AU2004292397B2 - A ruminant zinc containing bolus - Google Patents

Description

WO 2005/051487 PCT/GB2004/004875 A Ruminant Bolus Field of the Invention The present invention relates to the provision of a sustained release zinc containing bolus administered to 5 ruminant animals, especially to supply high levels of zinc to combat disease. Background to the Invention There are large tracts of grassland throughout the world that are deficient in one or more of the mineral elements 10 required by grazing animals. A large number of grazing species of animals, including cattle, sheep, goats and deer are classified as ruminant animals. Such animals possess four stomach compartments as part of their digestive system. A convenient way of 15 supplying these animals with minerals, vitamins or other dietary or medicinal needs is by means of a slow release bolus. A bolus is an object containing and releasing the required supplement or medicine at the required rate to improve or maintain the health of the animal. Such a 20 device is administered to the animal by mouth and lodges naturally (by means of being sufficiently dense or by being fitted with tags or wings which deploy after administration) in either of the first two stomach compartments of the subject animal. Thereafter the 25 supplement or medicament is released over a period of time influenced by the size, shape and constituent ingredients of the bolus. Many different bolus designs have been utilised to satisfy the particular needs of animals, especially sheep and cattle under different grazing 30 conditions. Zinc deficiency is a well known problem that affects cattle and sheep in several countries. In many cases low levels of zinc are supplied to animals (as part of a WO 2005/051487 PCT/GB2004/004875 2 mixture of the most important trace elements and vitamins) by means of sustained release boluses such as described above. The required low levels of zinc are normally supplied as zinc salts such as the oxide or sulphate. 5 In certain circumstances however, substantially higher levels of zinc are required to maintain the health of the subject animals and prevent the occurrence of particular conditions. In New Zealand Veterinary Journal 45, p93-98, 1997 (cf EP-A-0739 198) Munday et al discuss the 10 requirement for such high levels of zinc (of the order of 25mg/kg live weight/day for a sheep), in the treatment and prevention of facial eczema, and the results of supplying a zinc oxide containing bolus are presented. Blood serum zinc levels in lambs treated with a zinc oxide bolus are 15 shown with levels elevated from 12.5pmoles/l before administration of the bolus to above 19pmoles/l during the period of action of the bolus. The design of that bolus consists of a core containing a binder and solubilising agent together with zinc oxide. The core is coated with 20 wax, which in use gradually erodes to expose more of the core which dissolves, releasing zinc oxide into the subject animals digestive system. Such boluses are by their nature bulky, only some 80% of zinc oxide is zinc and the zinc content of the bolus is further reduced by 25 the requirement to provide a binder, a solubilising agent and a wax coating. Alternative means of supplying zinc to ruminants, by means of boluses comprising alloys of zinc or boluses consisting of zinc metal shot compressed together with 30 iron are also known. In Aust. J. Agric. Anim. Husb (1980) 20:547-551 Masters and Moir describe an experimental bolus of zinc shot and iron filings. That bolus provides zinc by the electrolytic action of the rumen or reticulum 3 liquids (about pH 6) on the zinc/iron couple. However these boluses can become coated, probably with zinc phosphate, reducing their effectiveness. Zinc alloy boluses have been proposed in EP-A-1225 238, especially for the relief of 5 facial eczema in ruminants. These zinc alloy boluses also function by controlled dissolution in the rumen juices, and it is noted that high zinc content alloys (with more than 70 wt% zinc) are regarded as unsuitable for use in cast boluses, (because of insufficient electrolytic action when 10 subjected to the rumen juices). The administration of biologically beneficient, relatively high density, materials such as copper oxide or zinc metal by means of a rapidly dissolving bolus is described in GB A-2297484. The beneficient materials are delivered to the 15 digestive system of the animal by the bolus which then rapidly dissolves, ideally within five to sixty minutes, to release large particles which then lodge in various parts of the intestinal tract. The particles of beneficient material are then expected to dissolve slowly in the subject animal's 20 digestive system. This approach is likely to be problematic in terms of delivering sustained and controlled zinc dosage to a subject animal. Unlike copper oxide, zinc metal will dissolve rapidly in the true stomach of a subject animal which has a low pH (2). 25 One or more embodiments or aspects of the present invention may provide improvements relating to a zinc containing bolus for ruminant animals such that the aforesaid disadvantages of existing boluses, designed to supply sustained high levels of zinc to a subject animal, are obviated or 30 mitigated. Furthermore, one or more embodiments or aspects of the invention may provide a zinc containing bolus capable of 4 providing sustained high levels of zinc, over a period of 35 to 70 days or more, Furthermore, one or more aspects of embodiments may provide a medicament for administration to ruminant animals for the purposes of addressing zinc 5 deficiencies and contribute to maintenance of their health. The invention also has the purpose of providing prophylactics and medicaments for preventing the occurrence of, or promoting recovery from liver damage and facial eczema resulting from a diet contaminated with Pithomyces 10 chartarum or the toxins produced by it. Summary of the Invention The present invention provides a bolus for sustained release of zinc, the said bolus essentially comprising particulate zinc metal and a slow release wax binder. 15 Thus, in a first aspect, the invention provides a slow release bolus comprising zinc metal particles of less than 1mm largest dimension dispersed in a wax binder, wherein the zinc metal particles provide 85-95% by weight of the bolus, and are uniformly dispersed in bolus to present a generally 20 homogenous composition and the wax binder confers shape and form to the bolus whilst permitting controlled and sustained release of zinc from the bolus. The bolus of this invention offers an advantage over known products by providing a bolus that is more durable, does not 25 disintegrate in a short period and yet delivers consistent slow release of zinc over a desired treatment period. Thus it is found that such a bolus offers advantages over the available prior art in that it retains its integrity throughout its useful life of from about 40-50 days, and in 30 use acts to continuously release useful quantities of fine metallic zinc particles which then dissolve in the abomasum.

4a More specifically, according to the present invention there is provided a bolus containing zinc metal particles of less than 1mm largest dimension, dispersed in a wax binder, wherein the quantity of zinc metal provides at least about 5 85% by weight of the bolus, and preferably up to about 95% by weight of the bolus. The particle size of the zinc employed is preferably less than 0.25mm largest dimension, WO 2005/051487 PCT/GB2004/004875 5 The zinc metal particles are preferably uniformly dispersed in the bolus to present a generally homogeneous composition. The wax binder is designed to provide shape and form for 5 the bolus, and also controlled slow and sustained release of zinc from the bolus. Typically zinc release is sustained over a period in excess of 40 days. The characteristics of the slow release wax binder are chosen to provide a bolus that is stable on manufacture 10 and storage and can be readily administered to the subject animal without breaking or substantially losing shape. When in place in the rumen or reticulum of the subject animal the wax binder erodes to release particulate zinc into the digestive system at a rate sufficient to achieve 15 the desired dosage of zinc in the bloodstream principally via dissolution in the true stomach. The wax binder preferably has a congealing point of less than 50 deg C. The wax binder preferably consists of a wax such as 20 paraffin wax, carnauba wax, beeswax or mixtures thereof. A most preferred binder is a paraffin wax with a congealing point of below 50 deg C. The use of the preferred paraffin wax has been found to provide a high uptake of zinc into the bloodstream of animals requiring 25 zinc in order to maintain their health as shown hereinafter in the Examples. Other wax binders can be selected to adjust the release rate of the zinc as desired. A typical bolus of this invention for cattle has a 30 diameter of about 26mm, a length of about 50mm, a weight of about 100g, and contains about 90% zinc metal powder in a mixed paraffin wax binder.

WO 2005/051487 PCT/GB2004/004875 6 A bolus according to the invention can be manufactured by forming a slurry of zinc particles with molten or softened wax into the desired bolus shape. In such a method, use of reduced amounts of zinc metal particulates could lead 5 to compromising the desired homogeneous dispersion of the zinc throughout the bolus due to settling of the zinc particles before the wax hardens again. Such inhomogeneity may result in uneven release of the zinc particles as the bolus erodes. If it is desired to reduce 10 the zinc content below 90% then addition of suitably dense particulate filler, such as iron particles, can be used to assist the even dispersion of the zinc particles during manufacture. The density of a bolus is preferably at least 3.0g/ml, 15 more preferably 3.5g/ml or greater in order to prevent regurgitation of the bolus in practical use. The bolus of the present invention easily meets this requirement by virtue of the use of metallic zinc, which is naturally sufficiently dense, as a high percentage component of the 20 bolus composition. The combination of say 90% by weight zinc particles and the preferred paraffin wax produces a bolus with a density of about 3.6g/cm 3 . The present invention further provides a method of manufacturing the bolus from wax and particulate zinc. 25 Thus according to the present invention a process for the manufacture of a bolus is provided wherein a slurry of zinc metal particles and molten wax binder is prepared and the mixture is then formed into a bolus by cooling in a mould or by extruding through a die. The extrusion method 30 can be a continuous or semi-continuous process. The shape of the bolus produced can be modified if desired by compressing the bolus in a further mould or by trimming with a knife. Forming the bolus in this way makes it 7 possible to achieve-a substantially uniform distribution of zinc metal particulates throughout the wax binder. Preferably the bolus is shaped to a form in which the longer dimension (length 1) is not excessively greater than the 5 shorter dimension (width/diameter s). Thus a shorter-fatter bolus is more stable than a longer slimmer bolus. A ratio of 1:s about 2:1 would provide favourable results, whilst a ratio of about 3: 1 provides poor results. The invention also encompasses a method of treatment of 10 conditions such as facial eczema and the like zinc deficiency manifestations in ruminants. Thus, in a further aspect, there is provided a method for the treatment and prevention of facial eczema in ruminants, said method comprising the steps of administering to a 15 ruminant at least one slow release bolus consisting of particulate zinc metal dispersed substantially uniformly in a wax binder, said bolus comprising from 85% to 95% zinc metal by weight of the bolus. Yet another aspect provides a method for the treatment and 20 prevention of zinc-deficiency in ruminants, said method comprising the steps of administering to a ruminant at least one slow release bolus consisting of particulate zinc metal dispersed substantially uniformly in a wax binder, said bolus comprising from 85% to 95% zinc metal by weight of the 25 bolus. Still another aspect provides a method for the treatment and prevention of liver damage in ruminants, wherein the liver damage results from a diet contaminated with Pithornyces chartarum or the toxins produced by it, said method 30 comprising the steps of administering to a ruminant at least one slow release bolus consisting of particulate zinc metal 7a dispersed substantially uniformly in a wax binder, said bolus comprising from 85% to 95% zinc metal by weight of the bolus, Preferably, a plurality of boluses are administered at the 5 same time, say 3 or 4 for cattle, or 2 or 3 for sheep, the bonuses being designed to deliver a sufficient dosage for the size/weight of ruminant being treated. A dosage of from 0.75-1.0 g per day for sheep, and 4-8 g per day for cattle would be considered appropriate. 10 An advantage of this method is that the attendant stresses associated with catching and handling of the ruminants for administration of regular supplements are minimised due to the fact that the administered bolus is anticipated to provide the required daily therapeutic dose for at least 15 about 40 days, and typically 50 days with continued zinc release for up to 90 days if more than 1 bolus is administered. The invention will now be more thoroughly explained and described by way of the following illustrative examples 20 WO 2005/051487 PCT/GB2004/004875 8 which include the best mode for performance of the invention as currently conceived. Examples 1 Sustained Zinc Release from the Bolus 5 The bolus of the present invention is sized and shaped to suit the size of animal being treated. For cattle a bolus of 26mm diameter and for sheep a bolus of 20mm diameter have been used in trials. The size of bolus and the number of boluses administered to the animal can be varied 10 as needed to supply the required zinc dosage. The benefit of the high zinc metal (90%) content of the bolus means that high levels of zinc can be supplied in a bolus that is compact in relation to the dosage of zinc that is available for release. 15 From the results of tests in cattle and sheep, it has been determined that the daily release rate per bolus can be adjusted by a judicious combination of 4 varying factors viz: a) The choice of waxes used in that a suitable mixture 20 can be found of waxes with different congealing points to give the desired release rate. One preferred mix for a zinc bolus is 60% paraffin wax with a 41-46 'C congealing point/40% paraffin wax with a 57-59 0 C congealing point. This composite mix 25 has a congealing point of 490C. If, however, it is desired to have a higher or lower bolus release rate different proportions of these or other waxes can be used. To exemplify this point, the following release rates 30 were measured in a trial where a treatment of 4 boluses of 26mm diameter/50mm Length/100g weight/90% zinc metal powder were tested in three cows per WO 2005/051487 PCT/GB2004/004875 9 group. The boluses were identical apart from the differing stated wax proportions. Mean Daily Release Rates per Bolus 0-7 days 7-14 days 14-21 days 21-28 Days 5 50% 41-46'C wax/ 50% 57-59'C wax 1.5g 1.8g 1.5g 1.0g 60% 41-46'C wax/ 40% 57-59'C wax 1.8g 2.lg 1.7g 1.3g b) The number of boluses per treatment affects the total 10 daily release to the animal not only by the presence of more or fewer eroding objects, but also by the release rate being greater per bolus in proportion to the presence of more boluses. The following results exemplify this point: A treatment of the same bolus 15 (26mm diameter/50mm length/1Og weight) was given to groups of cows as a 3 or 4 bolus treatment. Mean Daily Release Rate per Bolus 0-7 days 7-14 days 14-21 days 3 bolus treatment 1.2g 1.2g 1.Og 20 4 bolus treatment 1.5g 1.8g 1.5g A similar example of this effect in sheep is where the same formulation of bolus was given to 3 sheep as a 1 or 2 bolus treatment: 1 bolus - Mean wt loss of 1 bolus (55mm length) over 45 25 days - 0.3g/bolus/day 2 bolus - Mean wt loss per bolus (40mm length) over 36 days - 0.9g/bolus/day c) The relative proportions of the length and diameter of the bolus affect the release rate in that, as well as 30 influencing the exposed surface area, the relative length WO 2005/051487 PCT/GB2004/004875 10 is important because it ias been found that a shorter fatter bolus is a more stable configuration whereas a longer slimmer bolus has a tendency to break into two parts which in turn not only increases the number of 5 objects present (ref: point made in (b) above) but, in addition, smaller objects then lose weight more rapidly due to the hammer action of larger objects. This is illustrated by the following comparative results: Where multiple bolus treatments of boluses of 26mm 10 diameter/50mm length were given to 6 cows and examined over a 42 day period, every bolus maintained its integrity. In contrast, where multiple bolus treatments of boluses of 26mm diameter/80mm length were given to 6 cows and examined over a 35 day period, in 3 of the 6 15 cows, at least one of the boluses broke into 2 parts. Whereas the release rate of entire boluses remained reasonably constant at around 2.3g/day, the release rate of fragmented boluses averaged 7.0g/day. The generally accepted dosage for the prevention of facial 20 eczema is 0.75-l.0g per day for sheep and 4-8g per day for cattle. Thus it can be seen that the administration of 3 or 4 boluses to cattle and 2 or 3 boluses for sheep (of the appropriate size) would be expected to provide the required daily dose for about 50 days with zinc release 25 continuing for up to 90 days. 2 Zinc Uptake Into the Bloodstream For sheep, trials have been carried out which included the measurement of zinc uptake into the blood serum. Four sheep were each given 2 boluses of 90% by weight zinc, 10% 30 paraffin wax of 41/46 deg C congealing point, and sized 20mm diameter by 40mm length. Blood samples were taken weekly before and after treatment, which was carried out on day 0. The results, quoted as pmol/l of zinc in the WO 2005/051487 PCT/GB2004/004875 11 serum, are compared with those obtained from 3 untreated sheep in Table 1 below. Table 1 Day Day Day Day Day Day Day Day -6 -4 0 7 14 20 29 35 4 treated 16.3 11.8 14.4 42.5 37.3 37.1 31.5 29.3 sheep 3 16.3 11.8 14.4 12.7 9.9 10.9 10.5 11.5 Untreated sheep 5 On day 36 the boluses were recovered and weighed. The mean weight loss found was equivalent to 1.7g/day of zinc. These results show that the use of a pair of boluses easily provided sufficient zinc, in substantial excess of the 20pmol/l in serum found to be effective against facial 10 eczema in sheep in the trials reported in the New Zealand Veterinary Journal 1997, 45, p93-98, for a period of 35 days. Protection for up to 70 days or more can be anticipated from these results. A second trial, using a 3 bolus treatment, demonstrates 15 the same point and it shows more moderate blood zinc level increases as a reflection of the more moderate daily bolus weight losses which are more in accord with the levels desired. The 3 boluses weighed 25g each with a formulation of 90% zinc metal particles/5% 41-46'C wax/5% 20 56-58'C wax. Mean plasma zinc levels (pmol/l DayO Day7 Day14 Day2l Day28 10 treated sheep 13.2 21.3 35.5 23.4 22.1 Boluses recovered indicate a daily release rate of 0.65g 25 zinc/sheep over days 0-14 and 1.3g zinc/sheep over days 14-28.

WO 2005/051487 PCT/GB2004/004875 12 The various experiments quoted have shown that it is preferable to use a plurality of boluses rather than a single bolus, the rate of erosion of the boluses being increased and better regulated by the attrition between 5 boluses in the reticulum. Therefore, the dose of zinc administered could best be reduced, if desired, by reduction in the size of each bolus rather than by administering a single bolus. Alternatively a grinder could be administered with a single bolus but this has the 10 disadvantage of lodging an unnecessary object in the rumen or reticulum of the subject animal. Whilst the examples show that reasonable constant daily release can be achieved, certainly for the first 21 days of treatment, there will be a point in the later stages of 15 bolus erosion where the daily release rate will decrease due to the reducing surface area of the boluses. This can be largely compensated for by designing the bolus treatment to supply initially higher than necessary amounts of zinc such that it extends the period over which 20 the dose remains within the range considered necessary for effective therapeutic treatment. Industrial Utility The invention is useful in animal husbandry, particularly in the rearing and care of ruminants. 25 13 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or 5 step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is 10 known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. 15

Claims (20)

1. A slow release bolus comprising zinc metal particles of less than imm largest dimension dispersed in a wax 5 binder, wherein the zinc metal particles provide 85-95% by weight of the bolus, and are uniformly dispersed in bolus to present a generally homogenous composition and the wax binder confers shape and form to the bolus whilst permitting controlled and sustained release of 10 zinc from the bolus.

2. A bolus according to claim 1, wherein the wax binder contains wax selected from the group consisting of paraffin wax, carnauba wax, beeswax and mixed waxes. 15

3. A bolus according to claim 1, or claim 2, wherein the wax binder contains waxes of different congealing points. 20

4. A bolus according to any one of claims 1 to 3, wherein the wax binder has a congealing point of less than 50 deg C.

5. A bolus according to any one of claims 1 to 4, wherein 25 the zinc metal particles are less than 0.25mm largest dimension.

6. A bolus according to any one of claims 1 to 5, wherein the density of the bolus is 3.0 g/cm 3 or greater. 30

7. A bolus according to any one of the preceding claims, wherein the quantity of zinc metal provides about 90% by weight of the bolus and the binder is a paraffin wax. 15

8. A bolus according to any one of the preceding claims, wherein the bolus has a diameter of about 26mm, a length of about 50mm, a weight of about 100g, and 5 contains about 90 zinc metal particles in a mixed paraffin wax binder,

9. A bolus according to any one of claims I to 8 for use as a medicament or prophylactic in the treatment or to inhibition of facial eczema in ruminant animals.

10. A bolus according to any one of claims 1 to 8 for use as a medicament or prophylactic in the treatment or prevention of zinc deficiencies in ruminant animals. 15

11. A bolus according to any one of claims 1 to 8 for use as a medicament or prophylactic in the treatment or prevention of liver damage in ruminant animals, wherein the liver damage results from a diet contaminated with 20 Pithomyces chartarum or the toxins produced by it.

12. A process for the manufacture of a bolus according to any one of the preceding claims wherein a slurry of zinc metal particles and molten wax binder is prepared 25 and the slurry is then formed into a bolus by cooling in a mould

13. A process for the manufacture of a bolus according to any one of the preceding claims wherein a slurry of 30 zinc metal particles and molten wax binder is prepared and the slurry is then formed into a bolus by extruding through a die. 16

14. A process according to claim 12 or claim 13, wherein the bolus has longer dimension (length) to shorter dimension (diameter/width) of about 2: 1. 5

15, A method for the treatment and prevention of facial eczema in ruminants, said method comprising the steps of administering to a ruminant at least one slow release bolus consisting of particulate zinc metal dispersed substantially uniformly in a wax binder, said 10 bolus comprising from 85%- to 95% zinc metal by weight of the bolus.

16. A method for the treatment and prevention of zinc deficiency in ruminants, said method comprising the 15 steps of administering to a ruminant at least one slow release bolus consisting of particulate zinc metal dispersed substantially uniformly in a wax binder, said bolus comprising from 85% to 95% zinc metal by weight of the bolus. 20

17. A method for the treatment and prevention of liver damage in ruminants, wherein the liver damage results from a diet contaminated with Pithornyces chartarum or the toxins produced by it, said method comprising the 25 steps of administering to a ruminant at least one slow release bolus consisting of particulate zinc metal dispersed substantially uniformly in a wax binder, said bolus comprising from 85% to 95% zinc metal by weight of the bolus. 30

18. A method according to claim 15, wherein the facial eczema results from a diet contaminated with Pithomyces chartarum or the toxins produced by it. G:\NRronIVGU\}LI~'M 4'.'m .[PU'2,|'/2)I 17

19. A method according to any one of claims 15 to 18, wherein a plurality of boluses are administered at the same time, the boluses being designed to deliver a sufficient dosage for the size/weight of ruminant being 5 treated.

20. A bolus according to claim 1; or a process according to claim 12; or a method according to any one of claims 15 to 17 substantially as hereinbefore described with 10 reference to the Examples.