Antimicrobial and immunostimulatory system comprising an oxidoreductase enzyme

Abstract

The present invention relates to an antimicrobial and immunostimulatory system, applications thereof and a process for the production of the antimicrobial and immunostimulatory system. The present invention provides a storage-stable antimicrobial and immunostimulatory system comprising an oxidoreductase enzyme, a substrate for the oxidoreductase enzyme and hydrogen peroxide in an aqueous solution wherein the substrate for the oxidoreductase enzyme is present up to 90% by weight and water is present up to 20% by weight based on the weight of the total composition; the system has a pH from approximately 4 to 8; and the system provides a two-stage hydrogen peroxide release.

Description

FIELD OF THE INVENTION[0001]The present invention relates to an antimicrobial and immunostimulatory system, applications thereof and a process for the production of the antimicrobial and immunostimulatory system.BACKGROUND TO THE INVENTION[0002]Well-known antimicrobial compositions include conventional treatments such as antiseptics and antibiotics. Other treatments include silver-containing gels, compounds containing heavy metals and solutions of hydrogen peroxide and natural and synthetic pharmaceutically active substances. However, treatments such as antibiotics have disadvantages because of the emergence of antibiotic resistance. Furthermore, high levels of hydrogen peroxide have a toxic effect. In addition, hydrogen peroxide in solution is typically unstable and it is difficult to provide a sustained delivery system for this material. Thus, for a wide variety of different reasons, conventional antimicrobial treatments have many drawbacks.[0003]Additionally, there are a number o...

AI Technical Summary

Benefits of technology

[0031]This initial endogenous reservoir of hydrogen peroxide present in the system is storage-stable and remains in the system until the second tier of hydrogen peroxide is released. This storage-stability aspect is another advantage of the present invention. In the context of this application, storage-stable means that the endogenously produced hydrogen peroxide is maintained within the system for a period of from approximately 3 months up to approximately 36 months. Furthermore, the system does not degrade, separate or lose activity during this time period. The expected shelf life for the system under normal conditions is approximately 36 months. In addition, the system when subject to sterilisation, for example by irradiation, does not deteriorate in quality or activity.

[0032]Upon use or application of the system of the present invention, a second-tier of hydrogen peroxide is released where the level of sustained release hydrogen peroxide produced upon rehydration of the system is at least 10 mg, preferably 20 mg of hydrogen peroxide per litre or parts per million. Again, the level of sustained release hydrogen peroxide generated will depend on the amount of oxidoreductase enzyme and / or substrate for the oxidoreductase enzyme present in the system. We have advantageously found that after a set time period and subsequent dilution / rehydration the amount of sustained release hydrogen peroxide exceeds that present in natural honey. Furthermore, we have advantageously found that the sustained release of further hydrogen peroxide in the system of the invention occurs for at least a twenty-eight, if not a forty-eight hour period.

[0033]Generally, the immunostimulatory effect of the system of the present invention is mediated by interleukin-1. The system of the present invention promotes the release of interleukin-1 (IL-1) from skin cells. IL-1 is a cytokine which is also secreted by macrophages, monocytes and dendritic cells. It is an important part of the inflammatory response of the body against infection. It increases the expression of adhesion factors on endothelial cells to enable transmigration of leukocytes to sites of infection. It also acts on the thermoregulation centre of the brain leading to an increased body temperature in the form of a fever. It is therefore called an endogenous pyrogen. The increased body temperature helps the body's immune system to fight infection. This is the initial phase of an inflammatory immune response which augments the antimicrobial activity of the system. The inflammatory response plays a central role in wound healing through its defence against possible infection and by participating in cell and tissue repair and re-growth. The antimicrobial effect of the system of the present invention is aided and complemented by the immunostimulatory effect which aids the regrowth and repair of damaged tissues and / or cells.

[0034]The system of the present invention is based on the unexpected findings of our research which is contrary to the accepted perception in the field. We have established that UMF does not have a role in the antimicrobial / antibacterial activity of Manuka honey and that there is no detectable endogenous hydrogen peroxide in diluted or undiluted Manuka honey. We have found that the glucose oxidase pathway is not operational on initial application of Manuka honey and is only operational to provide an antimicrobial effect following dilution of honey after a period of time has elapsed. Contrary to the common perception in the field, we conclude that Manuka honey antimicrobial efficacy is more than likely mediated through a growth limiting available water content, a marked low initial pH and the production of hydrogen peroxide via the glucose—glucose oxidase pathway only

[0035]The system of the present invention advantageously utilises these new and unexpected findings and provides a system which gives a regulated, defined and reproducible level of antimicrobial activity and demonstrates a significant difference and increase in activity over the natural honey product. Thus, the system of the present invention overcomes the many disadvantages, in terms of variability, activity, viscosity and additional components which can cause allergic reaction, associated with the natural honey product, Manuka honey.

[0036]An additional benefit from the system of the invention is the ability to alter the quantity of active and excipient ingredients thereby permitting the production of a range of formulations of various strengths and properties. This includes the ability to optimise the pH for the required target site.

Problems solved by technology

However, treatments such as antibiotics have disadvantages because of the emergence of antibiotic resistance.

Furthermore, high levels of hydrogen peroxide have a toxic effect.

In addition, hydrogen peroxide in solution is typically unstable and it is difficult to provide a sustained delivery system for this material.

However, despite a significant amount of research aimed at identifying the substance(s) mediating the non-peroxide activity, or UMF, as yet, the precise nature of this activity is currently not known and no such substance has been clearly identified.

Some of the disadvantages associated with conventional treatments are outlined previously.

In this respect it can be expected to demonstrate a degree of variability which may be unacceptable for its use in many clinical applications.

Secondly, honey is mainly used for topical application.

Finally, honey is a natural product, which will have many additional compounds present and some of these compounds may give rise to an allergic reaction when it is applied.

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