WO2021205250A1

WO2021205250A1 - A gel

Info

Publication number: WO2021205250A1
Application number: PCT/IB2021/051987
Authority: WO
Inventors: Paolo Narciso
Original assignee: Hsd Holding Smart Device S.R.L.
Priority date: 2020-04-07
Filing date: 2021-03-10
Publication date: 2021-10-14
Also published as: IT202000007348A1

Abstract

Use of a gel comprising a reticulated dextran polymer and a gelling polymer for antibacterial and antiviral treatments, the reticulated dextran polymer having the glucose molecules linearly linked together by α1->6 glycosidic bond, reticulated by α1->4, α1->2 or α1->3 glycosidic bonds and having one or more ionic functional groups, the gel also comprising dispersed silver which is segregated on the outer surface of the gel by the reticulated dextran polymer.

Description

A GEL

DESCRIPTION

Field of application

The present invention is applicable in the field of healthcare and, in particular, relates to medical devices for healthcare treatment.

More in detail, the present invention relates to the use of a gel as an aid directly on a patient as well as in combination with other aids such as, for example, breathing devices or ventilation devices of rooms in order to purify the air flows passing through them.

Background art

It is historically known that silver has antimicrobial properties thanks to which it constitutes a valid inhibitor of viruses and bacteria.

As for the antimicrobial action mechanisms of silver, it binds to the thiol - SH groups present in enzymes, causing the deactivation thereof. In particular, silver forms stable S-Ag bonds with compounds containing the -SH groups present in the cell membrane which are involved in energy production and ion transport. Silver also seems to take part in the catalytic oxidation reactions that lead to the formation of R-S-S-R disulphide bonds. Therefore, the formation of disulphide bridges catalysed by silver leads to the variation of the structure of the enzymes influencing the function thereof.

Ag+ silver ions were then found to exhibit increased antimicrobial activity. In particular, such ions enter the cell and intersperse between the complementary purine and pyrimidine bases, resulting in denaturation of the DNA molecule. Moreover, it is certain that silver ions associate with DNA once they enter the cell.

In extreme synthesis, therefore, silver is able to “enter” bacterial or viral cells, damaging them, and it is believed that in order to do this, it makes use of membrane proteins which have, among other things, the function of transporting molecules across the membrane by means of specific pores, ion channels, ion pumps or carriers.

As just mentioned, it has been found that in order to accentuate the antimicrobial activities thereof, it is ideal that the silver is in ionic form, for example as silver nitrate or in a zeolitic matrix or as nanoparticles.

It has been observed, however, that the toxicity of silver is minimal if not nil, also due to the fact that the antibiotic action is exerted on lower order organisms such as bacteria (prokaryotes) and not on complex cells (eukaryotes).

However, the difficulty of increasing the antimicrobial and antibacterial effect of silver to make it increasingly effective has been found over time.

It was then discovered and experimentally verified that silver exhibits an accentuated antimicrobial activity in the presence of electric fields. This effect increase occurs near the anode and can be associated with an electrochemical injection effect. Obviously, this feature was found interesting, but not easily exploitable except by means of specific bulky tools and therefore of little use to the end user.

As a result, the use of silver for such purposes has been almost eliminated due to the development and mass production of antibiotics. The latter were equally effective and the effect thereof was more easily increased.

However, frequent use of the same antibiotics has resulted in the development of new bacterial strains which are antibiotic-resistant.

The existence of numerous forms of air filters specialised in the purification thereof from atmospheric particulates as well as from other micro- and nano agents present in the air is also known.

In this sense, small face masks and filtering devices for personal use are known to be inserted into the nasal cavities and provided with both crossing and turbulence filters.

In particular, among the latter, a particular type of filters is known which implement a shaped duct in order to create a turbulent effect on the air flow which causes the atmospheric particulates to collide with the walls of the duct itself. Such walls are then coated with gel whose composition is such as to allow the micro and nano-particles to penetrate it and remain trapped therein.

Similar types of filters are also applicable in machines for assisted breathing or the ventilation of environments.

However, a recognised drawback of such filters is their inability to clean the air filter from the bacterial and viral load present therein. In some cases, moreover, the same viruses and bacteria can colonise such filters, making them particularly dangerous.

Unfortunately, the use of the aforesaid antibiotics is impracticable in these cases.

Presentation of the invention

The object of the present invention is to at least partially overcome the drawbacks noted above, providing a medical aid whose use allows overcoming the drawbacks noted hitherto in the use of silver or antibiotics for the inhibition or destruction of bacteria and viruses.

Within this general object, a particular object is that such a medical aid is also effective against the new antibiotic-resistant bacterial strains.

A further object is that the same medical aid is easily usable by the end user.

Another object is that such an aid is also capable of trapping harmful particulates so as to be usable within filters for the purification of air flows.

Accordingly, a further object is to provide a filter of an air flow which allows to purify such flow from both harmful particulates and viruses and bacteria.

Such objects, as well as others which will become clearer below, are achieved by the use of a gel according to the following claims, which are to be considered as an integral part of the present patent.

In particular, the gel comprises a reticulated dextran polymer and a gelling polymer. The reticulated dextran polymer has glucose molecules linearly linked to each other by a1->6 glycosidic bond, reticulated by a1->4, a1->2 or a1->3 glycosidic bonds. The same reticulated dextran polymer also has one or more ionic functional groups, i.e., the reticulated dextran polymer is electrostatically charged.

Typically, but not necessarily, the electrostatically charged reticulated dextran polymer consists of QAE Sephadex®.

Sephadex® is a reticulated dextran polysaccharide in which glucose molecules are linearly linked together with a1->6, glycosidic bond while the reticulating is due to a1->4 glycosidic bonds, sometimes also a1->2 and a1->3. In particular, in QAE Sephadex®, the QAE prefix indicates that glucose molecules are functionalised with diethyl-2-hydroxypropyl amino ethyl quaternary amine.

According to an aspect of the invention, the gel also comprises dispersed silver.

As mentioned, the application of an electrical polarisation to a silver element results in an antibacterial and antiviral effect by such a silver element. More in detail, since the dispersed silver is metallic, part of it assumes ionic form over time and it is this form, as mentioned, which has an antibacterial function. The presence of an electric charge amplifies such an effect at the anode: it stimulates a greater generation of ions and concentrates the presence of ions produced in surrounding areas.

Advantageously, therefore, in the case of the present invention the electrostatically charged reticulated dextran polymer polarises the silver dispersed in the gel allowing to decrease, if not eliminate, the bacterial and viral charge of everything with which it comes into contact. In particular, advantageously, the silver present in the peripheral surface of the gel is polarised above all. In fact, the anion exchanger causes a separation of the charges and the anodic ones are segregated on the outer surface, which is also the one that comes into contact with the bodies to be disinfected. The dispersed silver then becomes more active or more available near such anodic areas.

The above-mentioned reticulated dextran polymers are generally used in the laboratory in column chromatography to separate molecules. However, it was found that, still advantageously, a gel based on such polymers and electrostatically charged, such as QAE Sephadex®, can also be used as a filter against the inhalation of substances harmful to health, for example atmospheric particulates or cigarette tar.

With regard to dispersed silver, according to another aspect of the invention, it is in an amount between 100 ppm and 1000 ppm by weight based on the total weight of the same gel.

The silver dispersion can occur in different modes. For example, it can be dispersed in a colloid subsequently used in the gel synthesis, for example by replacing the aqueous part used in the synthesis of known analogous gels. According to another example, the silver is deposited by stable nanocoating on amorphous particles subsequently dispersed in the gel. In the latter case, the amorphous particles typically comprise, but not necessarily, hydroxyapatite and/or teflon.

It follows that the authors of the present invention have found that a gel such as the one described thus far finds an advantageous use as a medical aid in all those internal or external treatments, for example also of wounds, skin infections or other, in which an antibacterial and antiviral treatment is also necessary or advisable.

The authors of the present invention have found that a gel such as the one described thus far finds an advantageous use also as a filter against the inhalation of harmful particulates, such as atmospheric particulates, and of viruses and bacteria. In other words, it was found advantageous to use a gel comprising a reticulated dextran polymer, a gelling polymer and dispersed silver (where the reticulated dextran polymer has glucose molecules linearly linked together by a1->6 glycosidic bond, reticulated by a1->4, a1->2 or a1->3 glycosidic bonds and one or more ionic functional groups) so as to purify an air flow from harmful substances, a viral load and a bacterial load.

In addition to the effect due to the dispersion of silver in the gel combined with the presence of reticulated dextran polymers and ionic functional groups, it is noted that the aforementioned gel allows the adsorption of particulates, not only by physical impact on the gel itself, but also by the electrostatic interaction due to the diethyl-2-hydroxypropyl amino ethyl functional group which makes the gel a strong anion exchanger. A strong or weak exchanger depends on the pK of the substituent: a strong exchanger has a very high pK for acids, so that it remains ionised in a wide pH range, in this case between 2 and 12 pH units.

Typically, QAE Sephadex® is prepared in the form of polyvinyl alcohol hydrogel (PVA, about 2%), also harmless and biocompatible, which, if necessary, can be reticulated by means of a chemical agent, borax, or more correctly sodium tetraborate decahydrate (Na2B4O7^*10H2O). The latter is a natural compound which covers a wide variety of uses. The absolute compound itself, like most chemical compounds, is toxic and therefore, like all chemical compounds, it is the amount used which determines the degree of danger. In this case the concentration of borax, which is not in the absolute form thereof but is chemically bound, is less than 0.3%. The amounts of the indicated components constituting the gel are indicative and may vary over the percentage unit, the remainder being entirely distilled water greater than 97%. The gel is therefore almost harmless, as it consists almost entirely of water.

The gel is prepared starting from a 4% hot-prepared PVA solution, about 90°C, to which QAE Sephadex is then added, which takes 48 hours at room temperature or 2 hours at 90°C to reinflate; the solution is then allowed to cool.

A second 4% borax solution is prepared at room temperature or hot- prepared to facilitate dissolution, which is diluted with sufficient distilled water for the desired gel dilution. The two solutions are then stirred and mixed together at room temperature to form the gel phase.

Additives can be added to the gel of the present invention to further improve the desired properties. Merely by way of non-limiting example, activated carbons, zeolites, beta-glucan, panthenol, lactic acid and propolis can be mentioned.

The authors of the present invention have found that the gel described thus far is particularly suitable for use in a nasal filtering device comprising: a containment body provided with an intake opening and a delivery opening for the air flow passing through it; one or more partitions impermeable to air, arranged inside the containment body and shaped to force the air flow to collide with the partitions and with the inner walls of the containment body, the partitions identifying a path free of obstacles for the air flow between the intake opening and the delivery opening,

Such a device is therefore characterised in that it comprises a gel according to what has been said thus far, arranged at least on the partitions so that the particulate matter, the viral content and the bacterial content present in the air flow, colliding against the gel, is retained therein and/or otherwise inhibited or destroyed.

In addition to the antibacterial and antiviral function, the device is able to reduce exposure to PM10 or smaller dimensions up to 0.1 pm for a number of hours. In this case, the principle of operation consists in the elimination, or in any case inhibition, of the bacterial and viral load as well as in the capture of airborne particulates which pass through the nasal cavity as a result of breathing.

The filtration of the bacterial and viral load occurs by polarisation of the dispersed silver which provides for and eliminates such viruses and bacteria.

The particulate filtration occurs both by mechanical impact and by an electrostatic process capable of absorbing and incorporating solid particles in a stationary fixed phase located inside the device. In a possible configuration, the device is made of medical PVC with additives included in Italian Ministerial Decree of 21 March 1973 and subsequent updates, corresponding to European Regulation 2008/39 EEC, biocompatible, very soft. The device consists of a container having a helical wall therein with the aim of increasing the active inner surface of the device by maximising the contact with the breathed air as much as possible. The gel according to the present invention is coated on the inner surface of the device, capable, by virtue of the electrostatic charge and viscosity thereof, of attracting and trapping both chemical agents in the form of airborne particles as well as the transported viruses and bacteria. The gel according to the present invention is in fact characterised by a high viscosity and has been selected for the strong anion exchanger property thereof. This principle can be extended to different types of applications which include an air flow through a labyrinthine system which brings the atmospheric particulates into contact with the gel.

Furthermore, the authors of the present invention have found that electrostatically charged reticulated dextran polymers, such as QAE Sephadex®, can advantageously be used as a filter for the solid fraction of airborne tar. Therefore, these compounds can be used in the preparation of cigarette filters capable of drastically decreasing the percentage of inhaled tar as well as neutralising airborne viruses and bacteria. According to an embodiment, the QAE Sephadex® and PVA gel described above, possibly in the presence of adsorbent additives such as activated carbons or zeolites, can be used to soak the fibres for preparing cigarette filters, for example cellulose acetate fibre. The gel is dried, leaving the QAE Sephadex® attached to the fibres.

Among the electrostatically charged reticulated dextran polymers, mention may be made of QAE Sephadex®, DEAE Sephadex®, CM Sephadex® and SP Sephadex® which, as the different prefixes suggest, have different substituent groups, which are diethyl-2-hydroxypropyl amino ethyl (QAE), a diethyl amino ethyl (DEAE), a carboxymethyl group (CM) and a sulphopropyl group (SP), respectively, which differ in the potency thereof in terms of ion exchangers. DEAE Sephadex® is a weak anion exchanger working in a pH range 2 to 9; while CM Sephadex® is a weak cation exchanger working in the pH range 6 to 10; finally SP Sephadex® is a strong cation exchanger working in the pH range 2 to 12.

The gelling polymer can be diluted using the colloid containing the dispersed silver or distilled water if the silver is deposited on microparticles and then dispersed in the gel. The same polymer can be selected from the group consisting of polyvinyl alcohol, agar agar, silicones, polyacrylamide, preferably polyvinyl alcohol. In general, hydrogels are formed from water-dispersed polymer chains whose aqueous medium content may exceed 99%. The hydrogels can form different natural compounds such as agar agar and various saccharide molecules, but also artificial compounds such as silicones and polyacrylamide. The choice of QAE Sephadex and PVA was dictated by the need for biocompatibility. If the use of the gel is envisaged in a filtration process which does not include direct contact with the human body, a different formulation can be considered, taking other polymers and copolymers into consideration.

In addition to comprising the electrostatically charged reticulated dextran polymer, the gel can further comprise sodium tetraborate decahydrate.

The present invention will now be described by way of non-limiting illustration, according to the preferred embodiments thereof.

Examples

Example 1 : Preparation of QAE Sephadex gel, PVA and sodium tetraborate gel

Preparation of solutions for about 2.5 kg of gel

Preparation of the PVA solution

Prepare a colloid in which silver particles of approximately 50 to 200 nm in size are dispersed in distilled water. Dissolve 40g of PVA in 960ml of such colloid; such an operation can be performed in two modes: (1) bringing PVA and colloid to 90°C for at least 8h avoiding boiling the solution, without mixing; (2) actively mixing PVA and colloid at temperatures below 90°, for the time necessary to achieve the complete dissolution of PVA, which must not be visible with the naked eye.

Allow to cool to room temperature.

Addition of QAE Sephadex

Add 5g of QAE Sephadex powder to the PVA solution for 48 hours at room temperature for 2 hours at 90°C.

Preparation of sodium tetraborate solution

Dissolve 9.6g of decahydrated sodium tetraborate in 240ml of hot distilled water (e.g., 90°C) to facilitate the formation of the solution until it becomes transparent and allow to cool.

Dilute the sodium tetraborate solution with 1320ml of distilled water and stir.

Hydrogel formation

Slowly add the PVA and QAE Sephadex solution to the sodium tetraborate solution while stirring everything with a glass rod until the gel is formed, i.e., until there is no phase separation between the gel phase and the aqueous phase.

The gel must be stored in an airtight container, with a layer of distilled water over it in order to avoid drying.

Example 2: Preparation of QAE Sephadex, PVA and sodium tetraborate gel in the presence of additives

Preparation of solutions for about 2.5 kg of gel Preparation of the PVA solution

Dissolve 40g of PVA in 960ml of distilled water, at 90°C for at least 8h avoiding boiling the solution. Alternatively, actively mix PVA and distilled water at temperatures below 90°, for the time necessary to achieve complete dissolution of PVA, which must not be visible with the naked eye.

Allow to cool to room temperature. Addition of QAE Sephadex

Preparation of sodium tetraborate solution Dissolve 9.6g of decahydrated sodium tetraborate in 240ml of hot distilled water (e.g., 90°C) to facilitate the formation of the solution until it becomes transparent and allow to cool. Dilute the sodium tetraborate solution with 1320ml of distilled water and stir.

Addition of additives (alternatively) · Add 50g of fine powder of additives (activated carbon and/or zeolite) to the sodium tetraborate solution at room temperature and stir.

• At room temperature, add granules of inert material (e.g., PFE or Hydroxyapatite), of grain size approximately between tens and hundreds of microns, on the surface of which metallic silver cores have been previously deposited and firmly adhered, of dimensions approximately between a few tens and a few hundred nanometres.

Hydrogel formation

Slowly add the PVA and QAE Sephadex solution to the sodium tetraborate solution while stirring everything with a glass rod until the gel is formed, i.e., until there is no phase separation between the gel phase and the aqueous phase. The gel must be stored in an airtight container, with a layer of distilled water over it in order to avoid drying.

Claims

1. Use of a gel comprising a reticulated dextran polymer and a gelling polymer for antibacterial and antiviral treatments, said reticulated dextran polymer having the glucose molecules linearly bound together by a1->6 glycosidic bonds, reticulated by a1->4, a1->2 or a1->3 glycosidic bonds and having one or more ionic functional groups, said gel also comprising dispersed silver, said dispersed silver being segregated on the outer surface of said gel by said reticulated dextran polymer.

2. Use according to claim 1 , wherein said dispersed silver is in an amount between 100 ppm and 1000 ppm by weight based on the total weight of said gel.

3. Use according to claim 1 or 2, wherein said dispersed silver is dispersed in a colloid with which to synthesise said gel.

4. Use according to claim 1 or 2, wherein said dispersed silver is deposited by stable nanocoating on amorphous particles subsequently dispersed in said gel.

5. Use according to claim 4, wherein said amorphous particles comprise hydroxyapatite.

6. Use according to claim 4, wherein said amorphous particles comprise teflon.

7. Use of a gel according to one or more of the preceding claims in the preparation of a filter for the purification of an air flow from harmful substances, a viral particles and a bacterial particles.

8. Use according to claim 7, wherein the filter is a nasal filter.

9. Use of a gel according to one or more of claims 1 to 6 as a medical aid for the treatment of infections or the like.

10. A nasal filtering device comprising: a containment body provided with an intake opening and a delivery opening for an air flow passing through it; one or more partitions impermeable to air, arranged inside said containment body and shaped to force the air flow to collide with said partitions and with the inner walls of said containment body, said partitions identifying a path free of obstacles for the air flow between said intake opening and said delivery opening, characterised in comprising a gel according to any one of claims 1 to 6 arranged at least on said partitions so that the particulate, viral content and bacterial content present in the air flow colliding against said gel penetrates at least partially and is retained therein.