HK40057660A - Various uses of the nanoparticulate compound of titanium dioxide functionalized - Google Patents

Description

Various uses of nanoparticle compounds of functionalized titanium dioxide

Technical Field

The present invention relates to the techniques and principles used in nanotechnology for manipulating substances at the atomic and molecular level for various purposes such as industry or pharmacy, etc., and more particularly it relates to various uses of nanoparticulate compounds of titanium dioxide functionalized with functional organic groups, inorganic radicals and fruit and/or herbal extracts adsorbed on their surface and pores as described in patent MX 339086.

Background

Throughout history, the use of antibiotics has been repeated, even in the oldest cultures. These substances capable of eliminating microorganisms have not been perfected and industrialized until now. Developed countries today have banned the use of some of these substances.

A microbial substance is a substance that is capable of eliminating or inhibiting the growth of fungi, bacteria and parasites. It does not take into account the vegetative form of the spore, nor the virus. Antibodies belong to this class. Nevertheless, it should be pointed out that not all microorganisms developed in the past centuries have a broad spectrum, nor do they take into account viruses, spores or mycobacteria.

The historical event that marked the age of antibiotics was the discovery of penicillin, which led to an intensive search for other natural or synthetic compounds that could be used to treat other pathogenic microorganisms. The exploration of certain microorganisms is more difficult than the exploration of other microorganisms. Bacterial cells differ from human cells in many fundamental ways, so that they offer more opportunities for the development of new drugs. In contrast, fungi, parasites and viruses share many metabolic pathways and structures with human cells, providing researchers with fewer therapeutic targets and posing more toxicity risks to patients.

This occurs because penicillin, after several years of use, has been shown to develop microbial resistance, that is, there are strains that can be immunized against it. In such cases, the therapeutic effect is lost not only in humans, but also in cattle and even in agricultural use.

Proper and timely treatment with antibacterial drugs is a life-to-death distinction, otherwise chronic disability results. However, the lack of use and the excessive use of these substances have caused microorganisms to develop super-resistance thereto, which is why there are fifth generation antibiotics. Despite the application of these new generations of antibiotics, the so-called hyper-resistant microorganisms protect themselves, or their use cannot be inhibited or eliminated by antibacterial agents or even mixtures thereof.

Thus, the new antibacterial agents are of importance not only to inhibit or eliminate fungi, bacteria and parasites, but also to eliminate or inhibit the growth of mycobacteria, spores or inactivate viral particles, all of which are infectious pathogens.

Moreover, the abuse of large numbers of microbial agents in food production and their extensive natural release in the environment through residual water from humans and animals and crop water has serious consequences for public health, which are significant in the case of zoonotic bacteria causing human diseases transmitted through food.

Although the qualitative and quantitative importance is still uncertain, it is of particular interest that drug resistance genes from bacteria may be transmitted from animals to human pathogens.

In combination with the above, the excessive use of pesticides in agricultural crops also contributes to the unfortunate acceleration of microbial resistance. Antiseptics and disinfectants are not effective in reducing microbial charges on biological or inert surfaces, as today antibiotics are not sufficient to eliminate microbial charges of infectious diseases. In addition, pesticides are not sufficient to combat microbial charges that affect, destroy the entire crop and cause extinction of various species in the current field of plants.

The use of toxic pesticides in agricultural crops, coupled with the involvement of antibiotics contained in animal manure, which in combination with groundwater to provide a source of water for humans, makes this a global alarm problem.

For the above reasons, the need to use new antibacterial agents that can have a broad spectrum is of crucial economic importance for agriculture and animal husbandry as well as for human health.

Molecular nanotechnology is a very important advance, the global impact of which can be compared with that of the industrial revolution, but with a significant difference, the enormous impact will emerge within a few years in nanotechnology.

There are documents in the prior art relating to the subject matter of the present invention, for example in the case of international patent application No. PCT/KR 02/02142 (corresponding to international publication No. WO 2003/059070), which describes a liquid composition for promoting plant growth, comprising a nanomaterial derived from titanium dioxide. The composition comprises an aqueous solution containing a colloid derived from titanium dioxide as a main component. The size of the nanoparticulate titanium dioxide is such that it can be readily absorbed by plants. The pH of the aqueous solution was adjusted to prevent rapid precipitation of TiO2 in the aqueous solution, giving the desired concentration of TiO2 before diluting the aqueous solution with water. In addition, the composition comprises an adjuvant for plant growth and a surfactant for dispersion. Besides increasing the bactericidal activity of the plant to pathogens, the composition can also improve the performance of the crop and increase the photosynthesis efficiency of the plant. In addition, the composition can improve the problem of environmental pollution caused by excessive use of biochemical fertilizers, and also contribute to increase of income of crop farmers.

As can be seen from the above, this composition brings the inconvenience that pure TiO2 (unfunctionalized) is an inert material and that it requires the presence of additional nutrient materials in solution despite the composition. The solution must be a nutrient solution containing different oxides or surfactants and suspended TiO2 particles, which in use presents the problem of the diluted heavy metal oxides contaminating the soil, which is a health problem since the diluted heavy metal oxides are absorbed by plants eaten by humans. TiO2 is defined to have bactericidal activity due to the semiconductor properties obtained upon exposure to light. It has been demonstrated that TiO2 is not itself a crop enhancer, as it is an inert material.

Furthermore, patent MX 339086 describes functionalized TiO2 nanoparticle materials prepared with herbal and/or fruit extracts capable of inactivating viruses and eliminating bacteria, fungi, spores, mycobacteria and trypanosomes. The nanoscale modification (functionalization) in the material of said PCT application confers its properties that make it different from the same type of material without said modification and from the compounds currently used for the applications found so far.

Disclosure of Invention

For a better and clearer understanding of the present invention, the nanoparticulate compound of titanium dioxide is indifferently referred to throughout the description as "nanoparticulate compound of functionalized titanium dioxide" or "nanoparticulate compound of titanium dioxide modified with organic functional groups, inorganic groups and fruit and/or herb extracts adsorbed on its surface and pores", and the same compound is mentioned in both cases. Further, said nanoparticulate compounds have been described and protected in patent MX 339086.

The present invention relates to functionalized titanium dioxide (TiO)₂) Various uses of the compounds, mixed with water and optionally with at least another material to produce liquid aqueous compositions with a wide range of microbial applications with different uses and purposes, such that they can be used in the pharmaceutical, food, agricultural, animal and aquaculture industries, as well as in the medical field.

The use of nanoparticulate compounds of functionalized titanium dioxide, the percentage of which recommended for the elimination of different proven microorganisms varies from one bacterial population to another, as water disinfectants and purifiers. It is effective in disinfecting water in samples of different origin with different microorganisms, such as mesophilic and fecal coliform and total coliform, pseudomonas, acinetobacter, aeromonas and escherichia coli, etc., as shown in the graph of fig. 1, wherein the nanoparticle compound does not affect the controlling physicochemical parameters of the water, whereby the treatment process does not require further steps to eliminate it.

In another embodiment of the present invention, the nanoparticulate compounds of functionalized titanium dioxide are useful as biopesticides in different types of vegetables and seeds, as seed fungicides, and as post-harvest disinfectants for various crops to eliminate or reduce the presence of microorganisms and viral particles mainly including bacteria, fungi, and virosomes.

As biopesticides, it is used to eliminate the contamination of the source of seeds or to disinfect/disinfect them, for example in the case of tomato seeds, where a delay of charvibacterium michiganensis is observed, or in the case of corn seeds, where the functionalized nanoparticle TiO2 compound is applied directly, or dosed in the form of an emulsion or solution, proved to be effective in reducing the incidence of diseased plants.

Furthermore, it is also used as a biopesticide in plantations or crops, where the incidence of fungi, bacteria and/or viruses in crops, such as, but not exclusively, fruits, green vegetables, perennial grasses, forests, legumes and fruit tree cultures, such as papaya, cocoa, apple, mango, onion, vanilla, avocado, citrus fruits, capsicum, maize, coffee, sorghum, alfalfa, squash, potatoes, exotic woods (exotic woods), walnut, cedar, beans, chickpeas, roses, orchids, tulips and carnation crops and the like, is reduced by foliar and systemic application in a demonstration plot.

It can also be used for post-harvest disinfection, that is, to eliminate microbial charge of, for example but not exclusively, papaya, lemon, pumpkin and tuber crops and to help extend their shelf life by about 40%. In the case of post-harvest use, washing or immersing the fruit in the nanoparticle compound of functionalized titanium dioxide helps to extend the shelf life of the product by about 40%, as can be found in papaya, lemon, pumpkin and tuber crops.

In another embodiment of the invention, the nanoparticulate compound of functionalized titanium dioxide is used as a preservative to prevent the growth of microorganisms, mainly bacteria and fungi, although it has already been mentioned, the activity of which is not limited thereto. Due to the residual properties, the microbial effect has an extended period of action, which makes it possible to protect food and/or cosmetics from microbial attack. The nano-particulate compound of functionalized titanium dioxide can be used in the food industry as a preservative in canned foods, dairy products, meats, cheeses, fish, prepared foods, processed and industrialized foods, refrigerated and frozen foods, desserts, beverages, and the like, but is not limited thereto.

The nano-particulate compound of functionalized titanium dioxide may also be used in other industries where substances are protected from microbial activity, such as in the manufacture of cosmetic or personal care products, for example in the formulation of lipsticks, coloured powders and liquids, shampoos, creams, conditioners, soaps, toothpastes, but not limited to these products.

The TiO is₂The nanoparticle compounds of (3) are useful for tissue regeneration, in different cell lines and tissues to verify compatibility, for cytotoxicity and cell viability studies. The nanoparticulated titanium dioxide compound is not only selective for pathogenic microorganisms, but it also promotes an increase in the proliferative response of the tissues in contact therewith. This induction of the nanoparticulate compound scar formation and/or regenerative cellular effects imparted to the functionalized titania as applied to tissue treatment has been evaluated in various tissues and cell lines, although not necessarily limited thereto.

The TiO is₂The nanoparticulate compounds of (a) can be administered by different systemic routes for the pharmaceutical industry, effectively treating and preventing infectious processes caused by viruses, bacteria, fungi, spores, mycobacteria and parasites. Because the functionalized titanium dioxide nanoparticle compound acts on a variety of microorganisms, it can be pharmacologically classified as an anti-infective or antimicrobial agent.

The TiO is₂The nanoparticle compounds of (a) are useful as microbial agents, and are effective against cell lines infected with different microorganisms.

The TiO is₂Are useful as anti-tumor agents against pathogenic microorganisms, with central effectsProduced in genetic material by breaking down the genetic strand of DNA or RNA. The mechanism is the same as that adopted in the anti-tumor cell toxic medicine, and the nano particle material has the advantages that the nano particle material can specifically target cancer cells and can be directly applied to cancerous tumors. The nanoparticulate compound of functionalized titanium dioxide acts at the molecular level by degrading the DNA and RNA molecules of the cancer cells, with a mechanism of action similar to that of eliminating microorganisms, thus eliminating not only the malignant cells, but also their proliferation. This effect is due to the bioselective ability of the nanoparticle compound of functionalized titanium dioxide to recognize the negative charge and be attracted thereto. The latter is based on the general principle that opposite charges attract each other.

The TiO is₂The nanoparticulate compounds of (a) are used as microbial agents in animal husbandry, livestock and aquaculture, mixed with various types of commercially available foods in the above-mentioned industries, and it has been demonstrated that the mortality rate is reduced mainly in the early stages by up to about 33% by ingestion by different animal species such as shrimp, poultry, sheep and many cattle.

Object of the Invention

In view of the disadvantages found in the prior art, it is an object of the present invention to provide various uses of nanoparticle compounds of functionalized titanium dioxide, because of its broad spectrum of utility against viruses, bacteria, fungi, spores, mycobacteria, parasites and against negatively charged cells such as those of cancer.

Another object of the present invention is to provide the use of a nanoparticulate compound of functionalized titanium dioxide as a water disinfectant, in pure form or in the form of a composition, which allows to eliminate in a more efficient manner the different microorganisms, in particular pathogens, which can be present in water, making it suitable for human consumption in terms of physicochemical and microbiological parameters.

It is another object of the present invention to provide the use of the nanoparticle compounds of functionalized titanium dioxide as biopesticides, in pure form or in the form of compositions which allow to eliminate or reduce the presence of microorganisms and virus particles, mainly including bacterial groups, fungi and viruses in different vegetables and seeds, as well as the use as seed bactericides and post harvest disinfectants for various crops.

It is another object of the present invention to provide the use of the nano-particulate compound of functionalized titanium dioxide as a preservative in the preparation of industrial hygiene products, cosmetics and food products, in pure form or in the form of a composition for use in humans as well as in the livestock and aquaculture industry, wherein the antibacterial effect is not limited to the exposure time defined by the disinfection process.

It is a further object of the present invention to provide the use of the nanoparticle compound providing functionalized titanium dioxide in pure form as an inducer or activator of tissue regeneration, since it promotes an increase in the proliferative response of the tissue with which it is in contact.

Still further, it is another object of the present invention to provide the use of nanoparticulate compounds with functionalized titanium dioxide added with herbal and/or fruit extracts, in pure form or in the form of pharmaceutical compositions, which, thanks to their effectiveness, bioselectivity and harmlessness, can be administered by different systemic routes, effectively treating and preventing the infectious processes caused by viruses, bacteria, fungi, spores, mycobacteria and parasites.

These and other objects, features and advantages of the various uses of the functionalized titanium dioxide nanoparticle compounds of the present application will be apparent to those skilled in the art from the detailed description of certain embodiments and the accompanying drawings and appended claims.

Brief Description of Drawings

The features of the present invention which are believed to be novel are set forth with particularity in the appended claims. The invention itself, however, both as to its organization and method of operation, together with further objects and advantages thereof, will be best understood from the following detailed description of an embodiment of the invention when read with the accompanying drawings in which:

FIG. 1 is a graph showing the percent reduction of fecal Escherichia coli (A) and total Escherichia coli (B) in water.

Fig. 2 is a graph showing the test results in the control (a) and test (B) demonstration graphs, additionally showing the ratio of healthy to diseased plants, wherein a reduction in the affected area of the different crops is observed.

Figure 3 is a graph showing the increase in mold and yeast counts associated with shelf life of different fruits and vegetables.

Fig. 4 shows the results of the thermal analysis, in which it can be observed that decomposition occurs in one stage at a temperature of not higher than 200 ℃. Thermogravimetric analysis and differential thermal analysis showed that weight loss and decomposition are brought about by thermal degradation of the nanoparticle material in one step.

Fig. 5 shows an example of efficacy results of the preservation effect test in the food (a) and the cosmetic (B).

Fig. 6 is a graph showing the viability of cell lines and tissues after contact with nanoparticulate compounds of functionalized titanium dioxide compared to other active ingredients.

Fig. 7 is a graph showing the lethal dose 50, the maximum toxic dose, and the minimum effective dose.

Fig. 8 is a graph showing the microbial activity of compositions based on the functionalized titanium dioxide nanoparticle compounds of the present invention.

Figure 9 is a graph showing cumulative mortality during 48 hours of PI (post infection).

Detailed description of the embodiments

For a better and clearer understanding of the invention, throughout the detailed description, no distinction is made between functionalized titanium dioxide (TiO)₂) Or to a nanoparticulate titanium dioxide compound modified with functionalized organic groups, inorganic groups, and fruit and/or herbal extracts adsorbed on its surface and pores, but in both cases will refer to the same compound. Further, said nanoparticulate compounds have been described and protected in patent MX 339086.

Also, in interpreting the broader scope of the invention, except in the claims and/or the operating examples, all numerical quantities in this specification relating to amounts of material and/or reaction conditions should be understood as modified by the term "about" unless otherwise expressly stated. In light of the above, the present invention refers to, but is not limited to, the amount of material or reaction conditions expressed within the numerical limits set forth. Additionally, the description of a group of elements or class of materials selected as being preferred or sufficient to achieve the objects of the invention implies that mixtures of two or more of the group or class of elements are equally prepared or applicable.

Now, surprisingly, in addition to the disinfectant and aseptic characteristics disclosed in patent MX 339086, functionalized titanium dioxide (TiO) has been found₂) The nanoparticle compounds of (a) have a function and properties as antimicrobial substances due to the following properties:

broad spectrum of cells resistant to viruses, bacteria, fungi, spores, mycobacteria, parasites and to negatively charged cells such as those of cancer.

Biodegradability: it has biodegradable properties because it is a nanoparticle containing organic plant extracts and low levels of inert materials. The above situation has been confirmed using laboratory evaluations of established models.

Biological selectivity: since it is a material that is so small, the effect at the cellular level is also evaluated, finding that neither the size nor the surface modification of the particles damages the cells of the biological medium in which it is used, but only acts on or attacks the microorganisms. This property is defined as biological selectivity, where selectivity is directly related to the surface functionalization of the material that enables it to chemically recognize pathogenic microorganisms.

Biocompatibility: it refers to the ability to perform a desired function according to medical treatment without interfering with or destroying the biological medium in which it is used, that is, it does not have a secondary effect on the human, animal or plant user. This makes it a completely harmless material, for example the functionalized titanium dioxide, which has no secondary, adverse or toxicological effects and also no cytotoxic effects. The above provides the advantage of being non-toxic. This is demonstrated by the evaluation of acute, sub-chronic and chronic exposures by different systemic routes of administration without affecting the normal function of the test organism. These tests were conducted through a suitably organised (economic cooperation and development organisation) approved model.

The use of this compound does not cause resistance in microorganisms, since the degradation mechanism of the genetic material DNA or RNA occurs by the breakdown of peptide bonds, C-C bonds and C-N bonds in nucleic acids. The chemical attractive forces that promote molecular access are due to the functional groups adsorbed on the surface and are cleaved by the lewis and bronsted acid sites on the metal oxide surface. By this mechanism of action, the ability of negatively charged microorganisms, viral particles or cells to transmit genetic information against the substance to the next generation is defeated.

Thus, its broad microbial action is due to a dual mechanism of action, acting on the cell membranes of microorganisms such as bacteria and fungi that have one mechanism of action, but at the same time acting on genetic material. The second point is the mechanism of inactivation of the virus, which, unlike other microorganisms, has no membrane.

Also, as known from the mentioned patent MX 339086, the nanoparticle functionalized titania material has the following general formula:

E/MaO2(c)(OH)v(P04)w(S04)xCly(NH2)z (1)

wherein E is a complex solution of fruit and/or herbal extracts and M is titanium. The fruit and/or herbal extract is selected from grapefruit, lemon, tangerine and other citrus fruits.

As mentioned above, the present invention describes various uses of the nanoparticulate compounds of functionalized titanium dioxide, preferably but not limited to, in pure form (100%) or in an effective amount ranging from 10% to 90% for products requiring dilution, in the form of a solution comprising said compounds as active ingredient.

In another embodiment of the invention, the nanoparticle compound of functionalized titanium dioxide can be used in low proportions, wherein an effective amount of said compound is found up to 1%. The concentration used will depend on the dilution specified in the final product, so that a final concentration of 0.125% up to 0.625% is guaranteed.

Will functionalize the dioxideTitanium (TiO)₂) The compounds of (a) are mixed with water and optionally with at least another material to produce liquid aqueous compositions with a wide range of microbial applications with different uses and purposes, making them useful in the pharmaceutical, food, agricultural, livestock and aquaculture and medical industries.

A. Use of a nanoparticle compound of functionalized titanium dioxide as a water disinfectant or scavenger:

drinkable means that the water is suitable for human consumption in terms of its physicochemical parameters and in terms of microbiological indicators, and that water disinfection simply means the inactivation of microorganisms, in particular pathogens, causing diseases for water consumers, wherein the intensity and severity will depend on many factors such as the type of microorganism and the concentration of infectious agents in the water. Microbial disinfection is probably the most important treatment and also a major breakthrough in drinking water.

In a particularly preferred embodiment of the invention, a nanoparticulate compound of functionalized titanium dioxide is used as water disinfectant or decontaminant, preferably using an aqueous-based suspension, the percentage of which as active ingredient is present in an effective amount of from 30% to 99%. The percentage recommended for eliminating different test microorganisms varies from one bacterial population to another.

Tests conducted using the nanoparticle compound of functionalized titanium dioxide showed about a 99.999% reduction in the presence of microorganisms in water from residual water treatment plants and from springs and wells associated with drinking water distribution networks. Their water disinfection efficacy in the mentioned samples of different origin containing different microorganisms, such as mesophilic and fecal coliform and total coliform, pseudomonas, acinetobacter, aeromonas and escherichia coli, etc., has been demonstrated, as shown in the graph in figure 1 of the accompanying drawings.

Tests have shown that the use of nanoparticulate compounds of functionalized titanium dioxide does not affect the physicochemical parameters of water control, so that the treatment process does not require a subsequent step for eliminating it.

Moreover, by acting on the genetic material of the microorganism, a "natural" death occurs, avoiding the release of endotoxins in the water. Biodegradability tests carried out on nanoparticulate compounds of functionalized titanium dioxide show that the nanoparticulate compounds are 100% biodegradable when exposed to biological and non-biological elements of the environment.

Water and measured contaminant parameters such as turbidity, pH, solid color, temperature, conductivity, total solids, total dissolved solids, residual chlorine, phenolphthalein alkalinity, total alkalinity, bicarbonate, carbonate, hydroxide, total hardness, sulfate, chlorine, total coliform and fecal coliform are shown in table 1. Notably, the physicochemical parameters of the water as well as the conductivity were not changed, which are reflected in table 1.

Table 1-physical-chemical and microbiological tests from different water sources before and after administration of the formulation of the invention.

Comparing the use of nanoparticulated functionalized titanium dioxide compounds in drinking water with the traditional chlorination process, it is clear that the microbial elimination of faecal coliform is 100%, the microbial elimination of mesophilic aerobic bacteria is 100%, whereas in said chlorination process 87% to 99%, but the use of nanoparticulated functionalized titanium dioxide compounds does not result in toxicity and collateral damage from the use and abuse of chlorinated substances.

It should be noted that the chlorination process is associated with the process of liver injury, asthma and heavy metal accumulation, while toxicity tests on nanoparticulated functionalized titanium dioxide compounds prove to be harmless. As the results in Table 1 show, the physico-chemical variables are in the functionalized TiO₂The nanoparticle compounds of (a) show no change between pre-application and post-application sample sets, demonstrate microbial effectiveness and do not alter physico-chemical characteristicsAnd (4) sex.

The colony forming units of the different microorganisms present in the water from the various sources are shown in table 2. In the presence of a catalyst derived from functionalized TiO₂The efficacy of the nanoparticle compounds was quantified by the total amount of pathogen eliminated in the pre-application data and post-application data of the nanoparticle compounds of (1), as also demonstrated in fig. 1.

Table 2-shows the 100% effectiveness of the nanomaterials against various microorganisms

Microorganisms	Previous UFC/ml	After UFC/ml
			Total coliform bacteria count	400	0
Total coliform in feces	100	＜1.1
			Pseudomonas sp	800	0
Acinetobacter sp	996	0
			Aeromonas sp	432	0
Escherichia coli	1267	0

These unique properties confer the feasibility of modifying nanoparticulate titanium dioxide compounds with organic functional groups, inorganic groups and fruit and/or herbal extracts adsorbed on their surfaces and pores to act as active ingredients in liquid, colloidal and solid water treatment disinfectant products by eliminating microorganisms during their disinfection, which properties were previously thought to be impossible, since it is believed that the material will lose its properties in large quantities of water.

B. Use of nanoparticulate compounds of functionalized titanium dioxide as biopesticides and after harvest:

due to its mode of application, pesticides can be classified as surface applications, as they act only on the outer surface, or are systemically delivered to the interior of the plant upon absorption.

In another aspect of the invention, the nanoparticulate compound of functionalized titanium dioxide is used as a biopesticide and after harvesting, wherein the nanoparticulated compound is used in admixture with water in an effective amount of 0.8% to 30%, preferably 0.8% to 15%; furthermore, the use comprises the addition of an ionic surfactant in an amount of up to 4% and an organic or inorganic foliar adhesive in an amount of up to 6%, which allows the nanoparticulate compound of functionalized titanium dioxide to remain adhered to the leaves of the plant and prolong its effect, wherein the organic foliar adhesive is preferably, but not limited to, a resin or a polymer and the inorganic foliar adhesive is preferably, but not limited to, an acrylate.

The use of functionalized titanium dioxide nanoparticle compounds as pesticides was evaluated using different types of vegetables and seeds, as seed disinfectants and as post-harvest disinfectants for various crops to eliminate or reduce the presence of microorganisms and virus particles, including primarily bacteria, fungi and viruses. These are those which are often found in different process stages of the agricultural and food industry, leading to problems in crops and/or livestock, even affecting the production process, shelf life and human life.

In a first alternative embodiment using a nanoparticulate compound of functionalized titanium dioxide as pesticide, it is intended to eliminate sources of contamination or the sterilization/disinfection of seeds, for example in the case of tomato seeds, in which a delay in the growth of Haemophilus michiganensis (Ciavibacter miciganensis) is observed, or in the case of maize seeds, in which the functionalized titanium dioxide compound of the nanoparticles is applied directly, or dosed in the form of an emulsion or solution, proved to be effective in reducing the incidence of diseased plants. The results of the comparison of the studies in the exemplary plot are shown in the graph in fig. 2 of the accompanying drawings, with red indicating the proportion of healthy plants.

In a second alternative embodiment of the use of the nanoparticulate compounds of functionalized titanium dioxide as biopesticides for plantation or crops where the efficiency of incidence of fungi, bacteria and/or viruses on crops, such as, but not exclusively, fruits, green vegetables, perennial pastures, forests, leguminous plants and fruit tree cultures, such as papaya, cocoa, apple, mango, onion, vanilla, avocado, citrus fruits, capsicum, corn, coffee, sorghum, alfalfa, pumpkin, potato, fantastic wood, walnut trees, cedar, beans, chickpeas and roses, potatoes, tulips and carnation crops and the like, has been reported to be reduced by up to 100% by foliar and systemic application on a demonstration plot.

The pesticidal effects of the nanoparticle compound of functionalized titanium dioxide as a pesticide on various diseases and plagues of various types of crops such as solanaceae, tubers, berries, fruits, flowers, orchids, etc. are shown in table 3, where the efficacy of reducing the incidence of fungi, bacteria and/or viruses in crops from 93% to 100% can be seen.

Table 3-results of comparison of studies in exemplary plots

In another aspect of the invention, the nanoparticle compounds of functionalized titanium dioxide are used for post-harvest disinfection, that is, post-harvest elimination of microbial charge and help to extend shelf life by about 40% for, for example and not exclusively, papaya, lemon, pumpkin and tuber crops. In the graph of fig. 3 of the accompanying drawings, the increase in shelf life of different fruits and vegetables is shown.

In the case of post-harvest use, washing and immersion of the fruit in the nanoparticulated functionalized titanium dioxide compound was shown to help extend the shelf life of the product by up to about 40%, as can be seen in papaya, lemon, pumpkin and tuber crops, as shown in table 4.

In another aspect of the invention, the nanoparticle compound of functionalized titanium dioxide is present in the oily formulation in an effective amount of from 70% to 90% to improve the uptake by the plant.

TABLE 4 shelf life extension of different fruits and vegetables

C. Use of a nanoparticulate compound of functionalized titanium dioxide as a preservative:

from the above use, the use of nanoparticulate compounds of functionalized titanium dioxide as preservatives for the preparation of hygiene articles, cosmetics and industrial food products, was tested both in human beings and in animal husbandry and aquaculture, where the antibacterial effect is not limited to the exposure time defined by the disinfection process.

In another aspect of the invention, a nanoparticle compound of functionalized titanium dioxide is used as a preservative, wherein the nanoparticle compound is mixed with water in an effective amount of 0.02% to 5%. The most important characteristics are the microbiological activity, the residual properties and the thermal stability of the nanoparticle compounds of functionalized titanium dioxide.

The use of the nanoparticulate compound of functionalized titanium dioxide as a preservative strictly refers to its effectiveness in preventing the growth of microorganisms, mainly bacteria and fungi, although as already mentioned above, the activity is not limited thereto. Due to the residues, the microbial effect has an extended period of action, which makes it possible to protect food and/or cosmetics from microbial attack.

The use of the functionalized titanium dioxide nanoparticle compound was evaluated by differential thermal analysis and thermogravimetric analysis, with which it was demonstrated that the functionalized titanium dioxide nanoparticle compound remained stable in the temperature range-10 ℃ to 200 ℃, so that it could be used in the processes from cold storage or cryopreservation to cooking, without altering its structure or affecting the food concerned. These characteristics may also be beneficial in other industries such as chemical, pharmaceutical or cosmetic to maintain good condition or to extend the average life of products and raw materials.

The nanoparticulate compounds of functionalized titanium dioxide are useful in the food industry as preservatives in canned foods, dairy products, meats, cheeses, fish, prepared foods, processed and industrialized foods, refrigerated and frozen foods, desserts, beverages, and the like, but are not limited thereto.

The nanoparticulate compounds of functionalized titanium dioxide can also be used in other industries to protect substances from the action of microorganisms, for example in the case of the production of cosmetic or personal care products, for example in the formulation of lipsticks, coloured powders and liquids, shampoos, creams, hair conditioners, soaps, toothpastes, but not exclusively these products.

The results of the thermal analysis are shown in the graph of fig. 4 of the accompanying drawings, where the occurrence of decomposition can be observed at a stage at temperatures above 200 ℃. An example of the efficacy results as a preservative is shown in the graph of figure 5 of the accompanying drawings.

D. Use of a nanoparticle compound of functionalized titanium dioxide as an inducer or activator of tissue regeneration: tissue engineering changes the field of biomaterial development, referring to the practice of combining bioactive scaffolds, cells and molecules to create functional tissues.

Tissue engineering changes the field of biomaterial development, a practice that combines bioactive scaffolds, cells and molecules to create functional tissues. The goal of tissue engineering is to recall ideas or theories to restore, maintain, or improve damaged tissues or intact organs. Artificial skin and cartilage are examples of tissues engineered, which have been approved by the FDA. However, their use in human patients is currently limited.

The functionalized titanium dioxide nanoparticle compounds were tested with different cell lines and tissues to verify their compatibility for cytotoxicity and cell viability studies. Studies were conducted to compare the use of the functionalized titanium dioxide nanoparticle compounds with disinfectants or preservatives commonly used in medical practice. Said studies show that the nanoparticulate compounds of titanium dioxide are not only selective for pathogenic microorganisms, but they also promote an increase in the proliferative response of the tissues with which they come into contact. Such induction of nanoparticulate compounds conferring functionalized titanium dioxide useful in tissue therapy has been evaluated in various tissues and cell lines, but is not necessarily limited thereto, for imparting scarring and/or cell regeneration effects to the compounds.

In this aspect of the invention, the nanoparticulate compound of functionalized titanium dioxide can be used in a low proportion, with an effective amount of said compound of up to 1%. The concentration used will depend on the specified dilution in the final product, so that a final concentration from 0.125% to 0.625% is guaranteed.

The results of the cell lines, tissues and cell viability tested are shown in the graph of figure 6 of the accompanying drawings, showing proliferation and activation.

Use of nanoparticulate compounds of functionalized titanium dioxide in the pharmaceutical industry:

a drug is known to be a chemical substance used in the treatment, cure, prevention or diagnosis of a certain disease or also used to inhibit the initiation of an undesired physiological process. The salient and characteristic feature of the drug would be a substance that is applied to the body in a foreign way, which would result in a drastic change in the activity of the cells, which is the purpose of its use, in particular medical use.

The effectiveness, bioselectivity and harmlessness of nanoparticle compounds derived from functionalized titanium dioxide allow for the effective treatment and prevention of infectious processes caused by viruses, bacteria, fungi, spores, mycobacteria and parasites by administration through different systemic routes. Because of their action on a variety of microorganisms, the nanoparticle compounds of functionalized titanium dioxide are pharmacologically classified as anti-infective or antimicrobial agents. It should be noted that this category is more important than the antibiotic category, as it includes antiviral, antifungal/antimycotic, antimycotic and antiparasitic effects.

The specific action of a drug, compound, molecule or antimicrobial agent (nanoparticle compound in which functionalized titanium dioxide is contained) to achieve its efficacy is referred to as the "mechanism of action," which may be a biochemical process, an enzymatic reaction, movement of charge, Ca2+ transmembrane movement, or a catalytic process that causes observable and quantifiable effects.

The microbial agents currently available act through a series of mechanisms that are very different from each other, targeting different regions of the attacked cell. Various areas of microbial attack are generally considered: cell wall, cell membrane, protein synthesis and nucleic acid synthesis.

For the use of the nanoparticulate compounds of functionalized titanium dioxide in the pharmaceutical industry, tests were carried out to determine the lethal dose and the dose 50(LD and D50). In the graph of fig. 7 of the accompanying drawings, the lethal dose 50, the maximum toxic dose and the minimum effective dose are shown. In this aspect of the invention, the titanium dioxide (TiO) is functionalized₂) The nanoparticulate compound of (a) can be used in low proportions, wherein the effective amount of said compound is up to 1%, wherein the concentration used will depend on the specified dilution of the final product, so that a final concentration from 0.125% to 0.625% is guaranteed.

F. Use of a nanoparticle compound of functionalized titanium dioxide as a microbial agent:

generally, the microbial substance is of fermentative, biosynthetic or chemical origin and its action is to reduce the number of bacteria, mycoplasma, fungi or protozoa present in animals, plant species or humans, as well as in inert surfaces.

Antibacterial agents can be classified according to the microorganism they act upon:

-antibacterial agents: inhibiting or reducing the number of bacteria present;

antifungal/antimycotic agents: inhibiting or reducing the number of fungi present;

-antiviral agents: inhibition or reduction of the number of viral particles present:

-an antimycobacterial agent: inhibiting or reducing the number of mycobacteria present; and

-antiparasitic agents: inhibiting or reducing the number of parasites present.

In another aspect of the invention, a nanoparticle compound of functionalized titanium dioxide is used as the microbial agent, wherein the nanoparticle compound is mixed with water in an effective amount of 0.00025% to 34.97%.

For the use of nanoparticulate compounds functionalized titanium dioxide, efficacy tests were initially carried out on cell lines infected with different microorganisms, such as VERO (african monkey Kidney) confluent cells, dog Kidney or MDCK (Madin-Darby Canine Kidney ), and the necessary tests were carried out in small species by research protocols using methods approved by the institutional guidelines for the assessment of toxicity, cytotoxicity, irritation, absorption or lethal doses, etc.

Preliminary in vitro experiments with human cell lines demonstrated antifungal, antibacterial, antiviral or virucidal, mycobacterial and antiparasitic activity. For example, in one case diagnosed with pulmonary candidiasis treated with fluconazole, the fungus was eradicated within 3 days using an ingestible, functionalized titanium dioxide nanoparticle compound.

Another example is the treatment of tuberculosis and nontuberculous mycobacteria, where mycobacterium avium and mycobacterium abscessus are eradicated using pure nanoparticle compounds of functionalized titanium dioxide and with topical colloidal formulations. In the graph of fig. 8 of the accompanying drawings, anti-infective activity from various microorganisms is shown.

Gastrointestinal disorders such as helicobacter pylori bovine escherichia coli were initially treated with a liquid formulation in the form of a suspension, with concentrations of the nanoparticle compound of functionalized titanium dioxide ranging from 80ppm to 300ppm, with proven effective doses ranging from 0.001 ml to 2.1 ml per kg of body weight.

G. Use of a nanoparticle compound of functionalized titanium dioxide as an anti-tumor agent:

an antitumor agent is a substance that prevents malignant tumor cells from occurring, growing, or proliferating. These substances may be of natural, synthetic or semisynthetic origin.

The mechanism of action of antineoplastic drugs is characterized by affecting the process of cell division. Most effective are alkylating agents that form bonds with DNA that prevent RNA replication and transcription. They may function at any stage of the cell cycle, but are cytotoxic and may have a collateral effect on cancer of reproductive organs and other tissues. Antimetabolites can also act, by incorporation into their molecules, on cell cycle synthesis, in particular DNA and RNA synthesis, avoiding their correct transcription and replication. These drugs do not act specifically because they do not target cancer cells or tumors, which cause collateral effects on the genetic material of healthy cells, causing irreversible damage to the organism.

In addition, nanotechnology is an emerging field with applications in the medical field, a technology for designing and synthesizing anticancer nanoparticles. The advantage provided by these innovations, rather than strict drugs, is that they can be manipulated to specifically target a cancer or cancerous tumor. For the above reasons, the nanoparticle compound of functionalized titanium dioxide is a biotechnological product aimed at combating pathogenic microorganisms, whose central role is to take place on the genetic material by disjointing the genetic strand of DNA or RNA. The mechanism is the same as that adopted by antitumor cytotoxic drugs, and the advantage is that the nanoparticle material can specifically target cancer cells and can be directly applied to cancerous tumors.

Other tests were performed on tissues extracted from brain tumors induced by Wistar rats by TUNEL staining method through an animal model of glioblastoma multiforme that produces cancerous tumors in rats similar to tumors produced by the disease in humans. In these tests, it was observed that the nanoparticulate compounds of functionalized titanium dioxide act at the molecular level by degrading DNA and RNA molecules from cancer cells, with a mechanism of action similar to that of microbial elimination, thus eliminating not only malignant cells but also proliferating malignant cells. This effect is due to the ability of the nanoparticle compounds of functionalized titanium dioxide to recognize negative charges and the biological selectivity they attract. The latter follows the general principle of opposite charges attracting each other.

In this aspect of the invention, the titanium dioxide (TiO) is functionalized₂) The nanoparticle compound of (a) may be used in a low proportion, wherein the effective amount of the compound is up to 1%. The concentration used will depend on the dilution specified for the final product, so that a final concentration of 0.125% to 0.625% is guaranteed.

H. Use of a nanoparticle compound of functionalized titanium dioxide as an antimicrobial agent for animal husbandry, livestock and aquaculture:

the persistent resistance of microorganisms to antibiotics has prompted researchers to develop new molecules for controlling infections caused by pathogens. Various studies conducted to blend the nanoparticle compounds of functionalized titanium dioxide with various types of commercially available food products from the above-mentioned industries have demonstrated that mortality is reduced by about 33% mainly in the early stages when ingested by different animal species such as shrimp, poultry, goats and cattle. For example, comparative bioassay using shrimp larvae supplemented with a certain amount of nanoparticle material with other foods demonstrated that there is a preventive effect on Vibrio parahaemolyticus (Vibrocarahe oiyticus) and that the larval mortality decreased by 33% after 14ml/kg of food was added.

Histopathology, polymerase chain reaction testing, physico-chemical, bacteriological and toxicological analysis all demonstrated no changes, secondary or adverse effects, no toxicological effects on the digestive, respiratory or nervous systems.

In the graph of FIG. 9 of the accompanying drawings, the cumulative mortality is shown, where Tl-1.6 is the nanoparticle compound containing the smallest dose of functionalized titanium dioxide to 100% of the diet, T2-1.12 is the nanoparticle compound containing the effective dose of ml of functionalized titanium dioxide to 100% of the diet, T3-0.56 is the nanoparticle compound containing the excess dose of functionalized titanium dioxide to 100% of the diet, T4-C + is the positive control, and T5-C-is the negative control.

Although in the above description there has been mentioned various uses of the titanium dioxide nanoparticle compounds of the invention modified with organic functional groups adsorbed on their surface and pores, inorganic groups and fruit and/or herbal extracts, it should be stressed that a number of possible modifications can be made to said uses, without departing from the true scope of the invention, so that the technical features of the invention described in the uses of the invention claimed can be used alone or in any combination for the manufacture of the invention, as well as different uses not described herein. Accordingly, it should be understood that the use of the present invention is illustrative only and is not intended to limit the scope of the invention except as determined by the prior art and the appended claims.

Claims (24)

1. Use of a nanoparticulate compound of titanium dioxide modified with functional organic groups, inorganic groups and fruit and/or herbal extracts adsorbed on its surface and pores, wherein said compound is mixed with water and with at least another material to prepare a liquid aqueous composition with a wide range of microbiological applications with different uses and purposes, making it useful in the pharmaceutical, food, agricultural, livestock and aquaculture and medical industries.

2. Use of the nanoparticle compound of modified titanium dioxide according to claim 1, wherein the nanoparticle compound is used as a water disinfectant or water scavenger in the form of a water-based suspension.

3. Use of the nanoparticle compound of modified titanium dioxide according to claim 2, wherein said functionalized TiO as active ingredient₂Is present in an effective amount of 30% to 99%.

4. Use of the nanoparticle compound of modified titanium dioxide according to claim 1, wherein said compound is used as a biopesticide and post harvest.

5. Use of the nanoparticle compound of modified titanium dioxide according to claim 4, wherein said nanoparticle compound is used to eliminate a source of contamination or to disinfect/disinfect seeds.

6. Use of the nanoparticle compound of modified titanium dioxide as claimed in claim 4, wherein the nanoparticle compound is used in plantations and crops, wherein the incidence of fungi, bacteria and/or viruses in crops is reduced by foliar and systemic application.

7. Use of the nanoparticle compounds of modified titanium dioxide according to claim 6, wherein the nanoparticle compounds are used in fruit, green vegetables, perennial grasses, forests, legume crops and in fruit tree cultivation such as papaya, cocoa, apple, mango, onion, vanilla, avocado, citrus, pepper, corn, coffee, sorghum, alfalfa, pumpkin, potato, fantastic wood, walnut, cedar, beans, chickpea and rose, orchid, tulip and carnation crops.

8. Use of the nanoparticle compound of modified titanium dioxide according to any one of claims 4 to 7, wherein the nanoparticle compound is used directly or dosed in an effective amount of 0.8% to 30% in the form of an emulsion or solution; in addition, the use comprises the addition of an ionic surfactant in an amount of up to 4% and an organic or inorganic foliar adhesive in an amount of up to 6%, which allows the nanoparticulate compound of functionalized titanium dioxide to remain adhered to the leaves of the plant and prolong its effectiveness.

9. Use of a nanoparticle compound of modified titanium dioxide according to claim 8, wherein said nanoparticle compound is present in an effective amount of 0.8% to 15%.

10. Use of the nanoparticle compound of modified titanium dioxide according to claims 4 to 7, wherein the nanoparticle compound is present in an effective amount of 70% to 90% in an oily formulation.

11. Use of the nanoparticle compound of modified titanium dioxide according to claim 8, wherein the organic foliar adhesion agent is a resin or a polymer.

12. Use of the nanoparticle compound of modified titanium dioxide according to claim 8, wherein the inorganic foliar fertiliser is an acrylate.

13. Use of the nanoparticle compound of modified titanium dioxide according to claim 1, wherein the nanoparticle compound is used as a preservative in the preparation of industrial hygiene products, cosmetics and food products for the human and livestock industry and aquaculture industry, wherein the antimicrobial effect is not limited by the exposure time defined by the disinfection process.

14. Use of the nanoparticle compound of modified titanium dioxide of claim 13, wherein the nanoparticle compound is mixed with water in an effective amount of 0.02% to 5%.

15. Use of the nanoparticle compound of modified titanium dioxide according to claim 14, wherein said nanoparticle compound is used in the food industry as a preservative in canned foods, dairy products, meats, cheeses, fish, prepared foods, processed and industrialized foods, refrigerated and frozen foods, desserts and beverages and the like.

16. Use of the nanoparticle compound of modified titanium dioxide according to claim 14, wherein said nanoparticle compound is used for protecting substances from the effects of microbial activity, for example in the case of the manufacture of cosmetic or personal care products, for example in the formulation of lipsticks, coloured powders and liquids, shampoos, creams, conditioners, soaps, toothpastes.

17. Use of a nanoparticle compound of modified titanium dioxide according to claim 1, wherein said nanoparticle compound is used as an inducer or activator of tissue regeneration, since this compound, in addition to being selective for pathogenic microorganisms, also promotes an increase in the proliferative response of the tissues with which it comes into contact, conferring on it a cicatrizing and/or cell regenerating effect.

18. Use of a nanoparticle compound of modified titania according to claim 17, wherein the nanoparticle compound is present in an effective amount of up to 1%, whereby the concentration used will depend on the specified dilution in the final product, such that a final concentration of 0.125% to 0.625% is guaranteed.

19. Use of the nanoparticle compound of modified titanium dioxide according to claim 1, wherein said nanoparticle compound is administered by different systemic routes for the pharmaceutical industry, effective in the treatment and prevention of infectious processes caused by viruses, bacteria, fungi, spores, mycobacteria and parasites.

20. Use of a nanoparticle compound of modified titania according to claim 19, wherein the nanoparticle compound is present in an effective amount of up to 1%, whereby the concentration used will depend on the specified dilution in the final product, such that a final concentration of 0.125% to 0.625% is guaranteed.

21. Use of a nanoparticle compound of modified titanium dioxide according to claim 1, wherein said nanoparticle compound is used as a microbial agent, mixed with water in an effective amount of 0.00025% to 34.97%.

22. Use of the nanoparticle compound of modified titanium dioxide according to claim 1, wherein the nanoparticle compound is used as an anti-tumor agent against pathogenic microorganisms, producing its central effect in genetic material by disjointing the genetic strand of DNA or RNA.

23. Use of a nanoparticle compound of modified titania according to claim 22, wherein the nanoparticle compound is present in an effective amount of up to 1%, whereby the concentration used will depend on the specified dilution in the final product, such that a final concentration of 0.125% to 0.625% is guaranteed.

24. Use of the nanoparticle compound of modified titanium dioxide according to claim 1, wherein the nanoparticle compound is used as a microbial agent in livestock industry, livestock and aquaculture industry by mixing it with various types of commercially available food from said industry, when it is ingested by different animal species such as shrimp, poultry, goat and cow head, the mortality rate is mainly reduced by about 33% in the early phase.