FORMULATION COMPRISING NANOSTRUCTURED, BIOCOMPATIBLE AND BIOCATALYTIC MATERIAL FOR THE TREATMENT OF WOUNDS AND INFECTIONS

Abstract

Formulation comprising nanostructured, biocompatible and biocatalytic material comprising a solid acid consisting of mixed oxides of silica and titania (TiO.sub.2SiO.sub.2); supporting in its dispersed matrix: copper, silver, gold, iron, rutenium, palladium, zinc, manganese, iridium and/or platinum metals at minimal concentrations, for use in the treatment of wounds and infections.

Claims

1. A formulation comprising a nanostructured, biocompatible and biocatalytic material consisting of a solid acid made of mixed oxides of silica and titania (TiO.sub.2SiO.sub.2); supporting in its dispersed matrix: copper, silver, gold, iron, rutenium, rhodium, cobalt, zinc, palladium, zinc, manganese, iridium and/or platinum metals at minimal concentrations, for use in the treatment of wounds and infections.

2. The formulation for use in the treatment of wounds and infections of claim 1, wherein the metal supported in the dispersed matrix is acetil platinum acetonate (Pt(acac).sub.2).

3. The formulation for use in the treatment of wounds and infections of claim 1, wherein the formulation is in the form of a gel.

4. The formulation for use in the treatment of wounds and infections of claim 1, wherein the formulation is in the form of a liquid.

5. The formulation for use in the treatment of wounds and infections of claim 1, wherein the wounds and infections to be treated are wounds and infections of patients diagnosed with Diabetes Mellitus.

Description

DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 is the infrared spectrum with Fourier transform in the interval of 4000-400 cm.sup.1 of the nanostructured biocompatible and biocatalytic material prepared by the sol-gel method.

[0020] FIG. 2 is a photograph at three different resolutions, obtained by a scanning electron microscope of the nanostructured biocompatible and biocatalytic material prepared by the sol-gel method.

[0021] FIG. 3 are photographs at three different times after application of: 0 days, 8 days and 20 days, showing effects of the formulation comprising the nanostructured biocompatible and biocatalytic material.

DETAILED DESCRIPTION

[0022] The presentation invention refers to a formulation comprising a new nanostructured, biocatalytic, biocompatible and non-toxic material obtained by the sol-gel chemical synthesis method. The sol-gel methodology is used to control the physico-chemical properties of the material in a thin, nanometric size and with a wide surface area. Biocompatibility is achieved by the superficial incorporation of functional groups of sulfates, amines and phosphates that allow the easy interaction of the cellular membrane nanoparticle, and thus easily enter the cell and perform the necessary (catalytic) specific activity. The material is a nanoparticle characterized by being a solid acid consisting of mixed oxides of silica and titania (TiO.sub.2SiO.sub.2), further specification of the nanoparticle can be observed in FIGS. 1 and 2 that show the infrared spectrum with Fourier transform in the interval of 4000-400 cm.sup.1 of the biocatalyzer prepared by the sol-gel method; supporting in its dispersed matrix: copper, silver, gold, iron, rutenium, palladium, zinc, manganese, iridium and/or platinum metals at minimal concentrations. The components that integrate the nanoparticles are very stable and have been tested experimentally extensively in vitro and in vivo, and there is scientific literature evidence of its biocompatibility and low cytotoxicity.

Sol-Gel Process Using Metal Alkoxides.

[0023] At the functional group level, three reactions are generally used to describe the sol-gel process: hydrolysis, alcohol condensation, and water condensation. However, the characteristics and properties of a particular sol-gel inorganic network are related to a number of factors that affect the rate of hydrolysis and condensation reactions, such as, pH, temperature and time of reaction, reagent concentrations, catalyst nature and concentration, H.sub.2O/M molar ratio (R), aging temperature and time, and drying. Of the factors listed above, pH, nature and concentration of catalyst, H.sub.2O/M molar ratio (R), and temperature have been identified as most important. Thus, by controlling these factors, it is possible to vary the structure and properties of the sol-gel-derived inorganic network over wide ranges. For example, Sakka et al. observed that the hydrolysis of TEOS utilizing R values of 1-2 and 0.01 M HCl as a catalyst yields a viscous, spinnable solution. It was further shown, that these solutions exhibited a strong concentration dependence on the intrinsic viscosity and a power law dependence of the reduced viscosity on the number average molecular weight.sup.(31-34):

[n]=k(Mn)a(1)

[0024] Values for a ranged from 0.5 to 1.0, which indicates a linear or lightly branched molecule or chain.

[0025] Values of a in eq. 1 ranged from 0.1 to 0.5, indicating spherical or disk shaped particles. These results are consistent with the structures which emerge under the conditions employed by the Strber process, for preparing SiO.sub.2 powders. It was further shown that with hydrolysis under basic conditions and R values ranging from seven (7) to twenty-five (25), monodisperse, spherical particles could be produced.

##STR00001##

[0026] Generally speaking, the hydrolysis reaction (Eq. 2), through the addition of water, replaces alkoxide groups (OR) with hydroxyl groups (OH). Subsequent condensation reactions are made, involving the silanol groups (SiOH) produce siloxane bonds (SiOSi) plus the by-products water or alcohol in the case of silica. Under most conditions, condensation commences before hydrolysis is complete. However, conditions such as, pH, H.sub.2O/Si molar ratio (R), and catalyst can force completion of hydrolysis before condensation begins. Additionally, because water and alkoxides are immiscible, a mutual solvent is utilized. With the presence of this homogenizing agent, alcohol, hydrolysis is facilitated due to the miscibility of the alkoxide and water. As the number of siloxane bonds increases, the individual molecules are bridged and jointly aggregate in the sol. When the sol particles are aggregate, or inter-knit into a network, a gel is formed. Upon drying, trapped volatiles (water, alcohol, etc.) are driven off and the network shrinks as further condensation can occur. It should be emphasized, however, that the addition of solvents and certain reaction conditions may promote esterification and depolymerization reactions. The hydrolysis/condensation reaction follows two different mechanisms, which depend of the coordination of metallic central atom. When the coordination number is satisfied the hydrolysis reaction occurs by nucleophilic substitution (S.sub.n):

##STR00002##

[0027] When the coordination number is major, the hydrolysis reaction takes place by nucleophilic addition:

##STR00003##

[0028] These mechanisms need that the oxygen coordination is increased from 2 to 3, the additional bond generation involves one electron pair of the oxygen and the new bond can be equivalent to the other bonds. During the condensation step an enormous concentration of hydroxyl groups are formed. This OH can be linked between the metallic atoms or only be simple OH ligand in the surface.

##STR00004##

Acid-Catalyzed Mechanism

[0029] Under acidic conditions, it is likely that an alkoxide group is protonated in a rapid first step. Electron density is withdrawn from the silicon atom, making it more electrophilic and thus more susceptible to attack from water. This results in the formation of a penta-coordinate transition state with significant SN.sub.2-type character. 13 The transition state decays by displacement of an alcohol and inversion of the silicon tetrahedron, using silica as example:

##STR00005##

Base-Catalyzed Mechanism

[0030] Base-catalyzed hydrolysis of silicon alkoxides proceeds much more slowly than acid-catalyzed hydrolysis at an equivalent catalyst concentration. Basic alkoxide oxygens tend to repel the nucleophile, OH. However, once an initial hydrolysis has occurred, following reactions proceed stepwise, with each subsequent alkoxide group more easily removed from the monomer then the previous one. Therefore, more highly hydrolyzed silicones are more prone to attack. Additionally, hydrolysis of the forming polymer is more sterically hindered than the hydrolysis of a monomer. Although hydrolysis in alkaline environments is slow, it still tends to be complete and irreversible. Thus, under basic conditions, it is likely that water dissociates to produce hydroxyl anions in a rapid first step. The hydroxyl anion then attacks the silicon atom. Again, an SN.sub.2-type mechanism has been proposed in which the OH displaces OR with inversion of the silicon tetrahedron.

##STR00006##

[0031] The nanoparticle formulation was invented to counteract one of the most terrible and disabling consequences of Diabetes Mellitus, such as diabetic foot. Diabetic foot consists of a condition of the blood vessels and nerves, leading to inadequate vascular and arterial irrigation, as well as lack of sensation, which promotes the formation of ischemic and/or neuropathic ulcers on the soles of the feet. Added to this, in many cases, the ulcers are infected by a variety of microorganisms which further hinder the closure of the lesion and can lead to the affection of bone and tendons. Both in the animal model and in a clinical trial with patients, antibacterial and healing effects have been demonstrated, promoting the granulation, regeneration, angiogenesis and epithelization of the tissues as shown in FIG. 3.

[0032] This nanoparticle is also capable of promoting the closure of other types of wounds, for example, but not limited to, fistulas, surgical wounds and burns; among others.

[0033] The nanostructured material is easy to apply by medical personnel with basic training in wound care. The procedure consists of: 1) washing the affected area with sterile or boiled water and surgical soap; 2) carving with a gauze and, if necessary, debride; 3) drying; 4) applying the nanoparticles directly on the lesion in a gel, powder or powder dissolved in saline solution formulation; and 5) dressing the wound. The treatment is applied every third day, except when the patient treated is very serious and/or under the consideration of the treating physician. It can be done daily.

[0034] It is important to note that no serious short-term side effects were observed (n=40 patients).

EXAMPLES

Example 1

[0035] 1.6871 g Of acetil platinum acetonate (Pt(acac).sub.2) were mixed with 246 ml of acetone. The mixture was maintained under agitation until the platinum complex was dissolved. To this mixture, 1.2501 g of GABA previously dissolved in 20 ml of deionized water was added. pH was adjusted to 3 with phosphoric acid. Simultaneously, 89 ml of TEOS and 9.8 ml of titanium butoxide dissolved in 70 ml of deionized water were added. Everything was maintained under agitation and at room temperature until de gel was formed.

Example 2

[0036] 1.6871 g Of acetil platinum acetonate (Pt(acac).sub.2) were mixed with 246 ml of acetone. The mixture was maintained under agitation until the platinum complex was dissolved. To this mixture, 1.2501 g of glutamic acid previously dissolved in 20 ml of deionized water was added. pH was adjusted to 3 with phosphoric acid. Simultaneously, 89 ml of TEOS and 9.8 ml of titanium butoxide dissolved in 15 ml of absolute ethanol. 1.7203 g of ammonium sulphate dissolved in 70 ml of deionized water was added. Everything was maintained under agitation and at room temperature until de gel was formed.

Example 3

[0037] 1.6871 g Of acetil platinum acetonate (Pt(acac).sub.2) were mixed with 246 ml of acetone. The mixture was maintained under agitation until the platinum complex was dissolved. To this mixture, 1.2501 g of GABA previously dissolved in 40 ml of deionized water was added. pH was adjusted to 3 with phosphoric acid. Simultaneously, 89 ml of TEOS and 9.8 ml of titanium butoxide dissolved in 15 ml of absolute ethanol were added. 1.7203 g of ammonium sulphate dissolved in 140 ml of deionized water was added. Everything was maintained under agitation and at room temperature until de gel was formed.