WO2010134091A1

WO2010134091A1 - A process for preparation of a non-antibiotic growth promoter formula / product and its use in food animals

Info

Publication number: WO2010134091A1
Application number: PCT/IN2010/000225
Authority: WO
Inventors: P. M. Radhakrishna; K. C. Sharadamma; Shivakumar
Original assignee: M/S. Provimi Animal Nutrition India Private Limited
Priority date: 2009-05-20
Filing date: 2010-04-06
Publication date: 2010-11-25

Abstract

A Non-antibiotic growth promoter product as feed additive comprised of stabilized organosulfur compound(s) with or without flavor in the food animals for growth promotion, wherein in the organosulfur compounds is from the class of compounds of formula R- (S)_n -R¹ and the process for the preparation of the same.

Description

Title of the Invention :

A PROCESS FOR PREPARATION OF A NON- ANTIBIOTIC GROWTH PROMOTER FORMULA/PRODUCT AND ITS USE IN FOOD ANIMALS:

Field of Invention:

This invention relates to the field of animal nutrition to improve productivity of animal by making use of a stable nature identical non-antibiotic growth promoter. This invention relates to the preparation of the product composed of stabilized selected organosulfur compounds. The present invention is also related to its use in the food animals as a non - antibiotic growth promoter.

Antibiotic growth promoters remain as residues in the meat of the food animals. The residues find their way into the humans who consume this meat. This often leads to the development of:

(i) Resistance to the antibiotics in pathogenic microbial flora found in humans and hence requiring higher dosage regimens.

(ii) Allergic reactions depending on the sensitivity to a particular antibiotic or a group of antibiotics.

PRIOR ART:

In the livestock farming, infectious agents reduce the yield of food animals. To control these, the administration of sub-therapeutic antibiotics and antimicrobial agents has been shown to be effective. This practice of using antibiotics in feed is known from more than 50 years. A publication by Moore et al in 1947 mentions the use of streptomycin in feed and where it has been observed to improve the growth of animals by 10-30 %. The objective of using antibiotic growth promoters (AGPs) is to "help growing animals digest their food more efficiently, get maximum benefit from it and allow them to develop into strong and healthy individuals (animals)".

Although the mechanism underpinning their action is unclear, it is believed that the antibiotics suppress sensitive populations of bacteria in the intestine. It has been estimated that as much as 6% of the net energy in the pig diet could be lost due to microbial fermentation in the intestine (Jensen, 1998). If the microbial population could be better controlled, reduction in gastrointestinal infections would result in the subsequent increase in muscle weight. US Patent # 5,686,092 discloses that Anabolic steroids are used to promote the growth of the cattle and other food animals. Both pelleted as well as specific dosage forms of , steroids are used in the animals for growth promotion

US Patent # 4758435 discloses the continuous release of Estradiol in a uniform manner over extended period of time and does not exhibit initial release of undesirably high levels of active ingredient and a method for administering estradiol parenterally to feedlot animals over extended period of time.

At present Antibiotic growth promoters (AGPs) are being widely used as growth promoters in livestock animals. Antibiotics like virginiamycin, salinomycin, neomycin, doxycycline, avilamycin, colistin sulfate etc are few of the commonly used AGPs.

US Patent # 3974142 tells the usage of penicillin compounds, their use in human and veterinary medicine, as therapeutic agents in poultry and mammals, and as feedstuff additives and as growth promoting agents in animals. US Patent # 7220779 indicates about a pig growth enhancer, which comprises an active ingredient, at least one compound selected from 5-amino levulinic acid, a derivative thereof and a salt thereof, and a method for enhancing pig growth, which comprises administering the growth enhancer to a pig.

US Patent # 4533553 deals with use of polycyclic ether antibiotics like monensin, nigericin, grisorixin, salinomycin etc., to promote the growth of the animals with increased feed efficiency.

US Patent # 4175126 reveals the use of cyclopeptide antibiotics 35665 RP as growth promoter in animal feeding.

However, the use of antibiotics in feed has shown several side effects like resistance towards the drug, residues in the meat and thereby the user getting resistance to the drug etc.; hence several countries have banned the use of antibiotic based growth promoters in the feed.

Human health can either be affected directly through residues of an antibiotic in meat, which may cause side effects, or indirectly, through the selection of antibiotic resistance determinants that may spread to a human pathogen. Hence there is a growing need for the use of alternatives to antibiotic growth promoter. Several options are under focus. Eckel 1997, Liang 1997, Radecki et al 1998, etc., focused on the use of several organic acids as growth promoters. In an another approach, Olsen (1996) focused on the use of probiotics as alternatives to AGPs.

According to Swan committee report it is dangerous to use the antibiotics applied in human therapy to animals as feed additives because of the risk of resistance and cross resistance. Hence there has always been a search for growth promoters as an alternative to the antibiotics intended for food animals. Products of herbal origin possessing anti microbial activity have got tremendous potential as an alternative to AGPs .

Instances of usage of the herbs have been reported by De Koning and Hingbiao (1999) where they have been used as growth promoters.

Plants that naturally contain higher level of the sulfur containing amino acids such as those from Allium genus are preferred for enrichment based on metabolic criteria, while the WO Patent 2007 / 067600 A2 teaches the use of garlic naturally enriched with organic selenium as a nutritional supplement. In the US Patent # 5,268,357 Yabiki et al claim the use of a feed additive for livestock, poultry and/ or fish for increasing pseudo rabies resistance, which comprises of a combination of bile powder and peptidoglycan from the cell walls of gram-positive bacteria in combination with at least one member selected from the group consisting of animal plasma (serum) powder, garlic powder, licorice, licorice extract and quillaja extract.

Garlic or garlic extracts are known to contain an array of substances with beneficial health-related biological properties. Moreover, Lemar et al. reported that garlic extracts displayed a growth-inhibiting activity against Candida albicans, a fungus multiplying in the oral- gastrointestinal tract.

Patent # CN1771832A discloses one kind of garlic health fowl feed, which comprises garlic 2-5 wt%, ginger 1-4 wt%, corn 40-60 wt%, soybean residue 20-28 wt%, corn protein powder 2-6 wt%, fish powder 2-5 wt%, vegetable oil 1-2 wt% and additive 2-6 wt% for the health and growth of fowl animal and has excellent disease preventing and treating (prophylactic and therapeutic) effect.

Though the usage of garlic is known, its active component allicin which is proven to be a potent antimicrobial compound undergoes fast degradation even when stored under normal storage conditions to yield several by products and the volatility of these compounds is a major concern.

The thioethers have been known to undergo oxidation to yield products which have little or no bio availability and whose activities may be less than the parent compound.

Neem seeds and the Neem fruits have been used as a feed ingredient in the animal feed for their anti protozoal, anti microbial properties and have proved the same.

Ferula asafoetida is often used in veterinary medicine. The essential oil of Ferula asafoetida has been found to be active against several micro organisms, the gram positive and gram negative.

The present invention is related to the production of a growth promoter product which is intended to be used in the animal feed diet as an alternate to antibiotic growth promoters for the purpose of growth promotion which is comprised of stabilized nature identical alkyl and or alkenyl sulfides which are similar to that present in natural resources like Ferula genus, Allium genus, Azadirachta genus etc.

Statement of Invention :

The objective of the present invention is to develop a stable product containing at least one organosulfur compound which is an alternative to antibiotic growth promoters. This product of the present invention comprises of nature identical organosulfur compounds which are present in Allium genus, Ferula genus, Azadirachta genus etc.

The nature identical organosulfur compounds are the aliphatic sulfides of the formula

where R and Ri are alkyl, allyl or vinyl groups and n is the number of sulfur atoms.

The number of Sulfur atoms (n) according to Structure 1 varies from 1-8. The selected organosulfur compounds are stabilized using cyclodextrin.

Stabilised aliphatic sulfides are further treated with flavour to mask the garlic odour in the product and converted into a growth promoter formulation which is henceforth referred to as G-PRO naturo ™*, a product of the present invention.

* Under trademark registration

The flavor is selected from cinnamon oil, cinnamic acid, cinnamaldehyde (Cinnamon species), parsley oil, geranium oil, lemongrass oil, cardamom oil, dil oil etc.

Administration of the product of present invention will enhance the immunity of the target species and help them to improve their performance with respect to growth.

Accordingly the present invention provides the methodology to prepare a growth promoter formula and its use in feed meant for food animals. This involves the following functions.

O Stabilizing the selected organosulfur compounds using cyclodextrin. O Formulation of the stabilized organosulfur compounds along with a selected flavor and also without flavor into a growth promoter formula.

O The use of this product in food animals for the purpose of growth promotion and immunity enhancement.

Novel features of the invention:

The uniqueness of the present invention is the stable formulation of selected nature identical organosulfur compounds. These organosulfur compounds belong to the family of aliphatic poly sulfides which are stabilized using cyclodextrin to enhance the shelf life of the growth promoter formula.

Use of such stabilized product of organosulfur compounds in the food animals for improving the weight gain and increased feed efficiency is novel.

Summary of the Invention:

The present invention provides the method for producing a stable growth promoter product which comprises nature identical organosulfur compound similar to those found in Allium genus, Ferula genus, Azadimchta genus etc. It also reveals about the usage of the stabilized product in the animal feed to enhance the health and growth of the food animal.

Detailed Description of the Invention: Examples: Example 1:

Dissolve 10 g of cyclodextrin in 50 - 500 ml of water. Cool to 60-80ºC. Add 0.1 - 5 g of Organosulfur compound. Cool to 30ºC. Filter the reaction mass. Dry the product at 40- 50ºC.

Yield: 8 - 1Og

Example 2:

Dissolve 1Og of cyclodextrin in 100 ml of water. Cool to 60ºC. Add 0.1 - 5 g of organosulfur compound in 50 ml alcohol. Cool to 30ºC. Filter the reaction mass. Dry the product at 40-50ºC.

Yield: 8-10g

Example 3:

Transfer 1Og of cyclodextrin to a pestle and mortar. Add 0.01 - 2.5 g of organosulfur compound. Knead the sample thoroughly for a minimum of 30 minutes. Dry the product at40-50°C

Yield: 8-1Og

Example 4: The growth promoter formula having the following composition

Stabilized Organosulfur compound (from example 1-3 ): 0.05 - 25%

Clay : 60-80% Silica: 1-25%

Essential oil as flavour. IN VIVO TRIALS

A total of 816 numbers of Cobb 500 male broiler chicks were distributed among eight treatments (given in the Table below) and six replicate pens (17 birds / pen) at 0 of age. The study was done to evaluate "G-PRO naturo™" (Code B169), a product developed by Provimi Animal Nutrition India Private Limited for determining the efficacy as a growth promoter in broilers. The trial was conducted at the focus Unit of Provimi Research Centre "De Viersprong", located at Velddriel, Netherlands.

The experimental treatments were imposed from Day 0 to 35 days of age. The test substance (invention) was mixed with the feed. Birds were fed on a normal diet.

Average body weight (BW, kg) for male Cobb 500 broiler chicks 5 fed diets without growth promoters, with Avilamycin or with G-PRO naturo ™ 35d of age.

a^b means with different column superscripts are significantly different by t-student test at P<0.05 Average feed conversion ratio (FCR) for male Cobb 500 broiler chicks fed diets without growth promoters, with Avilamycin or with G-PRO naturo™ to 35d of age.

a^b means with different column superscripts are significantly different by t-student test at P<0.05

This trial was to establish the value of G-PRO naturo™ as an alternative to growth promoters (antimicrobial) available in the market. The results indicated that G-PRO naturo™ at the recommended usage rate was efficient in enhancing broiler performance when compared to negative control (no coccidiostat) and comparable to the positive control in the overall trial period.

REFERENCES:

1. Peter Hughes, John Heritage, Antibiotic Growth- Promoters in Food Animals, www.fao.org/ docrep/ article/ agrippa/ 555_en.htm.

2. Antimicrobial Resistance from Food Animals,

International Food Safety Authorities Network

(INFOSAN), INFOSAN Information Note No. 2/2008 - Antimicrobial Resistance, 7 March 2008.

3. Harunobu Amagase, Brenda L. Petesch, Hiromichi Matsuura^*, Shigeo Kasuga^* and Yoichi Itakura^*, Intake of Garlic and Its Bioactive Components, Journal of the National Medical Association, Vol. 80, No. 4, 1988.

4. Murtaza AIi Tipu, T.N. Pasha and Zulfiqar AIi, Comparative Efficacy of Salinomycin Sodium and Neem

Fruit (Azadirachta Indica) as Feed Additive Anticoccidials in Broilers, International Journal of Poultry Science 1 (4): 91-93, 2002

5. Tariq H. Abdullah, MD, O. Kandil, phd, A. Elkadi, MD, and J. Carter, Garlic revisited: therapeutic for the major diseases of our times? J Natl Med Assoc, 80(4): 439-445, April 1988. 6. Mujeeb Ur Rahman, Shereen GuI and Ejaz AH Odhano, Antimicrobial Activities of Ferula assafoetida Oil against Gram Positive and Gram Negative Bacteria, American- Eurasian J. Agric. & Environ. Sci., 4 (2): 203-206, 2008

7. The Wealth of India, Raw materials, VoI IV, Council of Scientific & Industrial Research, New Delhi, 1972

8. Iranshahi M, Amin GR, Amini M, Shafiee A., Sulfur containing derivatives from Ferula persica var. latisecta., Phytochemistry, 63(8):965-6, Aug 2003

9. Chantana Aromdee and Nongluksna Sriubolmas, Essential oil of the flowers of Azadirachta indica (Meliaceae), Songklanakarin J. Sci. Technol, Vol. 28, No.l Jan. - Feb. 2006.

10. Wafaa A. Helmy, Howaida I. Abd-ALLA, Hassan Amer and El-Safty, M.M., Chemical Composition and ¹Jn vitro' Antiviral Activity of Azadirachta indica Juss (Neem) Leaves and Fruits Against Newcastle Disease Virus and Infectious Bursal Disease Virus, Australian Journal of Basic and Applied Sciences, 1(4): 801-812, 2007

11. J.F. Acar (1) & G. Moulin . Antimicrobial resistance at farm level . Rev. sci. tech. Off. int. Epiz., 25 (2), 775-792, 2006

12. De Koning.W. and Hongbiao, D., Chinese herbs as feed additives. Feed Mix, 6(3), 17-18, 1999.

13. Kirtikar & Basu, II, 1217, Subrahmanyan et al, J. Sci. Industrial Res., 13A, 381,1954.

14. Agarwal, K. C. Therapeutic actions of garlic constituents. Med. Res. Rev. 16: 111-124, 1996

15. K.M. Lemar, M.P. Turner and D. Lloyd, Garlic (Allium sativum) as an anti-Candida agent: a comparison of the efficacy of fresh garlic and freeze-dried extracts, J. Appl. Microbiol, 93: 398-405, 2002

16. Brodnitz, M.H. Pascale, J.V., and Derslice, L. V, Flavor components of garlic extract. J. Agr. Food. Chem. 19(2):273-275, 1971.

17 . Harris, J. C, Cottrell, S. L., Plummer, S., Lloyd.D, Antimicrobial properties of Allium sativum (garlic) , Applied Microbiology and Biotechnology, Vol. 57, pp. 282- 286, 2001.

Claims

We claim:

1. A Non-antibiotic growth promoter product as feed additive comprised of stabilized organosulfur compound(s) with or without flavor in the food animals for growth promotion, wherein in the organosulfur compounds is from the class of compounds of formula R- (S) _n -R¹ and the process for the preparation of the same.

2. The R group as per claim 1 refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, vinyl, ally 1, etc groups and the R¹ refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, vinyl, allyl groups.

3. The organosulfur compounds as claimed in claim 1, wherein R and R¹ as may be same or different.

4. The R and R¹ refers to allyl, propyl and vinyl groups.

5. The number of Sulfur atoms (n) in the claim 1 refers to n =1 - 6.

6. The number of Sulfur atoms (n) in the claim 5 is between 1- 4.

7. The number of Sulfur atoms (n) in the claim 6 is between 2-4.

8. A stabilized organosulfur compounds in the growth promoter formula as claimed in claim 1,

5 refers to the organosulfur compounds that are similar to those present in Allium genus, Ferula genus, Azadirachta genus etc which are stabilized using Cyclodextrin.

9. A stabilized organosulfur compounds in the 10 growth promoter formula as claimed in claim 1 &

8, wherein the cyclodextrin refers to α- Cyclodextrin, β - Cyclodextrin, γ - Cyclodextrin or any other derivatives of Cyclodextrin.

10. The use of stabilized Organosulfur compounds in 15 the growth promoter formula as claimed in claim 1, may be a single or combination of different organosulfur compounds.

11. The flavour as per claim 1 refers to the essential oil such as Cinnamon (species) oil, Cinnamic acid,

20 Cinnamaldehyde, Parsley oil, Geranium oil,

Lemongrass oil, Cardamom oil, DiI oil etc.

12. The process for the preparation of non-antibiotic growth promoter formula wherein the product comprises of a minimum of one stabilized organosulfur compound of formula R - (S) „ - R¹ is substantially described herein above with or without flavor .

13. Use of this growth promoter formula as feed additive for growth promotion and improving feed efficiency in the food animals, wherein in the food animals refers to poultry birds, dairy cattle, swine, goat and sheep.