| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | March 20, 2001 |
| PATENT TITLE |
Use of hydroxy acid or a product containing the same in animal feed |
| PATENT ABSTRACT | The present invention relates to a hydroxy acid or a product containing thereof and a product made containing the same. The invention is characterized by the use of the hydroxy acid as a feed additive, either alone or in combination with other useful compounds or a product containing the same |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | December 28, 1998 |
| PATENT CT FILE DATE | June 20, 1996 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | January 9, 1997 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Featherston et al., Poultry Sci., vol. 53(2), pp 680-686, 1974.* Monsanto, Chemical & Engineering News, Apr. 15, 1991.* Feedstuffs, pp. 13, Nov. 11, 1991.* The Merck Index, Eleventh Edition, p. 943 Published by Merck & Co, Inc., New Jersey, USA, 1989.* Morrison et al., "Diazonium Salts, Preparation and Reactions", Organic Chemistry, 5th Edition, pp 973-975. Hietala et al., Nutr. Metab. 23:227-234 (1979), with computer generated Abstract. Merck Index, "D-Lactic Acid", p. 842, Eleventh Edition |
| PATENT CLAIMS |
What is claimed is: 1. A method for promoting animal growth and improving feed utilization efficiency by an animal, comprising adding to animal feed at least one branched hydroxy acid which has four to six carbon atoms, and one substituent which is a hydroxy group in the .alpha.-position, at a rate of 200-800 mg per 1000 kg of animal feed, and feeding said animal feed to the animal. 2. A method as in claim 1, wherein the hydroxy acid is selected from the group consisting of 2-hydroxy-3-methyl butyric acid and 2-hydroxy-4-methyl valeric acid. 3. A method as in claim 1, wherein the hydroxy acid is selected from the group consisting of chemically synthesized hydroxy acids and biochemically produced hydroxy acids. 4. A method as in claim 1, wherein the daily administration rate of the hydroxy acid is not greater than 500 mg of hydroxy acid per lightweight kg. 5. A method as in claim 4, wherein the hydroxy acid is administered to the animal at a daily administration rate of 20-100 mg of hydroxy acid per lightweight kg. 6. A composition comprising: (1) an animal feed; and (2) at least one branched hydroxy acid which has four to six carbon atoms, and one substituent which is a hydroxy group in the .alpha.-position, wherein the amount of hydroxy acid is 200-800 g per 1000 kg of animal feed. 7. A method as in claim 6, wherein the hydroxy acid is selected from the group consisting of 2-hydroxy-3-methyl butyric acid and 2-hydroxy-4-methyl valeric acid. 8. A composition as in claim 6, wherein the hydroxy acid is selected from the group consisting of chemically synthesized hydroxy acids and biochemically produced hydroxy acids. 9. A method of producing an improved animal feed, comprising the step of adding to an animal feed at least one branched hydroxy acid which has four to six carbon atoms, and one substituent which is a hydroxy group in the .alpha.-position, at a rate of 200-800 g per 1000 kg of animal feed. 10. A method as in claim 9, wherein the hydroxy acid is selected from the group consisting of 2-hydroxy-3-methyl butyric acid and 2-hydroxy-4-methyl valeric acid. 11. A method as in claim 9, wherein the hydroxy acid is selected from the group consisting of chemically synthesized hydroxy acids and biochemically produced hydroxy acids. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
The present invention relates to the use of a hydroxy acid or a product containing the same and a product made thereof. Bacteria of the genus Salmonella are well known pathogenic organisms which are much feared when occurring in animal feed and foodstuffs of animal origin. A primary infection caused by Salmonella arises when the bacterium starts to multiply in the alimentary tract of animals and therefrom is capable of contaminating both the host body and the end products (eggs, milk) products by the animal and conventionally used as nutrients. If allowed to pass uncontrolled to distribution, such contaminated foodstuffs can cause serious health hazards and economic losses in the population. Besides pathogenic microbes such as Salmonella strains, enteropathogenic Escherichia coli strains and campylobacteria, the food production efficiency of animals is also negatively affected by a plurality of microbes normally present in the alimentary tract flora of animals when occurring in excessive amounts. These microbes utilize the nutrients contained in the feed in the same fashion as the host animal, thus competing with their host for the feed. To suppress these microbes, so-called growth-promoting antibiotics are conventionally added in the feeds. Microbes often isolated from the small intestine can be grossly categorized in three groups: coliforms, enterococci and lactic acid producing bacteria. The latter group species are claimed to have positive effects on animal health though the actual mechanisms involved are not known accurately. The use of lactic acid producing bacteria for processing and preserving different material has been long known. In addition to silage processing, lactobacilli are utilized in the manufacture of, e.g., a variety of dairy products. As known from long-term practical experience of every-day use, such fermented diary products in particular have advantageous health-promoting properties. Today, products containing lactobacilli are also available for the normalization of the bacterial flora in the alimentary tract when the microbial flora has changed due to, e.g., a treatment with an antibiotic drug. Typically, lactobacilli form an essential component in the microbial flora of the alimentary tract. The metabolic products of these commensal bacteria are considered to have a great importance to the welfare of animals and man. It is an object of the present invention to provide a novel use for hydroxy acids as antimicrobial components in animal feeds. It is a further object of the invention to provide a feed improver based on hydroxy acids. It is still a further object of the invention to achieve a method of producing and using such feed improvers containing hydroxy acids. The invention offers significant benefits. An important species in the genus of lactobacilli is Lactobacillus plantarum. This bacterium species is present in a plurality of different media. L. plantarum is a so-called homofermentative lactic acid producing species. Accordingly, fermentation by this species produces almost purely lactic acid with small amounts of acetic acid and ethanol. L. plantarum can by virtue of the present invention now be persuaded to use protein-containing animal and plant waste, whereby the fermentation forms beside lactic acid, also relatively high amounts of other hydroxy acids. Here, the invention makes it possible to utilize hydroxy acids particularly as a feed improver. The characterizing properties of the invention are disclosed in the annexed claims. Since hydroxy acids have a microbicidal effect, they can give the product a very long storage time as a feed. Simultaneously, any microorganisms pathogenic to animals or man contained in the raw materials are destroyed entirely. The hydroxy acids, or mixtures thereof, utilized in accordance with the invention can be either synthesized chemically or produced biotechnically into, e.g., a fermentation solution containing the bacterium. An essential requirement herein is that the acid contains most preferably at least 4 carbon atoms and/or having a branched carbon chain or an aromatic or other suitable substituent. Particularly advantageous in this aspect are 2-hydroxy-3-methyl butyric acid, 2-hydroxy-4-methyl valeric acid or a mixture thereof. Furthermore, the invention concerns a feed improver which contains a hydroxy acid in an amount which is effective either alone or in combination with other compounds. According to the invention, the feed improver is either added in the feed or produced therein. A feed improver is defined as a component added in the feed typically at a level of 0.01-1%, with its function being to improve the health, growth other productivity factor of an animal. The effect of the feed improver may be directed on the microbial flora, digestive enzymes, resorption of nutrients in the alimentary tract, metabolic processes of the host animal or some another selected object. Depending on the object animal, the feeds concerned are typically comprised of a cereal or other similar starch-containing component (wheat, oats, rye, corn, etc.), a protein source (soya, turnip rape, fish meal, etc.), a fat source (vegetable oil or animal fat), mineral salts, amino acid supplements if the protein source is unbalanced, and vitamins as well as trace elements. A feed ration for ruminants contains a substantial amount of fiber-rich forage (silage, grass, etc.) and less starch. According to examples to be described later, broiler chickens require about 400-1600 mg of hydroxy acid during their life (approx. 40 days). This amount corresponds to about 200-800 g of hydroxy acid per tn of feed. Other animals such as pigs and egg-laying hens received in said examples about 20-100 mg hydroxy acids per kg liveweight a day. According to the invention, the daily administration of hydroxy acid is less than 500 mg hydroxy acids per kg liveweight a day, advantageously 20-100 mg hydroxy acids per kg liveweight a day. Hydroxy acids were found to affect microbial growth in vitro already at a level less than 0.1% (1000 g/tn feed). Hence, the amount of hydroxy acids in feed is advantageously 0.01-1%, most advantageously not more than 0.1%. The adapted L. plantarum strain forms significant amounts of alpha-hydroxy acids, the hydroxy acid concentration in fermentation media being about 2%. In addition to d,l-lactic acid, the most important acids formed are d,l-2-hydroxy-3-methyl butyric acid and d,l-2-hydroxy-4-methyl valeric acid. The formation according to the invention of d,l-2-hydroxy-3-methyl butyric acid and d,l-2-hydroxy-4-methyl valeric acid in the fermentation media of L. plantarum has not been disclosed earlier nor the effect of these compounds on the growth of microbes has been investigated. In the recovery of d,l-2-hydroxy-3-methyl butyric acid and d,l-2-hydroxy-4-methyl valeric acid from the fermentation media, Escherichia coli was used as the test organism for determining the distribution of the antimicrobial effect in the different fractions. Particularly unexpected is that these acids have an antimicrobial effect on a very large selection of different types of microorganisms. As can be noted from Example 5 later, these compounds have been shown to exhibit an antimicrobial effect on about seventy different micro-organisms. Further unexpected is that the alpha-hydroxy acids concerned in the invention are compounds which are considered to be normally occurring metabolites in animal organisms. On this basis, it initially seemed plausible that at least some organisms could in their metabolic pathways transform these compounds, thus inactivating them. The fermentation is carried out in vessels of 2-10000 liter volume. The milled medium, which is preferably steamed to destroy an vegetative microbial cells contaminating the raw material consisting of fish cleaning waste, blood, leguminous material or abattoir waste is seeded with a suitable amount of cultivated seed suspension of L. plantarum, the medium is mixed and the fermentation is allowed to continue for 6-7 days. The temperature of the suspended medium rises to about +30.degree. C. At the end of the fermentation, the suspension pH is 3.8-4.0. During the fermentation, the initially thick pulped mass changes into a move fluid form, whereby it can be easily discharged into drums used as storage/transport containers. During extended storage of the fermentation product, the oil or fat contained in the solution forms a supernatant floating on the surface of the solution, whereby it by most can be skimmed off from above the solution. This possibility is particularly important when the raw material consists of a mixture of small fish and fish cleaning waste, because fish oil is rich with polyunsaturated fatty acids, particularly EPA and DHA. The acids isolated from the fermentation media principally comprise d,l-2-hydroxy-3-methyl butyric acid and d,l-2-hydroxy-4-methyl valeric acid. Comparison of the microbial growth inhibiting effect of pure synthetic acids with the anti-microbial effect of the fermentation medium indicated that said acids in combination with the d,l-lactic acid formed into the medium stand for the entire non-volatile and nonvanishing antimicrobial efficiency of the fermentation solution. Pure forms of the above-mentioned alpha-hydroxy acids can be made using a variety of conventional methods. One of such methods comprises deaminating an amino acid or a mixture of amino acids with nitrite into corresponding alpha-hydroxy acids, extracting the latter into an organic solvent and evaporating the solution thus obtained, whereby the end product remaining is a mixture of alpha-hydroxy acids. Now these conventional methods are surpassed by the method according to the invention which offers a new way of preparing alpha-hydroxy acids in a fermentation medium. The acting mechanism of alpha-hydroxy acids on microbes is unclear. It is plausible that these acids act as antimetabolites of the corresponding alpha-amino acids. It must be noted that, e.g., 2-hydroxy-4-methyl valeric acid is a competitive inhibitor of leucine amino peptidase. The acidities of the d,l-2-hydroxy-3-methyl butyric acid and the d,l-2-hydroxy-4-methyl valeric acid are identical: both have a pK.sub.a =3.80. Hence, the mixture of the acid and a salt of said acid with a strong base exhibits a maximum buffer capacity at pH 3.8, which is of particular importance in treating, e.g., microbial infection and inflammation conditions of the skin and the oral cavity. According to present understanding, these compounds have no active resorption mechanism in the gastrointestinal tract, but rather, their resorption occurs via passive diffusion. Therefore, their retention in the alimentary tract is longer than that of, e.g., lactic acid. After their resorption into the organism, these acids are metabolized through the same paths as the corresponding alpha-amino acids. As their catabolism in the animal organism is complete, no residues from, e.g., animal-waste-based feed will remain in the products. However, their catabolic disintegration rate in the organism may be relatively slow, because the lactic dehydrogenase enzyme produced by an animal organism is incapable of oxidizing such alpha-hydroxy acids whose structure contains a branched carbon chain into corresponding keto acids, as in the case with d,l-2-hydroxy-3-methyl butyric acid and d,l-2-hydroxy-4-methyl valeric acid. When administered intravenously to mice, the LD.sub.50 values of the sodium salts of these acids are: Na-salt of d,l-2-hydroxy-3-methyl 1080 mg/kg Na-salt of d,l-2-hydroxy-4-methyl 650 mg/kg In the following, the invention will be described in greater detail with the help of the following examples and with reference to annexed drawings in which BRIEF DESCRIPTION OF DRAWINGS FIGS. 1a and 1b are plots of growth inhibition of E. coli and S. aureus by HMV (L-2-hydroxy-4-methyl valeric acid) and HMB (L-2-hydroxy-3-methyl butyric acid), respectively; FIGS. 2a and 2b are plots of the efficacy of HMV and HMB, respectively, in inhibiting the growth of a coliform bacterium strain (104) isolated from the broiler chicken gastrointestinal tract; FIGS. 3a and 3b are plots of the efficacy of HMV and HMB, respectively, in inhibiting the growth of an Enterococcus bacterium strain (111) isolated from the broiler chicken gastrointestinal tract; FIGS. 4a and 4b are plots of the efficacy of HMV and HMB, respectively, in inhibiting the growth of a lactic acid bacterium strain (120) isolated from the broiler chicken gastrointestinal tract; FIG. 5 is plot of the average weight of broilers in the different test animal groups after three weeks feeding; FIG. 6 is plot of the effect of the hydroxy acids on the efficiency of feed utilization in test animal groups after three weeks feeding. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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