# US 10,501,331 B2 · Totally-mesoporous zirconia nanoparticles, use and method for producing thereof

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- Number: US 10,501,331 B2
- Document ID: US10501331B2
- Status: Granted
- Kind: B2
- Application number: 15/547,122
- Filed: 2016-01-27
- Published: 2018-01-25
- Granted: 2019-12-10
- Earliest claimed: 2015-01-28
- Assignees: Brenta S.R.L.
- Applicants: Brenta S.R.L.
- Inventors: Gabriele Sponchia; Alvise Benedetti; Pietro Riello
- Web page: https://patentgrep.com/patent/US10501331B2

## CPC

- C01G 25/02: Oxides
- A61K 8/025: {Explicitly spheroidal or spherical shape}
- A61K 8/0279: {Porous; Hollow}
- A61K 8/28: Zirconium; Compounds thereof
- A61K 9/00: Medicinal preparations characterised by special physical form {(nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12)}
- A61K 9/143: {with inorganic compounds}
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 41/0057: {Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent}
- A61Q 19/00: Preparations for care of the skin
- A61K 9/5115: {Inorganic compounds}
- A61K 2800/10: General cosmetic use
- A61K 2800/412: Microsized, i.e. having sizes between 0.1 and 100 microns
- A61K 2800/413: Nanosized, i.e. having sizes below 100 nm
- A61K 2800/56: Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
- C01P 2004/03: obtained by SEM
- C01P 2004/04: obtained by TEM, STEM, STM or AFM
- C01P 2004/32: Spheres
- C01P 2004/61: Micrometer sized, i.e. from 1-100 micrometer
- C01P 2004/62: Submicrometer sized, i.e. from 0.1-1 micrometer
- C01P 2004/64: Nanometer sized, i.e. from 1-100 nanometer
- C01P 2006/12: Surface area
- C01P 2006/13: thermal stability thereof at high temperatures
- C01G: COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F (metal hydrides {monoborane, diborane or addition complexes thereof} C01B6/00; salts of oxyacids of halogens C01B11/00; peroxides, salts or peroxyacids C01B15/00; thiosulfates, dithionites, polythionates C01B17/64; compounds containing selenium, or tellurium C01B19/00; binary compounds of nitrogen with metals C01B21/06; azides C01B21/08; {compounds containing nitrogen, other non-metals and metal C01B21/082}; metal amides C01B21/092; nitrites C01B21/50; {compounds of noble gases C01B23/0005}; phosphides C01B25/08; salts of oxyacids of phosphorus C01B25/16; carbides C01B32/90; compounds containing silicon C01B33/00; compounds containing boron C01B35/00; compounds having molecular sieve properties but not having base-exchange properties C01B37/00; compounds having molecular sieve and base-exchange properties, e.g. crystalline zeolites, C01B39/00; cyanides C01C3/08; salts of cyanamide C01C3/16; thiocyanates C01C3/20)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- C01P: INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS

## Abstract

The present invention relates to novel totally-mesoporous zirconium oxide nanoparticles as well as a sol-gel synthesis process thereof which include an innovative nanoparticles purification step. Said nanoparticles are characterized by a totally-mesoporous structure i.e. a distribution of pores within the so-called the mesoporous range uniformly distributed throughout the entire nanoparticle volume. Furthermore, said nanoparticles are non-cytotoxic and present a high surface area, which make particularly suitable in both biomedical and industrial applications (e.g. drug delivery, heavy metals ion sequestration). The manufacturing method is simple and advantageously allows for high control over the shape and diameter of the nanoparticles as well as over the nanoparticles pores.

## Claims

### Claim 1

A zirconium oxide having formula ZrO2 in the form of particles, wherein said particles:
are nanoparticles or microparticles of generally spherical shape; and
have a stable totally-mesoporous structure with a generally uniform pore distribution distributed throughout the entire volume of said particle; and
have a specific surface area of more than about 200 m2/g.

### Claim 2 (depends on 1)

The zirconium oxide in the form of particles according to claim 1, wherein said particles have an average diameter ranging between about 20 nm to about 2000 nm.

### Claim 3 (depends on 1)

The zirconium oxide in the form of particles according to claim 1, wherein said mesoporous structure contains pores having an average diameter ranging between about 2 nm to about 10 nm.

### Claim 4 (depends on 1)

The zirconium oxide in the form of particles according to claim 1, wherein said particles are well-separated particles.

### Claim 5 (depends on 1)

The zirconium oxide in the form of particles according to claim 1, wherein said particles are non-cytotoxic or substantially non-cytotoxic.

### Claim 6 (depends on 1)

The zirconium oxide in the form of particles according to claim 1, wherein said particles are functionalized with or bound or adsorbed to one or more compounds selected from the group consisting of: organic molecules, macromolecules, metalorganic compounds, inorganic phases, and a combination thereof.

### Claim 7 (depends on 1)

A biocompatible nano-bio system comprising:
the zirconium oxide in the form of particles, as recited in claim 1; and
at least one compound chemically bound or adsorbed onto one or more of said particles, said compound being selected from the group consisting of: enzymes, polypeptides, proteins, antibodies, DNA, RNA, drugs, chemotherapy drugs, chelating agents, nanoparticles, metal oxides inorganic phases, luminophore agents, fluorophore agents, photocatalyzer agents, magnetic oxides, magnetic resonance imaging agents, enhancing agents for optical imaging, and a combination thereof.

### Claim 8 (depends on 7)

The biocompatible nano-bio system according to claim 7, wherein said compound is selected from the group consisting of: taxol, doxorubicin, magnetic iron oxides, inorganic or organometallic gadolinium compounds, rare earth complexes, metal oxides doped with rare earths, and a combination thereof.

### Claim 9 (depends on 7)

The biocompatible nano-bio system according to claim 7, wherein said compounds are loaded in the pores of said particles.

### Claim 10 (depends on 1)

A biocompatible material comprising:
the zirconium oxide in the form of particles, as recited in claim 1; or
a biocompatible nano-bio system comprising the zirconium oxide in the form of particles, as recited in claim 1, and at least one compound chemically bound or adsorbed onto one or more of said particles, said compound being selected from the group consisting of: enzymes, polypeptides, proteins, antibodies, DNA, RNA, drugs, chemotherapy drugs, chelating agents, nanoparticles, metal oxides inorganic phases, luminophore agents, fluorophore agents, photocatalyzer agents, magnetic oxides, magnetic resonance imaging agents, enhancing agents for optical imaging, and a combination thereof; or
a combination thereof.

### Claim 11 (depends on 10)

The biocompatible material according to claim 10, wherein said particles are dispersed in a matrix, said matrix being selected from the group consisting of: a resin, a photocurable resin, a polymer, a photocurable polymer, a biopolymer, an hydrogel, an oligomer, a monomer, and a combination thereof.

### Claim 12 (depends on 1)

A method for producing the zirconium oxide in the form of particles as recited in claim 1, said method comprising one or more of the following steps:
a) preparing a solution containing a surfactant, preferably hexadecylamine, and a suitable solvent, preferably ethanol, in an amount ranging between about 1:200 v/v to about 1:800 v/v;
b) mixing the solution obtained at the end of the preceding step with an aqueous solution of an alkaline halide and stirring until a homogeneous first solution is obtained;
c) preparing a solution containing a zirconia precursor, preferably zirconium iso-propoxide, and a suitable solvent, preferably ethanol, and stirring till a homogeneous second solution is obtained;
d) reacting said first solution with said second solution, preferably at room temperature and for a period of time of about 10 hours, so that a third solution is obtained, said third solution containing a dispersion of zirconia particles containing said surfactant;
e) drying, preferably air-drying, the sediment obtained after separating said zirconia particles from said third solution, so that a powder substantially composed of dried zirconia particles encapsulating said surfactant is obtained;
f) preparing a dispersion of said dried zirconia particles in a suitable liquid, preferably ethanol and water milli-Q in a ratio of 2:1, and subject said dispersion to a thermal treatment by means of a suitable reactor so that said encapsulated surfactant is removed, and a solution containing a sediment composed of non-purified zirconia nanoparticles is obtained;
g) filtering, washing and drying the sediment obtained at the end of the preceding step, so as to obtain a powder substantially composed of non-purified dried zirconia particles;
h) purifying said powder by means of a purification process, so as to obtain dried purified zirconia nanoparticles characterized by a substantially spherical shape and a mesoporous amorphous structure.

### Claim 13 (depends on 12)

The method according to claim 12, wherein said surfactant is selected from the group consisting of: hexadecylamine, octadecylamine, an amphiphilic ionic surfactant, an amphiphilic non-ionic surfactant, a non-ionic amine surfactant, a primary amine having an alkyl or aliphatic long chain, and a combination thereof.

### Claim 14 (depends on 12)

The method according to claim 12, wherein said alkaline halide is selected from the group consisting of all possible salts resulting by a binary combinations between:
an alkaline cation in the group consisting of Li, Na, K, Rb, Cs; and
an halide anion in the group consisting of F, Cl, Br, I,
or consisting of a combination of one or more of said salts, said alkaline halide being preferably sodium fluoride, sodium chloride, sodium bromide or sodium iodide, or a combination thereof.

### Claim 15 (depends on 12)

The method according to claim 12, wherein in said first homogeneous solution the molar ratio between said surfactant and said alkaline halide ranges between about 0.05 to about 0.5.

### Claim 16 (depends on 12)

The method according to claim 12, wherein said zirconia precursor is selected from the group consisting of: zirconium iso-propoxide, zirconium etoxide, zirconium n-butoxide, and a combination thereof.

### Claim 17 (depends on 12)

The method according to claim 12, wherein the molar ratio of said second solution ranges between about 0.02 to about 0.2, preferably 0.1, with respect to the total moles of said zirconia precursor in said second homogeneous solution.

### Claim 18 (depends on 12)

The method according to claim 12, wherein said thermal treatment is a solvothermal treatment taking place at a temperature between about 50° C. to about 300° C. for a period of about 1 hour to about 24 hour.

### Claim 19 (depends on 12)

The method according to claim 12, wherein said purification process comprises a sublimation process, taking place under low temperature and pressure so as to extract said encapsulated surfactant, or other residual solvents, without damaging the mesoporous structure of said particles.

### Claim 20 (depends on 19)

The method according to claim 19, wherein said sublimation process takes place under one or more of the following conditions:
pressure between about 10−5 bar to about 10−3 bar;
temperature between about 50° C. to about 150° C.;
time period between about 240 minutes to about 600 minutes.

### Claim 21 (depends on 12)

The method according to claim 12, wherein the physical properties of said particle are tunable by setting one or more of the following process parameters:
composition of said alkaline halide;
amount of said alkaline halide in said first solution;
relative size of cation and anion of said alkaline halide;
composition of said zirconium precursor;
said physical properties being selected from the group consisting of: average diameter, shape, sphericity, pores size, pores distribution, pores shape, and a combination thereof.

### Claim 22 (depends on 21)

The method according to claim 21, wherein said process parameters further include:
amount of said zirconium precursor in said second solution;
temperature of said solvo-thermal treatment;
duration of said solvothermal treatment,
and said physical properties being selected from the group consisting of: average diameter, shape, sphericity, pores size, pores distribution, pores shape, surface charge, and a combination thereof.

### Claim 23 (depends on 7)

A method for drug-delivery comprising the step of using the biocompatible nano-bio system according to claim 7.

### Claim 24 (depends on 7)

A method for photodynamic therapy for cancer treatment comprising the step of using the biocompatible nano-bio system according to claim 7.

### Claim 25 (depends on 7)

A method for bio-imaging of biological systems, or for targeting of biological compositions comprising the step of using the biocompatible nano-bio system according to claim 7.

### Claim 26 (depends on 10)

A method for regenerative medicine in combination with bio-plotting techniques or additive manufacturing advanced techniques, preferably 3d jet-printing comprising the step of using the biocompatible material according to claim 10 as a scaffold.

### Claim 27 (depends on 10)

A method for using the biocompatible material according to claim 10 in dentistry or prosthesis.