MXPA99005684A - Antiinfective free intramammary veterinary composition - Google Patents

Abstract

An antiinfective-free formulation for prophylactic treatment of mastitis in dry cows comprises a seal formulation having approximately 65%by weight of bismuth sub-nitrate in a gel based on aluminium stearate. The seal formulation is prepared by adding the bismuth sub-nitrate to the gel base in at least two separate stages.

Description

INTRAMAMARY VETERINARY COMPOSITION FREE OF ANT! - INFECTIVE I ntroduction The invention relates to a veterinary composition, particularly for the prophylactic treatment of mastitis in cows.

Bacterial infection via the tits of the cow is the most common cause of mastitis. It is known that the tits of the cow are treated with a long acting antibiotic in a slow release form providing only an effective cover while maintaining levels of minimum inhibitory concentration (MIC) of the antibiotic. This coverage period may vary from 4 to 10 weeks. The infusion of a cloxacillin-based antibiotic into the udder after the last lactation and before the cow becomes sterile is also known, followed immediately by a sealant formulation to seal the teat canal. The invention is directed to the provision of an improved veterinary composition, particularly for the prophylactic treatment of mastitis in sterile cows. Statement of the Invention We have found that if a physical barrier is provided within the channel of the teat and / or lower breast of the teat during the period of sterility without the use of antibiotics, the incidence of mammary disorders is substantially reduced. This is very surprising given that all conventional treatments involve the use of antibiotics. Because antibiotics are not required, very substantial benefits result, without any significant reduction in effectiveness. According to the invention, an anti-infective free formulation for intramammary infection prophylaxis comprising a sealant formulation is provided to provide a physical barrier in the teat channel. This non-antibiotic approach to avoid the new period of infection in sterile dairy cows has greater potential for the dairy industry since it results in the reduction of the incidence of antibiotic contamination in milk production in the early season. Therefore, the invention provides a quality improvement for dairy production and will facilitate farmers to satisfy consumer preferences to reduce the level of antibiotics used in food production. According to another aspect, the invention provides an anti-infective method free of prophylactic treatment of mammary disorders in non-human animals during a period of sterility in animals by sealing the teat canal with a sealing formulation in order to provide a physical barrier in the teat channel.

The invention also provides a prophylactic method to control the infection of the mammary gland by an organism causing mastitis by sealing the gland with a sealing formulation to provide a physical barrier in the teat canal. In a particularly preferred embodiment of the invention, the sealant formulation comprises a non-toxic heavy metal salt in a gel base. Preferably, the heavy metal salt is present in an amount of between 50% and 75% by weight, more preferably approximately 65% by weight. We have found that these are optimal levels of the heavy metal salt to achieve an effective seal. In a preferred embodiment of the invention, the heavy metal salt is bismuth sub-nitrate. This is a non-toxic heavy metal salt particularly useful. In a preferred embodiment of the invention, the base is a gel based on aluminum stearate. Preferably, in this case, the gel includes a carrier such as liquid paraffin. This formulation has effective processing and use properties. In another embodiment of the invention, the gel comprises a polyethylene gel. The gel can be based on low density polyethylene or high density polyethylene. The invention also provides a veterinary composition for use in the prophylactic treatment of breast disorders in non-human animals during a period of animal sterility.

According to a further aspect, the invention provides a process for preparing a sealant formulation comprising the steps of adding a non-toxic heavy metal salt to a gel base in at least two separate steps. This process is particularly effective to produce a sealant formulation of the invention. Preferably, a first portion of the heavy metal salt is added to a gel base in a first stage and a second portion of the heavy metal salt is added to the gel base containing the first portion of the heavy metal salt . In this case, preferably the weight ratio of the second portion of the heavy metal salt is at least 1: 1, more preferably about 2: 1. Detailed Description of the Invention The invention will be understood more clearly from the following description given by way of example only. EXAMPLE 1 Raw Materials: Liquid Paraffin B.P. 434.8 Kg Alugel 30 DF (Sterile) 69.2 Kg Sub-Nitrate of Bismuth 936.0 Kg B.P.C. (Sterile).

To prepare a batch of a sealant formulation, the liquid paraffin is first supplied in a Skerman 800 liter pot. The mixer is operated at 20 RPM. The Alugel 300 DF (aluminum stearate) is then added through a transfer port. The mixer is switched off between the additions of the Alugel powder. The steam line opens and the temperature is allowed to rinse from 160 to 165 ° C. This temperature is maintained for approximately 2 hours to sterilize the mixture. At the end of the sterilization cycle, the condensate valve opens and is allowed to blow down. The cooling water is then left in the jacket to cool the contents to less than 40 ° C. The base thus formed is coated for quality. If necessary, the base of the batch can be homogenized for 10 minutes using a Silverson Homogenizer. Then the loading port opens and 296 kg are added. of bismuth sub-nitrate in batches of 10 kg. The content is mixed for one minute at 20 RPM between additions of every 10 kg. of bismuth subnitrate. Mixing was continued for about 1 hour at 45 RPM. The 640 Kg of the bismuth sub-nitrate is then added in batches of 10 Kg as before and mixing is continued for 1 hour after the final additions. We have found that the addition of bismuth sub-nitrate in two separate portions is important to produce a seal that can be processed and used effectively.

If necessary, the mixture is homogenized for 15 minutes using a Silverson Homogenizer. The product is then transferred to a Colibri filling machine to fill it in the injector tubes. EXAMPLE 2 Five cows in the four quarts were treated with the infusion by sterilizing with the formulation of sealant prepared as described in Example 1. Previously it had been determined that these cows were not infected in the four quarters. Starting at the first milking after giving birth, these cows were milked and the milk sample collected was recovered for analysis. This process was repeated for the first 10 milkings after giving birth. The milk samples were also collected in the same way as the 5 untreated cows. To stimulate the milk handling process within the milking system, these milk samples were passed through a fiber filter material used for milking machine filters. The milk samples were analyzed by mass spectrometry for bismuth concentration. The average level of bismuth in the milk extracted from the first milking was 3.3 ppm declining to 0.39ppm in milking No. 10. The maximum level recorded for any individual cow was 8 ppm in the first milking. For untreated cows, the levels ranged from 0.001 to 0.03 ppm.

The sealant formulation described in Example 1 was administered in the sterile period and has been shown to reduce the incidence of re-infection in the period of cow sterility and in the period near the delivery. This reduction seems to be comparable with that achieved by prophylactic treatment with antibiotics. Thus, the sealing of the invention surprisingly offers a non-antibiotic approach to prophylaxis in the period of cow sterility. EXAMPLE 3 Evaluation of the sealant of Example 1. • Four cows without mastitis were selected during the sterility period. • 2 Tits in each cow were treated with the infusion in the sterile period with the sealant and the remaining tits were not treated (day 0). • 8 Tits were sealed and 8 tits were not treated (controls). • 3 Days later (day 3) all the tits were inoculated in the teat canal (depth of 4 mm; using 22 cfu M code of Streptococcus dysgalactiae and an inoculum volume of 0.1 ml). • The new infections that result from the use of the inoculum occurred in five (5) of the rooms not treated in the period from day 3 to day 13.

• The new infections that result from the use of inoculum occurred in two (2) of the rooms treated in the period from day 3 to Day 13). • The resulting new infections were monitored daily for 10 consecutive days after the inoculum (until day 13). • Secretion samples were collected in an aseptic form of the rooms showing signs of clinical mastitis before treatment with antibiotics. • All the rooms in the 4 cows were sampled in an aseptic way on day 13 (the last day of the analysis), these samples were also used to: (1) check the amount of remaining seal on the tits (2) monitor the level of Str. dysgalactiae survivor in the tits after 10 days. • Results of clinical infection Number of new infections' Number of rooms confronted with Str. Dysgalactide EXAMPLE 4 Evaluation of the sealant of Example 1. • 17 Mastitis-free cows were selected during the sterility period. • 2 Tits in each cow were treated with the infusion in the sterility period with the sealer and the remaining tits were not treated (day 0). • 32 Tits were sealed and 32 Tits were not treated (controls). • 3 days later (day 3) all the tits were inoculated in the teat canal (depth of 17 mm, using 1, 190 cfu M code of Streptococcus dysgalactiae and an inoculum volume of 0.1 ml).

• The new infections that result from the use of the inoculum occurred in twenty (20) of the rooms not treated in the period from day 3 to day 13. • The new infections that resulted from the use of the inoculum occurred in eight (8) of the rooms treated in the period from day 3 to day 13). • The resulting new infections were monitored daily for 10 consecutive days after inoculum (until day 13). • Secretion samples were collected in an aseptic form of the rooms showing signs of clinical mastitis before treatment with antibiotics.

• The quarters of the 17 cows were sampled in an aseptic manner on day 13 (the last day of the analysis) - these samples were also used for. (1) check the amount of remaining seal on the tits (2) monitor the level of Str. Dysgalactiae survivor on the tits after 10 days. • Results of clinical infection Number of new infections "Number of rooms confronted with Str. Dysgalactide * A total of 4 quarts were infected in three cows and these rooms were excluded from the study, therefore, 32 quarts were assigned to each treatment. total of 528 cows from three commercial herds, each flock had a general study of mastitis in the sterile period, the progeny of the flocks were predominantly Fresian or Fresian crosses, cows with at least three non-infected quarters, immediately before the sterility, they were identified within the three flocks.It was assumed that all the individual rooms were independent units.The treatments used were the following: 1. Negative Control -Not treated, without infusions in the period of sterility, but the ends of the tits were cleaned with cotton swabs soaked in alcohol 2. Positive Control-treated with 250 mg of cephalonium in a long-acting base, treated as with the infusion during the period of sterility. This product is known as CEPRAVI N DRYCOW. Cepravina is a trademark of Mallinckrodt Veterinary. 3. Antibiotic with 600 mg of benzathine Cloxacillin Sealer in a unit dose of 4 g treated with the infusion in the sterile period and immediately followed by an infusion of 4 g of a mixture of bismuth sub-nitrate (66%) in paraffin liquid with 8.5% Alugel 30 DF. 4. Sealer - Bismuth sub-nitrate 66% w / w in liquid paraffin with 8.5% Alugel 30 DF in a unit dose of 4g treated with the infusion in the sterility period. These treatments were randomized among the 528 cows that were determined to have three or four uninfected quarters in the sterile period. The treatments were randomized between the rooms to randomize as much as possible, the same number of rooms per treatment, left and right, front and back. The bacteriological results for the individual quarters in the sterilization at birth were compared to calculate the incidence of new intramammary infections (IMl). Xi-square tests were used to compare the incidence of new infection between rooms, treatments and controls. The results of the treatments are summarized in Table 1. This experiment has shown that the formulation of anti-infective-free sealant of the invention administered in the sterile period is very surprisingly equivalent in terms of prophylactic efficacy, for an antibiotic for long-acting sterile cows. All three treatments reduced I MI during the sterility period by approximately 85%.

Surprisingly, there was no significant difference between the antibiotic-based treatments and the free antibiotic-free treatment of the invention. Therefore, this study has shown that by physically sealing the teat canal with a sealant that has no bacteriostatic or bacterial action, surprisingly, I M I can be controlled in the sterile period. Therefore, the invention has the potential to achieve prophylaxis in the sterility period on a large scale, at a lower unit cost and without risk of antibiotic residues after giving to lz. The invention is not limited to the modalities described above which may vary in detail.

Number of new IMIs (rooms) 1. C Controls 2. (Controls 3. A ntibiótico + 4. Positive Neaativos Sealer Se = -ldor Herd ID 1 2 3 1 2 3 1 2 3 1 2 3 No. Total rooms 249 141 138 249 141 138 249 141 139 249 141 138 PERIOD OF STERILITY 10 6 2 0 1 1 1 1 0 1 0 0 IMI clinic IMI WHEN GIVING LIGHT Strep. spp. 25 21 4 0 4 1 2 1 1 2 2 0 S. Aureus 1 2 0 0 0 0 0 0 0 0 1 0 Coag.Estaf.Neg. 2 0 4 0 0 1 1 0 1 4 0 2 Coliforms 1 2 1 1 2 1 1 0 0 0 1 0 Other agencies 0 2 0 1 1 0 0 1 0 0 0 0 Clinical, without growth 1 1 0 0 0 0 0 0 0 0 0 0 Total IMI when giving birth 30 28 9 2 7 3 4 2 2 6 4 2 Total IMI 40 34 11 2 8 4 5 3 2 7 4 2 Global IMI Regime 16.1 24.1 8.0 0.8 5.7 2.9 2.0 2.1 1.4 2.8 2.8 1.4? (%) Total IMI between the herd and periods of IMI in Strep. SPP. 68a 7b 6b 5b Other IMI routes 17 ° 7d 4d 63 All IMI Routes 85f 149 10g 13g Total Rooms 528 528 528 528 New global IMI Regime 16.1 2.7% 2.5% 1.9%% Table 1. New intramammary infections (IMI) identified during the study, grouped by period and by herd. (Within a row, the values with different superscripts are significantly different)

Claims (27)

1. REIVIN DICACIONES 1 . An anti-infective-free formulation comprising a sealant formulation that does not contain an anti-infective, formulation providing a physical barrier in the teat channel for intramammary infection prophylaxis.
2. 2. A formulation according to claim 1, wherein the sealant formulation comprises a non-toxic heavy metal salt in a gel base.
3. 3. A formulation according to claim 2, wherein the sealant formulation contains at least 40% by weight of the heavy metal salt.
4. 4. A formulation according to claim 3, wherein the sealant formulation contains from 50% to 75% by weight of the heavy metal salt.
5. 5. A formulation according to claim 4, wherein the sealant formulation contains about 65% by weight of the heavy metal salt.
6. 6. A formulation according to any of claims 2 to 5, wherein the salt is bismuth sub-nitrate.
7. 7. A formulation according to any of claims 1 to 6, wherein the base is a gel based on aluminum stearate.
8. 8. A formulation according to any of claims 1 to 7, wherein the base includes liquid paraffin as a carrier.
9. 9. Use of a sealant formulation that does not contain an anti-infective, to form a physical barrier free of anti-infective in the teat canal for the prophylactic treatment of mammary disorders in non-human animals during a period of sterility of the animals.
10. 10. Use of a sealant formulation to form a physical barrier in the teat canal to prophylactically control infection of the mammary gland by an organism that causes mastitis. 1.
11. Use according to claim 9 or 10, wherein the sealant formulation comprises a non-toxic heavy metal salt in a gel base.
12. 12. Use according to claim 9 or 11, wherein the sealant formulation contains at least 40% by weight of the heavy metal salt.
13. 13. Use according to claim 12, wherein the sealant formulation contains from 50% to 75% by weight of the heavy metal salt.
14. 14. Use according to claim 13, wherein the sealant formulation contains about 65% by weight of the heavy metal salt.
15. 15. Use according to claim one of claims 9 to 14, wherein the salt is bismuth sub-nitrate.
16. 16. Use in accordance with any of the claims 9 a 15, wherein the base is a gel based on aluminum stearate.
17. 17. Use according to any of claims 9 to 16, wherein the base includes liquid paraffin as a vehicle.
18. 18. A process for preparing a sealant formulation comprising the steps of adding a non-toxic heavy metal salt to a gel base in at least two separate stages.
19. A process according to claim 18, wherein the first portion of heavy metal salts is added to the gel base in a first stage and a second portion of the heavy metal salt is added to the gel base containing the first portion of the heavy metal salt.
20. 20. A process according to claim 19, wherein the weight ratio of the second portion of the heavy metal salt to the first portion of the heavy metal salt is at least 1: 1. twenty-one .
21. A process according to claim 20, wherein the weight ratio is about 2: 1.
22. 22. A process according to any of claims 18 to 21, wherein the sealant formulation contains at least 40% by weight. weight of heavy metal salt.
23. 23. A process according to claim 22 wherein the sealant formulation contains from 50% to 75% by weight of the heavy metal salt.
24. 24. A process according to any of claims 18 to 23, wherein the sealant formulation contains about 65% by weight of the heavy metal salt.
25. 25. A process according to any of claims 18 to 24, wherein the salt is bismuth sub-nitrate.
26. 26. A process according to any of claims 18 to 25, wherein the base is a gel based on aluminum stearate.
27. 27. A process according to any of claims 18 to 26, wherein the gel contains liquid paraffin as a carrier.