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Title:
PREVENTIVE PRODUCTS AGAINST PATHOGENIC GERMS, AND METHOD FOR USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2014/033490
Kind Code:
A1
Abstract:
The subject of the invention is a group of preventive products to be used against pathogenic germs, and the method for using these products, each product is being a special combined additive for preventive purposes, which could be used as additive or supplementary material in animal feed to produce products primarily for preventing and treating bacterial infection of poultry, which selectively inhibit the propagation of pathogenic germs that generate endo and exo toxins. The product according to the invention suitable primarily for preventing and treating bacterial contamination of poultry. It is charactrised by that, the product is prepared by homogenizing or blending methylglyoxal or its diacetate, i.e. methylglyoxal diacetate with some organic acids and/or in combination with Na salts of organic acids. During the method according to the invention the product is added to the drinking water of the animals and/or mixed in the feed, and in this way it is administered to the animals, and/or used for disinfecting the bedding materials.

Inventors:
HUTAS ISTVAN GEZA (HU)
Application Number:
PCT/HU2012/000088
Publication Date:
March 06, 2014
Filing Date:
August 31, 2012
Export Citation:
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Assignee:
PHARMATEKA KUTATO FEJLESZTOE ES SZOLGATATO KFT (HU)
HUTAS ISTVAN GEZA (HU)
International Classes:
A61P31/00; A01K1/015; A23K1/18; A61K31/121; A61K31/19; A61K31/375
Domestic Patent References:
WO2010082846A12010-07-22
WO2010044042A12010-04-22
WO2009066117A12009-05-28
WO2009066117A12009-05-28
WO2004080210A12004-09-23
Foreign References:
US4048299A1977-09-13
HUP0700745A22009-07-28
EP2224918A12010-09-08
EA201000854A12010-12-30
EP0005346A11979-11-14
EP0597167A11994-05-18
GB2027590A1980-02-27
US4716173A1987-12-29
US20030194451A12003-10-16
Other References:
MALETTA ANNE B ET AL: "Effect of Coffee Filtrate, Methylglyoxal, Glyoxal, and Caffeine on Salmonella Typhimurium and S. Enteritidis Survival in Ground Chicken Breasts", JOURNAL OF FOOD SCIENCE, vol. 77, no. 2, February 2012 (2012-02-01), pages M135 - M141, XP002694084
CAMPBELL ET AL: "Methylglyoxal and other carbohydrate metabolites induce lanthanum-sensitive Ca<2+> transients and inhibit growth in E. coli", ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, ACADEMIC PRESS, US, vol. 468, no. 1, 14 November 2007 (2007-11-14), pages 107 - 113, XP022344721, ISSN: 0003-9861, DOI: 10.1016/J.ABB.2007.09.006
TALUKDAR ET AL: "Further testing of antiviral activity of methylglyoxal urgently needed", MEDICAL HYPOTHESES, EDEN PRESS, PENRITH, US, vol. 67, no. 3, 1 January 2006 (2006-01-01), pages 673 - 674, XP005513897, ISSN: 0306-9877, DOI: 10.1016/J.MEHY.2006.04.005
Attorney, Agent or Firm:
VARGA, Tamás, Péter (Budapest, Bertalan Lajos u.20. Fsz. 3/A, HU)
Download PDF:
Claims:
CLAIMS:

1. Preventive products against pathogenic germs, primarily for preventing and treating bacterial contamination of poultry, charactrised by that, the product is prepared by homogenizing or blending methylglyoxal or its diacetate, i.e. methylglyoxal diacetate with some organic acids and/or in combination with Na salts of organic acids, and it is added to the drinking water of the animals and/or mixed in the feed, and in this way it is administered to the animals, and/or used for disinfecting the bedding materials.

2. Product according to claim 1, characterised by that, the product contains 10-1000 mg/kg methylglyoxal or methylglyoxal-diacetate.

3. Product according to claim 1 or 2, characterised by that, a 60 % aqueous solution of methylglyoxal, or powder methylglyoxal diacetate is used for its preparation.

4. Product according to any of the claims 1 - 3, characterised by that, organic acids are used as supplementary materials in the product, in the given case formic acid and/or ascorbic acid.

5. Product according to any of the claims 1 - 4, characterised by that, EDTA (ethylene diamine tetra acetic acid) and/or its sodium acid is used in the product as supplementary material.

6. Product according to any of the claims 1 - 5, characterised by that, malic acid is used in the product as supplementary material.

7. Product according to any of the claims 1 - 6, characterised by that, lactic acid and/or tetra sodium salt of EDTA (ethylene diamine tetra acetic acid) is used in the product as supplementary material.

8. Product according to any of the claims 1 - 7, characterised by that, the product is made in the from of powder mixture, in which tartaric acid and/or tannic acid is used as organic acid.

9. Method for the application of the product according to any of the claims 1 - 8, characterised by that, the product is mixed into the bedding material for the purpose of disinfecting the bedding material with the following proportions:

Mixed in 1000 g chaffed straw,

500 mg Methylglyoxal

50 g Ethanol 70%

10. Method for the application of product according to any of the claims 1 - 8, characterised by that, the product is mixed into the bedding material for the purpose of disinfecting the bedding material with the following proportions:

Mixed in 1000 g wood chips,

200 mg Methylglyoxal, sprayed with 60% aqueous solution

11. Method according to claim 9 or 10 characterized by that, the surface of the bedding material, in the given case straw or wood chips, is treated with the product in the form of spray, and in the given case the methylglyoxal is applied as dissolved in isopropyl aldehyde.

12. Method for the application of product according to any of the claims 1 - 8, characterised by that, the product is mixed into the feed for the application as an additive with the following proportions:

Mixed in 1000 g poultry feed

50 mg Methylglyoxal

10 g Essential oil mixture

1.0 g Non ionic emulgent, in the given case Chremophor

13. Method for the application of product according to any of the claims 1 - 8, characterised by that, the essential oil mix is added in the feed as an additive with the following proportions:

Mixed in 1000 g turkey feed

300 mg Methylglyoxal diacetal

1500 mg Essential oil mixture

14. Method for the application of product according to any of the claims 1 - 8, characterised by that, the product is added in the feed as an additive with the following proportions:

Mixed in 1000 g poultry feed

250 mg Methylglyoxal diacetal

1250 mg Ascorbic acid

500 mg Essential oil

15. Method for the application of product according to any of the claims 1 - 8, characterised by that, the product is mixed in the drinking water of the animals as an additive with proportions so that the concentration of methylglyoxal or methylglyoxal diacetal is 10-1000 mg/kg.

Description:
Preventive products against pathogenic germs, and method for use thereof

The subject of the invention is a group of preventive products to be used against pathogenic germs, and the method for using these products, each product is being a special combined additive for preventive purposes, which could be used as additive or supplementary material in animal feed to produce products primarily for preventing and treating bacterial infection of poultry, which selectively inhibit the propagation of pathogenic germs that generate endo and exo toxins.

The livestock is exposed to various bacterial infections during animal husbandry as a result of the circumstances the animals are kept. It is known in veterinary practice that certain pathogenic germs are obligate anaerobes that are associated with the living cells and animal species. Other germs can often play a characteristic role as carrier of disease, and these bacteria cause strong physiological symptoms in the human body. The first symptoms appear as a characteristic chock effect in the tissue with attack peristaltic clinical picture. The wall of the bowel exhibits an oedematous condition. Within a couple of days the pathogenic germs enter the vein system and paralyse the immune system, causing a so called blood poisoning. A critical situation can occur, if the bacterium body contains antitoxins, because these toxins escape (as a result of cell destruction) when antibiotics are used, and they cause strong toxic effect on parenchymal internal organs, the liver and the kidney. At the same time, their haemolysing ability leads to internal bleeding, and often causes the death of the infected organism.

The pathogenic germs are so called "intelligent" organisms, that can adapt quickly, and they can destroy one another also, usually the more aggressive one gets dominance, and the resistance to medication can also be attributed to this biochemical mechanism.

The defence against pathogenic germs is a complex tasks. The most important mode is the preventive protection, which should be multiple faceted. It is necessary to combine preventive material with multiple components, which can be used in a given case for pharmaceutical treatment while continuously dosing the preventive products.

Certain pathogenic germs propagate quickly, particularly in warm environment, and they exhibit rather high virulence in other closed bacterium media too, and they have double cell wall (like the salmonella enterintis), therefore, only small molecules can easily penetrate the cell membrane, such as the formic acid. These chemical materials can affect only young pathogenic germs among physiological conditions, they can inhibit the propagation, but they cannot kill the pathogenic germs.

The circumstances among which the animals are kept are very important, particularly the used bedding material. Bedding is usually made from straw in Hungary presently, but mostly wood chips are used for this purpose in other countries. The benefit of the wood chips is that it had less contact with the ground, it has less contamination, and although it cannot be regarded as free from contamination entirely, but if it is handled properly, then no contamination occur in practice, or serious contamination cannot be expected at least. Yet another problem in animal husbandry is that the base materials of feed may be contaminated too, particularly proteins, such as soy, rapeseed, corn and straw.

Pathogenic germs and moulds remain viable for a long time among humid conditions, and they tend to propagate quickly when affected by heat. In countries having moderately warm climate - like Hungary - they remain viable even as long as half a year. The contamination usually starts from below, from the external environment, from the bedding materials or from the gaps of the planking of stables from point-like locations. The collateral effect caused by rodents contribute to the start of contamination, because these animals are carriers of pathogenic germs. If a centre of infection starts to propagate in a barn containing 10,000 animals, then over 50 % of the animals will be contaminated within one or two weeks.

In practice, the animals defecate in the bedding material, and then they walk into the fodder, feeder and water one after another. As a result, the contamination spreads continuously, the pathogenic flagellar germs propagate by means of contact, which are very virulent as a result of the movement of the flagella. Therefore, it is very important to keep the number of pathogenic germs at properly low level in the bedding materials and in the feed.

According to the state of art, the Hungarian patent application P 07 00745 published on 2009-07-28 describes "A product containing EDTA, its salts and its complexes for preventing and treating bacterial intestinal diseases of pigs, and for enhancing the effect of antibiotics administered in case of such diseases". The solution described in this application is intended to be suitable for preventing and treating intestinal diseases of pig using ethylene diamine tetra acetic acid (EDTA) and its salts and complexes, as well as for enhancing the effect of antibiotics administered in case of such diseases. The animal husbandry products containing salt and complexes of EDTA are also subject of the invention.

Identical products are described by the PCT application published under number WO2009066117, as well as by the European application published under number EP2224918 and the Eurasian application published under number EA201000854.

According to the state of art furthermore, the patent document number EP0005346 describes enterochelin complexes, pharmaceutical products containing enterochelin complexes, as well as the procedures for producing these products. The patent document number EP0597167 describes a veterinary product, that contains an antibiotic mixture of gentamicin and lincomycin as additive to the drinking water or to the feed, including the application for breeding pigs. The patent document number GB2027590 describes parenteral product containing tiamuline. The patent document number US4716173 describes a procedure for treating malaria with a single intervention. The patent document number US2003194451 describes a pharmaceutical product to be used for preventing and treating gastrointestinal discinetic illnesses. The patent document number WO2004080210 describes compositions of nutritional metals to be used for strengthening physiological small intestines and for preventing diarrhoea. By creating the solution according to the invention our aim was to develop such a new product, which is suitable for preventing and treating bacterial infection of poultry, with particular attention to the fact, that resistance to medicines (antibiotics) develops quickly, and their effectiveness diminishes.

As certain bacteria are selectively sensitive to certain natural substances, we performed in vitro and in vivo experiments by adding multiple-component additives to feed, which do not kill the bacteria, but inhibit their propagation and reduce their virulence. This is particularly important in case of bacteria which produce toxic materials (endo and exo toxins). The European Union intends to implement this program for a couple of bacteria that are harmful for the human body, such as Salmonella typhi and Salmonella enteritis.

As far as we know, the methylglyoxal and its diacetate have not been used for elimination of germs in feed or during animal husbandry, e.g. for treating beddmg material or as additive in feed. When using methylglyoxal and its diacetate we observed the unexpected effect that the propagation of pathogenic germs had been inhibited by the use of these compounds and compositions. The methylglyoxal is a naturally occurring substance in the honey of certain bees, e.g. in the Manuka honey.

The invention is a preventive product against pathogenic germs, primarily for preventing and treating bacterial contamination of poultry, which is characterized by that, the product is prepared by homogenizing or blending methylglyoxal or its diacetate, i.e. methylglyoxal diacetate with some organic acids and/or in combination with Na salts of organic acids, and it is added to the drinking water of the animals and/or mixed in the feed, and in this way it is administered to the animals, and/or used for disinfecting the bedding materials.

In one preferred realization of the product according to the invention, the product contains 10-1000 mg kg methylglyoxal or methylglyoxal-diacetate.

In another preferred realization of the product according to the invention, a 60 % aqueous solution of methylglyoxal, or powder methylglyoxal diacetate is used for its preparation.

In a further preferred realization of the product according to the invention, organic acids are used as supplementary materials in the product, in the given case formic acid and/or ascorbic acid.

In a further preferred realization of the product according to the invention, EDTA (ethylene diamine tetra acetic acid) and/or its sodium acid is used in the product as supplementary material.

In a further preferred realization of the product according to the invention, malic acid is used in the product as supplementary material. In a further preferred realization of the product according to the invention, lactic acid and/or tetra sodium salt of EDTA (ethylene diamine tetra acetic acid) is used in the product as supplementary material.

In a further preferred realization of the product according to the invention, the product is made in the from of powder mixture, in which tartaric acid and/or tannic acid is used as organic acid.

During one of the method according to the invention, the product is mixed into the bedding material for the purpose of disinfecting the bedding material with the following proportions:

Mixed in 1000 g chaffed straw,

500 mg Methylglyoxal

50 g Ethanol 70%

During another, method according to the invention, the product is mixed into the bedding material for the purpose of disinfecting the bedding material with the following proportions:

Mixed in 1000 g wood chips,

200 mg Methylglyoxal, sprayed with 60% aqueous solution

During a preferred application of the product according to the invention, the surface of the bedding material, in the given case straw or wood chips, is treated with the product in the form of spray, and in the given case the methylglyoxal is applied as dissolved in isopropyl aldehyde.

During a further preferred application of the product according to the invention, the product is mixed into the feed for the application as an additive with the following proportions:

Mixed in 1000 g poultry feed

50 mg Methylglyoxal

10 g Essential oil mixture

1.0 g Non ionic emulgent, in the given case Chremophor

During a further preferred application of the product according to the invention, the essential oil mix is added in the feed as an additive with the following proportions: Mixed in 1000 g turkey feed

300 mg Methylglyoxal diacetal

1500 mg Essential oil mixture

During a further preferred application of the product according to the invention, the product is added in the feed as an additive with the following proportions:

Mixed in 1000 g poultry feed

250 mg Methylglyoxal diacetal

1250 mg Ascorbic acid

500 mg Essential oil During a further preferred application of the product according to the invention, the product is mixed in the drinking water of the animals as an additive with proportions so that the concentration of methylglyoxal or methylglyoxal diacetal is 10-1000 mg/kg.

The product according to the invention and its application are described on the basis of the following examples:

Examples for the composition of the product:

Example 1:

Water soluble powder mixture, related to 1000 g product

- 350 g Formic acid Na-salt

- 200 g Methylglyoxal diacetal

- 150 g Ascorbic acid

- 200 g EDTA Na4

- 100 g Na-glutamate

Example 2:

Powder mixture, related to 1000 g product

- 200 g Methylglyoxal

- 600 g Ascorbic acid

- 200 g EDTA Na2

Example 3:

Powder mixture, related to 1000 g product

- 300 g Malic acid

- 500 g Methylglyoxal diacetal

- 200 g Ascorbic acid

which is dissolved in 1000 1 water for the application. Example 4:

Solution, related to 1000 ml solution

- 200 g Lactic acid

- 250 g Methylglyoxal diacetal

- 250 g 60% H202

- 100 g Ascorbic acid

- 200 g EDTA Na4

Example 5:

Powder mixture, related to 1000 g product

- 350 g Tartaric acid

- 250 g Methylglyoxal diacetal

- 50 g Tannic acid or

- 250 g EDTA Na2

- 100 g Ascorbic acid Examples for the use of the product:

When used as disinfectant for the bedding material:

For this application, the product is mixed in the bedding material, and this way, the product performs its disinfecting and preventing action externally.

Example 6:

Mixed to 1000 g chaffed straw, for disinfecting the bedding material

500 mg Methylglyoxal

50 g Ethanol 70% covered in spray form of the surface of straw.

Or applied as dissolved in isopropyl aldehyde

Example 7:

Mixed to 1000 g wood chips, for disinfecting the bedding material

Contains 200 mg methylglyoxal, sprayed as 60 % aqueous solution

For application as additive mixed in feed:

With these applications the product is mixed in feed, which is consumed by the animal, therefore, the product performs its disinfecting and preventive function through the intestinal system.

Example 8:

Mixed in 1000 g poultry feed

50 mg Methylglyoxal

10 g Essential oil mixture

1.0 g Non ionic emulgent, in the given case Chremophor. Example 9:

Mixed in 1000 g turkey feed

300 mg Methylglyoxal diacetal

1500 mg Essential oil mixture

Example 10:

Mixed in 1000 g poultry feed

250 mg Methylglyoxal diacetal

1250 mg Ascorbic acid

500 mg Essential oil

Advantages:

The advantage of the product according to the invention is that it is able to inhibit the propagation of certain virulent pathogenic germs among in vitro conditions with the synergetic combination of materials exhibiting inhibitory properties even among physiological conditions, so that it is possible to maintain a condition free from infection if a healthy immunological background is present. This is particularly important in case of poultry breeding, because the bacteria having zoonotic properties can often infect the human population too.

The product according to the invention and their application ensures the chance of breeding an infected animal without additional medicinal treatment and avoiding the development of resistance, if no new (or continuous) infection exists.

The product can be applied in two different ways:

On the one hand, the animal eats the product with the feed or drinks it with water, and other hand, the product is mixed in the bedding material to inhibit the propagation of bacteria. Experiences conducted so far indicate that the number of germs can be reduced by two orders of magnitude with the product according to the invention relative to the control. It means that the product can efficiently reduce the propagation of pathogenic germs.

The product according to the invention is used primarily for poultry, e.g. chicken, turkey, duck, goose, because salmonella does not occur so often in pigs. It can be used for any of poultry, both for the chicks and the hens. It is important to continuously disinfect the bedding material in addition to administering the product through the feed to the animals.

The product according to the invention is a combination, which reduces the number of bacteria and the symptoms caused by them, as well as the number of pathogenic bacteria, in the given case e.g. continuously controls salmonella, it does not allow extreme propagation of it. The infantis bacterium type is characteristic in Hungary. The typhi and entretis types occur frequently in other countries. These bacteria require large amount of energy because of their movement, and they are very virulent. The number of bacteria can reach millions in half an hour depending on the temperature. The higher the temperature, the quicker is the replication. They react quickly to all external effects.

The essential property of the product is that it controls the replication by blocking the energy level of bacteria in a physiological manner. When administered in preventive dosages it will not kill the bacteria. The benefit of the preventive application is that it only controls the bacteria, and therefore no endotoxin is produced, and the harmful effect of toxins is avoided.

The major active ingredient of the product according to the invention is the methylglyoxal and the methylglyoxal diacetal, which we supplemented with adjuvant materials. These materials include vitamin C, which itself has an antibacterial effect on salmonella.