阅读说明：本技术 内部***密封剂及其在预防干奶牛的牛乳腺炎中的应用 (Internal teat sealant and its use in preventing bovine mastitis in dry dairy cattle ) 是由 B.G.史密斯 于 2019-01-17 设计创作，主要内容包括：一种乳房内注射器,其含有用于在非人动物的乳头管中形成物理屏障的密封制剂。该注射器含有0.25ml至2.0ml的减少体积的密封制剂。解决了在干奶期期间密封剂上升的问题。(An intramammary injector comprising a sealant formulation for forming a physical barrier in a teat canal of a non-human animal. The syringe contains a reduced volume of the sealed formulation of 0.25ml to 2.0 ml. The problem of sealant rising during the dry period is solved.)

1. An intramammary syringe comprising a sealant formulation for forming a physical barrier in a teat canal of a non-human animal, wherein the syringe contains from 0.25ml to 2.0ml of the sealant formulation.

2. The intramammary syringe of claim 1, wherein the syringe contains from 0.5ml to 2.0ml of the sealing formulation.

3. The intramammary syringe of claim 1 or 2, wherein the syringe contains from 0.75ml to 1.75ml of the sealing formulation.

4. The intramammary syringe of any one of claims 1 to 3, wherein the syringe contains from 1.0ml to 1.5ml of the sealing formulation.

5. An intramammary injector comprising a sealant formulation for forming a physical barrier in a teat canal of a non-human animal, wherein the injector comprises from 0.5g to 2.5g of the sealant formulation.

6. The intramammary syringe of claim 5, wherein the syringe contains from 1.0g to 2.5g of the sealing formulation.

7. The intramammary syringe of claim 5 or 6, wherein the weight of the sealing formulation contained in the syringe is from 1.5g to 2.0 g.

8. The intramammary injector of any one of claims 1 to 7, wherein the sealing formulation comprises a heavy metal salt in a base.

9. The intramammary injector of claim 8, wherein the heavy metal salt is bismuth subnitrate.

10. The intramammary injector of claim 9, wherein the bismuth subnitrate comprises about 65 wt% of the sealing formulation.

11. The intramammary injector of any one of claims 1 to 10, wherein the sealing formulation comprises a thixotropic agent.

12. The intramammary injector of claim 11, wherein the sealing formulation contains 0.1% to 1.5% of the thixotropic agent.

13. The intramammary injector of claim 11 or 12, wherein the sealing formulation contains from 0.6% to 1.0% of the thixotropic agent.

14. The intramammary injector of any one of claims 11-13, wherein the sealing formulation contains about 0.8% of the thixotropic agent.

15. The intramammary injector of any one of claims 11 to 14, wherein the thixotropic agent comprises colloidal anhydrous silica.

16. The intramammary injector of any one of claims 8 to 15, wherein the substrate is an aluminum stearate based gel.

17. The intra-mammary injector of any one of claims 8 to 16, wherein the base comprises liquid paraffin as a carrier.

18. A method for forming a seal in a mammary gland of a non-human animal comprising the step of injecting 0.25ml to 2.0ml of a sealing formulation into the teat cistern through the teat canal.

19. The method of claim 18, comprising injecting 0.5ml to 2.0ml of the sealant formulation through said teat canal.

20. The method of claim 18 or 19, comprising injecting 0.75ml to 1.75ml of the sealant formulation through the teat canal.

21. The method of any one of claims 18 to 20, comprising injecting 1.0ml to 1.5ml of said sealant formulation through said teat canal.

22. The method of any one of claims 18 to 21, wherein the sealing formulation comprises a heavy metal salt.

23. The method of claim 22, wherein the heavy metal salt is bismuth subnitrate.

24. The method of claim 23, wherein the bismuth subnitrate comprises about 65 wt% of the sealing formulation.

Background

All cows require a period of time before calving during which milk production is stopped in preparation for the next lactation and allowing mammary tissue repair and regeneration. Typically, the duration of this period is between 40 days and 70 days.

In the modern dairy industry, the process of stopping milk production is called dry milk and can be accomplished by a variety of methods, including reducing diet and water; introducing a biological response modifier (typically a hormone); and withdrawal of stimulation-in particular stopping of a regular milking program.

Once it has been decided to dry milk, and the cow is no longer being milked, the cow's system begins a process known as retrogradation. Cows are now in a state commonly referred to as the dry period.

During the dry period, the cow is very susceptible to bacteria entering through the teat canal, which can often remain open for a considerable period of time (and in some cases, will not close throughout the dry period). In a study in New Zealand 1995, Williamson et al found that 50% of the teats remained open after 10 days of dry milk (NZVet. J.43(6) 228-34). More recent studies on higher producing cows showed that after 6 weeks of observation 23.4% of the teats remained open (Dingwell et al. prev. vet. Med.2004April 30,63(1-2): 75-89).

In case the teat opens during the dry period, bacteria may invade the udder where they may cause infections, known as mastitis. Many bacteria will not be able to multiply at this time due to the high level of lactoferrin (a protein that binds available iron) present in the udder during the dry period. However, 50-60% of all new infections caused by environmental pathogens occur during the dry period (Bradley and Green, J.Dairy Sci.,2000, Sept; 83(9):1957-65), and more than 50% of clinical coliform mastitis events occur during the first 100 days of milk production, which originate from bacteria that enter the udder during the dry period (Bradley and Green, J.Dairy Sci.,2002, Mar; 85(3): 551-61).

Therefore, it is highly desirable to prevent bacterial invasion during the dry period and thereby prevent clinical mastitis in the next lactation.

The purpose of using an internal teat sealant when drying milk is to provide a continuous physical barrier in the teat cistern, thereby preventing the invasion of bacteria into the udder. This is a well-established practice in the dairy industry, for which many products are licensed on a global scale.

In the developed dairy market, teat sealants are used in many cows and heifers, where use levels of over 50% are not uncommon. In many markets, teat sealants are used in conjunction with long-acting antibiotic intramammary infusions that are administered immediately prior to the teat sealant. The antibiotic intramammary injection is massaged into the breast, while the teat sealant is held in the streak canal/teat cistern.

In many cases, the use of antibiotics in dry milk is not justified, and with global concerns regarding antibiotic resistance, this practice has now been stopped in many countries and allowed only if it has been established that there is a pre-existing sub-clinical breast infection.

In many developed markets, up to 70% of cows do not have such subclinical infections when dry, and do not require any antibiotic treatment.

With the decreasing use of antibiotics in dry milk, the use of internal teat sealants to prevent the ingress of bacteria during the dry milk period has increased dramatically in recent years.

Typically, the teat sealant includes 65% w/w bismuth subnitrate (a non-toxic heavy metal salt) in the gel base. A 4g sealant infusion was applied to each teat. The sealant is intended to maintain cohesion within the teat during the dry period. However, we have found that in some cases the three-dimensional structure of the sealant can change as the dry period progresses, and in some cases can break into individual pieces. Figures 1 and 2 are images from an x-ray study of teats during the 28 day dry period. In the 28 th day image, it will be noted that the upper part of the seal has risen from the papillary cistern into the glandular cistern. In some cases, the entire structure remains intact, but moves up into the gland pool, only descending again later in the dry period.

In some cases, the particles of internal teat sealant have become bound to the mammary tissue in the breast and will stay there at all times, and sometimes will stay for several days after calving. In the event this occurs, the particles will generally only separate from the mammary tissue when the cow has been milked multiple times and will become mixed with the milk. In such cases, for example, particles of internal teat sealant are known to be trapped in the milk line or may sometimes be allowed to reach the milk collection point.

Disclosure of Invention

According to the present invention there is provided an intramammary injector comprising a sealant formulation for forming a physical barrier in the teat canal of a non-human animal, wherein the injector comprises from 0.25ml to 2.0ml of the sealant formulation.

The reduced volume of the sealing agent is sufficient to form an effective seal while avoiding the risk of the sealant being forced upwards due to shrinkage of the breast anatomy during the partial dry period.

In one embodiment, the syringe contains 0.5ml to 2.0ml of the sealant formulation, 0.75ml to 1.75ml of the sealant formulation, or 1.0ml to 1.5ml of the sealant formulation.

The invention also provides an intramammary injector comprising a sealant formulation for forming a physical barrier in a teat canal of a non-human animal, wherein the injector comprises from 0.5g to 2.5g of the sealant formulation.

In one embodiment, the syringe contains 1.0g to 2.5g of the sealant formulation.

In some cases, the weight of the sealing formulation contained in the syringe is 1.5g to 2.0 g.

In some embodiments, the sealing formulation includes a heavy metal salt in the substrate.

In one instance, the heavy metal salt is bismuth subnitrate.

In some cases, bismuth subnitrate comprises about 65% of the sealing formulation.

Other examples of non-toxic heavy metal salts include zinc oxide, barium sulfate, and titanium dioxide. The sealant formulation may include a number of such heavy metal salts.

The sealing formulation may include a thixotropic agent. In some cases, the sealant formulation contains 0.1% to 1.5% thixotropic agent, 0.6% to 1.0% thixotropic agent, or about 0.8% thixotropic agent.

In some embodiments, the thixotropic agent comprises colloidal anhydrous silica.

In some embodiments, the substrate is an aluminum stearate based gel. The substrate may contain liquid paraffin as a carrier.

The invention also provides a method for forming a seal in a mammary gland of a non-human animal comprising the step of injecting 0.25ml to 2.0ml of a sealing formulation into the teat cistern through the teat canal.

In some embodiments, the method comprises injecting 0.5ml to 2.0ml of the sealant formulation, or 0.75ml to 1.75ml of the sealant formulation through a teat canal.

In some embodiments, the method comprises injecting 1.0ml to 1.5ml of the sealant formulation through a teat canal.

The formulation comprises a thixotropic agent or rheology modifier or emulsifier. One is fumed silica, which is also referred to as anhydrous colloidal silica. It is available from Evonik under the trade name Aerosil. It is also available from Cabot Corporation (Cab-o-sil) and Wacker Chemie-Owens Corning and OCI (Konasil).

The present invention provides a teat sealant that provides an effective physical barrier to the teat canal of a cow for preventing intra-mammary infection throughout the dry period of milk.

The teat sealant of the present invention has the following characteristics:

non-toxic, biocompatible and capable of being sterilized.

Persistence-the sealant remains in place for the duration of the dry cow period

Consistency-sealant does not break in the teat

Easy removal-at the end of the dry period, the sealant is easy to remove from the breast and no permanent residues of sealant are produced

Radiopaque easy delivery

Preferably, the teat seal formulation does not have antibiotic or anti-infective properties. The sealant should not contain antibiotics. In some cases, the sealant is free of vegetable oils, such as thyme oil.

Drawings

The invention will be more clearly understood from the following description, given by way of example only, in which: -

Figures 1 and 2 are x-ray studies of teats that have been infused with an internal teat sealant.

Detailed Description

When the cow is dried, a process called involution occurs within the udder. The degradation has three distinct phases.

1) Active degeneration

The first of these phases is called active involution and depends on the remaining time of calving (and therefore the length of the dry period), which will usually be completed within 21 to 30 days. During this time, the breast is more or less in its pre-dry state, with milk continuing to accumulate for approximately 4 days and then rapidly diminishing in the next week. The fluid volume continued to decrease over approximately 30 days (during the 45-60 day dry period).

2) Degradation of steady state

As the volume of fluid is reduced, the size of the breast shrinks significantly (upwards and inwards). Cows are now in a steady state of degeneration.

We have found that during this state, as the breast contracts, the available area within the nipple tunnel also contracts, sometimes leaving insufficient area to accommodate the sealed volume. This is the pressure within the constricted teat cistern so that the inner teat sealant can be torn, with a portion of the inner teat sealant being forced up into the breast. It has been observed that a teat sealant plug that has previously been formed in the teat cistern may in some cases be pressed up into the gland cistern in its entirety.

The length of the stationary phase depends on the total length of the dry period. If active involution takes about 4 weeks to complete in a cow, the re-breeding phase takes about 3 or 4 weeks. These periods will then constitute the recommended optimal 45-60 day dry period. Thus, cows with a dry period of 45-60 days may have a very short, or no, degenerative steady state phase at all. In situations where no steady state occurs, there is little or no pressure on the internal teat sealant.

3) Colostrum production

During the third phase of the dry period, also known as colostrum production and milk production, the breasts and nipples begin to expand again.

This phase of the dry period marks the transition from the non-lactating state to the lactating state. It is currently not clear when this period begins, but it usually occurs around 3 to 4 weeks before calving.

During this time, the volume of the teat canal increases, generally allowing unbound particles of the internal teat sealant that have been forced up into the breast during steady state degradation to settle back into the teat cistern. However, studies have also shown that some particles of internal teat sealant that have been forced upwards become bound to mammary tissue in the breast and will stay there, and sometimes will stay for several days after calving. In the event this occurs, the particles will generally only separate from the mammary tissue when the cow has been milked multiple times and will become mixed with the milk. In such cases, for example, particles of internal teat sealant are known to be trapped in the milk line or may sometimes be allowed to reach the milk collection point.

We have surprisingly found that when a small volume of teat sealant is initially infused, the likelihood of it being forced up from the teat cistern into the gland cistern is significantly reduced, or eliminated altogether.

EXAMPLE 1 Nipple seal formulation

Components	Amount per g	Amount (% w/w)
			Bismuth subnitrate	650.0mg	65％
Colloidal anhydrous silica	8.0mg	0.8％
			Aluminum di/tri stearate	48.0mg	4.8％
Heavy liquid paraffin	Appropriate amount of 1g	Proper amount is 100%

The preparation is prepared by the following process:

the heavy liquid paraffin was added to the vessel.

Aluminum di/tri stearate was added to heavy liquid paraffin, stirred and heated to a minimum of 150 ℃.

The mixture is held at this temperature for a minimum of 3 hours.

The mixture was cooled and then bismuth subnitrate and colloidal anhydrous silica were added and mixed until homogeneous.

The product is then filled into the intramammary injector. The amount filled into the syringe is 0.5ml to 2.0ml or 1.0g to 2.5g to be administered in a single dose.

The filled syringe may be sterilized by gamma irradiation.

EXAMPLE 2 use of teat seal formulation

Studies have shown that by reducing the dose of 4g per teat, which is routinely accepted for dry milk, to between 0.5g and 2.5g, the effectiveness of the internal teat sealant is not reduced, but the problem of internal teat sealant rising during deterioration is eliminated.

The invention is not limited to the embodiments described above, which may vary in detail.