KR102605808B1 - Composite Materials Manufacturing Method for Viruses Adsorption - Blocking and Apoptosis-Inactivation Function - Google Patents

Abstract

The present invention relates to a method for producing a composite with virus adsorption and killing properties, and more specifically, to a method for producing a composite material of hydroxyapatite with virus adsorption properties and copper or platinum with virus killing properties.

Description

Composite Materials Manufacturing Method for Viruses Adsorption - Blocking and Apoptosis-Inactivation Function }

Entering the 21st century, SARS (severe acute respiratory syndrome) in 2002, swine flu (swine flu) in 2009, MERS (Middle East respiratory syndrome) in 2015, and COVID-19 (coronavirus infection -19) in 2019 ), the emergence of new viruses with high human contagiousness and high risk of death is becoming more frequent, and their emergence cycle is shortening. And with globalization, movement/urbanization and movement between countries are easy, so the spread is fast, social and economic damage is rapidly increasing, and new viruses are rapidly mutating. Additionally, there is a problem that the time it takes to develop vaccines and treatments may increase as new viruses emerge. Therefore, materials that can be applied to personal and household quarantine products that can effectively block viruses are needed.

Hydroxyapatite is an inorganic component that makes up the teeth and bones of the human body, and is mainly used as a medical material such as a bioceramic material and bioreplacement material. Since it has both cation and anion exchange properties, it is a high-performance adsorption material for purifying high-purity biopharmaceuticals. It is being used. Therefore, it is used for adsorption and separation of RNA, Viruses, Membrane Proteins, Vaccines, Polyclonal & Monoclonal Antibodies, DNA, Antibody Fragment, etc.

In addition, metallic ions generally exhibit sterilizing properties, and have the effect of causing trace amounts of metal ions to disrupt the metabolic function of microorganisms and kill them through direct contact. Among these, copper ions penetrate through the outer cells of the virus, destroying the cell membrane and accelerating cell damage, damaging the DNA inside the virus and killing it. It is also reported that it has an excellent virus destruction effect and theoretically can be effective against all types of viruses. Also, platinum is known to destroy proteins and DNA when it comes into contact with bacterial viruses.

Accordingly, the invention of a composite material with virus adsorption-blocking and killing-inactivation properties was achieved through the combination of hydroxyapatite, which shows high adsorption properties for various viruses, and copper or platinum, which have virus killing properties.

Copper or platinum, which have a virus-killing effect, can only be expected to have a virus-killing effect if they come into contact with the virus. Therefore, if they do not come into contact with the virus, there is a problem that the virus-killing function can hardly be expected. Therefore, it is necessary to allow copper or platinum ions, which are effective in killing and inactivating viruses, to act directly.

Therefore, the present invention relates to a method of manufacturing a complex with virus adsorption-blocking and killing-inactivation functions, in which hydroxyapatite, which has adsorption properties for DNA, RNA, proteins, antibodies, viruses, etc., is mixed with copper or platinum, which have virus killing properties. It relates to a method of manufacturing a composite material capable of adsorption-blocking and killing-inactivating viruses by combining ions.

Complexes of hydroxyapatite and metal ions provide antibacterial properties using silver, such as domestic patent registration 10-1764596 and domestic patent application 10-2017-0049388, and minerals such as sericite and silitasol, as shown in domestic patent registration 10-2051622. There are methods for producing inorganic antibacterial agents complexed with silver, copper, zinc, etc. However, the above methods have the disadvantage of requiring complex processes and high manufacturing costs, such as requiring multiple reactions or sintering at high temperatures of 600 to 1,300 degrees.

Therefore, in the present invention, a composite material of hydroxyapatite and copper or platinum for adsorption-blocking and killing-inactivation of various viruses is manufactured through a simplified process and low-cost, economical method so that it can be applied to various hygiene/quarantine products. .

In order to solve the above problems, we have arrived at the present invention after much careful study.

In order to solve the above problems in the virus blocking composite material according to the present invention, (1) mixing a calcium salt-containing material, a phosphate-containing material, and a metal salt; (2) adding a weakly acidic to strongly alkaline aqueous solution to the mixture of (1); (3) reacting the mixture (2) by ball milling; (4) It consists of the step of drying and pulverizing the reactant of (3), and the above processes are used to produce a virus adsorption-blocking and killing-inactivation composite material.

Step (1) of the present invention is to prepare a mixture composed of a calcium salt-containing material, a phosphate-containing material, and a metal salt material. By preparing the above mixture, the molar ratio of calcium salt and phosphate, that is, Ca/P molar ratio, is 1.0 to 2.0. The most preferable Ca/P molar ratio is 1.6 to 1.8, and the metal salt is 0.1 to 0.1 of the total calcium salt and phosphate-containing materials. It is added at a weight ratio of 20%, and the most preferred content is 0.5 to 5% by weight.

Calcium salt sources in step (1) include calcium hydroxide, calcium carbonate, calcium chloride, calcium nitrate, calcium oxide, calcium sulfate, calcium silicate, calcium gluconate, calcium arsenate, calcium acetate, calcium broride, calcium glycerine phosphate, and calcium lactate. , calcium citrate, calcium pyropiionate, calcium ascotate and their anhydrates and hydrates, tetracalcium phosphate, tricalcium phosphate, octalcalcium phosphate, dicalcium phosphate dihydrate, dicalcium phosphate, calcium pyrophosphate, dihydrate calcium pyrophosphate, It is used by selecting from the group consisting of calcium dihydrogen phosphate and calcium metaphosphate. Sources of phosphate include orthophosphoric acid, phosphorus pentoxide, ammonium monophosphate, ammonium diphosphate, metaphosphoric acid, pyrophosphate, sodium diphosphate, triphosphate, phosphoric acid, potassium diphosphate, magnesium diphosphate, tripotassium phosphate, sodium phosphate, Monobasic sodium phosphate, monobasic potassium phosphate, phosphoryl chloride, polymetaphosphate, tricalcium phosphate, tetracalcium phosphate, tricalcium phosphate, octacalcium phosphate, dicalcium phosphate dihydrate, dicalcium phosphate, calcium pyrophosphate, dihydrate calcium pyrophosphate, It can be used by selecting from the group consisting of calcium dihydrogen phosphate and calcium metaphosphate. Sources of metal salts include copper compounds such as cuprous chloride, cupric chloride, cuprous iodide, copper nitrate, copper pyrophosphate, and copper sulfate, or chloroplatinic acid, platinum oxide, platinum dioxide, platinum chloride, platinum chloride, and platinum hydrochloride. , platinum hydroxide, platinum nitrate, etc. can be selected from the group consisting of platinum compounds.

Step (2) is a step of adding an aqueous solution to the mixture of calcium salts, phosphates, and metal salts prepared in step (1) above and adjusting the aqueous solution from weakly acidic to strongly alkaline. A method for controlling the pH of the aqueous solution in this step. You can adjust the pH by adding inorganic salts directly or using an aqueous alkaline solution mixed with inorganic salts. At this time, the pH of the weakly acidic and strongly alkaline aqueous solution is pH 6.0 to pH 14.0, and according to the present invention, pH 7.0 to pH 10.0 is most appropriate. If the pH is too low, the reactivity may be low and the formation of hydroxyapatite due to the reaction between calcium salt and phosphate may be delayed, and if the pH is too high, the pH of the composite material may become too high after the reaction. If the pH is high, there is no major problem when applied to products that do not come into contact with the human body, but when applied to products that come into contact with the human body, it may cause an allergic reaction.

The basic source may be selected from the group consisting of alkaline compounds such as sodium hydroxide, potassium hydroxide, ammonia, lithium hydroxide, calcium hydroxide, and magnesium hydroxide.

Step (3) is a step of reacting the mixture of steps (1) and (2) by ball milling. In this step, the mixture is reacted by wet reaction and ball milling, and rapid conversion to hydroxyapatite occurs. , the added metal salt material, copper or platinum, is more easily substituted into the hydroxyapatite crystal structure. Ball milling operates at a speed of 100Rpm to 400Rpm, with the most desirable speed being 200Rpm to 300RpM. In step (2), the aqueous solution adjusted to an appropriate pH and the aqueous solution added with the mixture are reacted for 1 hour to 240 hours at a ball mill temperature of 10℃ to 110℃. Most preferably, the ball mill reaction is performed at 25°C to 80°C for 24 to 72 hours. When reacting by ball milling, the higher the speed and temperature, the faster the reaction and substitution occur. The reaction temperature may be set to room temperature, but if set to room temperature, the reaction time may increase.

Step (4) is a step of drying and pulverizing the complex that has gone through the process of step (3) above. In this step, the synthesized complex can be filtered through a centrifuge or filter. During filtration, the pore size of the filter paper can be selected and used depending on the particle size, and the centrifuge can be used to filter at a speed of 1,000 RPM to 10,000 RPM, most preferably 3,000 RPM to 5,000 RPM. The filtered complex is dried at a temperature of 100°C to 500°C, most preferably at 150°C to 200°C. The dried composite is pulverized using a grinder. For grinding, grind to 1 mm or less through a coarse grinder and grind to 50 um or less through a fine grinder to produce composite fine powder.

In addition, when using it as a raw material for surface treatment of polymers such as fibers, metals, ceramics, etc. or for manufacturing a composite matrix, it is possible to omit the process of step (4) above and apply the composite manufactured only through the process up to step (3).

Therefore, the copper/platinum-containing hydroxyapatite produced by the present invention, that is, the virus adsorption-blocking and killing-inactivation complex, can be used to manufacture filters such as masks and air purifiers, household quarantine products, and medical and military products for blocking viruses. It can be applied to.

The present invention has the following effects.

Influenza viruses such as new influenza (swine flu), which have recently shown contagious worldwide, Severe Acute Respiratory Syndrome (SARS, SARS-CoV), Middle East Respiratory Syndrome (MERS-CoV), and Coronavirus Infectious Disease-19 (Coronavirus) It is important to effectively block coronaviruses such as COVID-19. In particular, in the case of SARS and MERS in the past, there was no contagious ability without symptoms, but COVID-19 has a risk of being very contagious even when asymptomatic, and various mutations of the virus are occurring. Therefore, it is necessary to develop and manufacture materials that can be applied to products that can fundamentally block various viruses and mutant viruses, such as the emergence of new viruses.

Hydroxyapatite has very strong adsorption properties for viruses and the DNA or RNA that forms the basis of viruses, and copper and platinum kill viruses. Therefore, it is possible to fundamentally block various viruses by adsorbing and blocking viruses and killing and inactivating them by supporting copper or platinum ions on hydroxyapatite.

Through the present invention, it is possible to manufacture a composite material that fundamentally blocks and kills various viruses, so it can be applied to hygiene/quarantine-related products such as masks and filters, enabling effective quarantine in everyday life during the development period of vaccines and treatments.

Figure 1 shows the results of X-ray diffraction analysis of hydroxyapatite prepared in Example 1.
Figure 2 shows a scanning electron microscope photograph of the hydroxyapatite-platinum ion composite particles prepared in Example 1.
Figure 3 shows a scanning electron microscope photograph of the hydroxyapatite-copper ion composite particles prepared in Example 2.

Weigh 74.09 g of calcium hydroxide, 115.3 ml of 85% phosphoric acid (Ca/P molar ratio 1.67), and 0.2 g of platinum chloride and mix them. While mixing the above mixed solution, the pH is adjusted to 10 by adding 3M sodium hydroxide aqueous solution. The adjusted mixed aqueous solution was added to the 1L Ball Mill Port, 1kg of 1mm and 3mm sized zirconia balls were added, the temperature of the ball mill was set to 60°C, and ball milled at a speed of 250RPM for 48 hours. After ball mill reaction, it was filtered, washed, and dried at 150°C for 15 hours. The dried composite was coarsely ground and finely ground to obtain composite fine powder.

Weigh and mix 378.17 g of dibasic calcium phosphate, 111.15 g of calcium hydroxide (Ca/P molar ratio 1.67), and 30 g of copper chloride. 500 ml of distilled water was added to the mixture, added to a 2L Ball Mill Port, 0.9 kg each of 1 mm, 3 mm, and 5 mm sized alumina balls were added, and ball milled at room temperature at a speed of 280 RPM for 48 hours. After the ball mill reaction, it was filtered, washed, and dried at 120°C for 24 hours. The dried composite was pulverized to obtain composite fine powder.

After weighing 236.15 g of calcium nitrate, 73.37 g of ammonium phosphate (Ca/P molar ratio 1.8), and 10 g of copper chloride, mix and place in a 2L Ball Mill Port. 1,000 ml of an aqueous alkaline solution containing 40 g of sodium hydroxide added to 1,000 ml of distilled water was placed in a 2L Ball Mill Port, then 1.3 kg of 3 mm and 5 mm sized alumina balls were added and ball milled for 12 hours at a speed of 200 RPM. After the ball mill reaction, it was filtered and dried at 150°C for 10 hours, and fine powder of 50um or less was obtained using a grinder.

Weigh and mix 344.18 g of dibasic calcium phosphate, 100.09 g of calcium carbonate (Ca/P molar ratio 1.67), and 20 g of copper chloride. Add 1,000 ml of distilled water to the mixture and adjust the pH to 10 by adding 1 M aqueous sodium hydroxide solution while stirring. The mixed aqueous solution was added to a 2L Ball Mill Port, 1.3 kg of 1 mm alumina balls and 1 kg of 3 mm alumina balls were added, and ball milling was performed at room temperature at a speed of 250 RPM for 72 hours. After the ball mill reaction, it was filtered, washed, and dried at 120°C for 24 hours. The dried composite was pulverized to obtain composite fine powder.

Claims (10)

(1) mixing a calcium salt-containing material, a phosphate-containing material, and a metal salt
(2) Adding an aqueous solution to the mixture and adjusting it to change from a weakly acidic to a strong alkaline aqueous solution.
(3) Ball milling the mixture to react
(4) Method for producing a complex of virus adsorption and killing functions, including the steps of filtration, washing, drying, and grinding. According to clause 1,
Method for producing a complex with virus adsorption and killing functions, characterized in that the concentration ratio of calcium salt and phosphate, that is, the molar ratio of Ca / P in step (1) is 1.0 to 2.0. According to clause 1,
In step (1), calcium salt raw materials include calcium hydroxide, calcium carbonate, calcium chloride, calcium nitrate, calcium oxide, calcium sulfate, calcium silicate, calcium gluconate, calcium arsenate, calcium acetate, calcium broride, calcium glycerin phosphate, and calcium lactate. , calcium citrate, calcium pyropiionate, calcium ascotate and their anhydrates and hydrates, tetracalcium phosphate, tricalcium phosphate, octalcalcium phosphate, dicalcium phosphate dihydrate, dicalcium phosphate, calcium pyrophosphate, dihydrate calcium pyrophosphate, Method for producing a complex with virus adsorption and killing function, characterized by calcium dihydrogen phosphate and calcium metaphosphate According to clause 1,
In step (1), the phosphate raw materials include orthophosphoric acid, phosphorus pentoxide, monobasic ammonium phosphate, dibasic ammonium phosphate, metaphosphoric acid, pyrophosphoric acid, sodium diphosphate, triphosphoric acid, phosphoric acid, potassium diphosphate, magnesium diphosphate, tripotassium phosphate, Sodium phosphate tribasic, sodium phosphate monobasic, potassium phosphate monobasic, phosphoryl chloride, polymetaphosphate, magnesium triphosphate, tetracalcium phosphate, tricalcium phosphate, octalcalcium phosphate, dicalcium phosphate dihydrate, dicalcium phosphate, calcium pyrophosphate, dihydrate. Method for producing a complex with virus adsorption and killing function, characterized by calcium pyrophosphate, calcium dihydrogen phosphate, and calcium metaphosphate. According to clause 1,
Method for producing a complex with virus adsorption and killing functions characterized by copper compounds and platinum compounds as metal salt raw materials in step (1) above. According to clause 1,
A method for producing a complex with virus adsorption and killing functions, characterized in that the content of the metal salt in step (1) is 0.1 to 30% of the total weight of the calcium salt and phosphate. According to clause 1,
A method for producing a complex with virus adsorption and killing functions, characterized in that the pH of the weakly acidic or strongly alkaline aqueous solution in step (2) is pH 6.0 to pH 14.0. According to clause 1,
A method for producing a complex with virus adsorption and killing functions, characterized in that the alkaline source in step (2) is sodium hydroxide, potassium hydroxide, ammonia, lithium hydroxide, calcium hydroxide, and magnesium hydroxide. According to clause 1,
A method for producing a complex with virus adsorption and killing functions, characterized in that the reaction is carried out at a ball mill temperature of 10 ℃ to 110 ℃ in step (3). According to clause 1,
A method for producing a complex with virus adsorption and killing functions, characterized in that the ball mill reaction is performed for 1 hour to 240 hours in step (3).