and salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁;
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of antibiotic and anti-fungal agents, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Ag, oxides, hydroxides and salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁;
- (iii) at least one organic therapeutic agent selected from the group comprising or consisting of anti-fungal agents, salts thereof and combinations thereof.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Ag, oxides, hydroxides and salts thereof;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁;
- (iii) sulfadiazine.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Ag;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 6, 7 or 8;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond or R₂;
  - Z is selected from —C═O and —C═S;
  - R₁is selected from H and optionally substituted short chain alkyls; preferably R₁is selected from methyl, ethyl propyl and butyl;
  - R₂is selected from optionally substituted short chain alkyls; preferably R₂is selected from methyl, ethyl and propyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁;
- (iii) sulfadiazine.

In one embodiment, the complex according to the present invention comprises or consists of

- (i) Ag;
- (ii) a cyclodextrin of formula (I), wherein:
  - p is 7;
  - R is —OH or —X—NH—Z—NHR₁;
  - X is a single bond;
  - Z is —C═S;
  - R₁methyl;
  - with the proviso that at least one R=—X—NH—Z—NHR₁;
- (iii) sulfadiazine.

Advantageously, the metal-organic therapeutic agent-cyclodextrin complexes of the present invention maintain substantially the same molar ratio between the organic therapeutic agent and the metal as compared to non-complexed metal-organic therapeutic agent associations.

The molar ratio of between the organic therapeutic agent and the metal in metal-organic therapeutic agent associations depends on the valence of the metal and the electron-donor moieties of the organic therapeutic agent. For example, in the case of silver sulfadiazine, this ratio is 1; and in the case of zinc pyrithione, this ratio is 2.

In one embodiment, the molar ratio between the cyclodextrin-complexed organic therapeutic agent and the cyclodextrin-complexed metal is ranging from about 200 to 1, from about 150 to 1, from about 100 to 1, from about 50 to 1, from about 20 to 1, from about 15 to 1, from about 10 to 1, from about 9 to 1, from about 8 to 1, from about 7 to 1, from about 6 to 1, from about 5 to 1, from about 4 to 1, from about 3 to 1, from about 2 to 1, from about 1.5 to 1.

In one embodiment, the molar ratio between the cyclodextrin-complexed organic therapeutic agent and the complexed metal is about 1, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 12, about 14, about 16, about 18, about 20, about 25, about 30, about 35, about 40, about 50, about 60, about 80, about 100, about 120, about 140, about 150, about 200.