NZ526939A - A release device such as a bolus having an outer shell containing magnesium and an inner core containing zinc for veterinary use - Google Patents

Abstract

A release device comprising an inner, core portion and an outer portion comprising a thin shell portion, which outer shell portion at least partially covers the inner, core portion, each of the said inner and outer portions comprising respective metal alloy compositions. The metal alloy composition of the inner portion comprises at least 35 wt.% of zinc, by weight of the total metal alloy composition of the inner portion, and the metal alloy composition of the outer portion comprises at least 60 wt.% of magnesium, by weight of the total metal alloy composition of the outer portion. Thus, a zinc alloy core is at least partially covered by a thin corrodible magnesium alloy shell.

Description

526 9 3 9 PATENTS FORM 5 Our Ref: 643000NZ PATENTS ACT 1953 Dated: 9 July 2003 COMPLETE SPECIFICATION Release Devices for Veterinary Use We, Castex Products Limited, of Woodside Street, New Mills, Stockport SKI2 3HG, United Kingdom, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 0 JUL 2003 RECEIVED [R:\LIB W]86909.doc:irg 1 Release Devices for Veterinary Use The use of sustained and pulse release boli for the delivery of active agents to ruminants over an extended period of time is a well established practice. The boli are administered orally and reside in the rumeno-reticular sac of the animal.

For many applications, the most practical bolus shape is that of a cylinder. This combines ease of administration with maximum volume and is hence the most economical shape where there is a requirement to maximise the active content of the bolus. The cost of such boli is always an important factor governing their use and this is particularly the case with sheep.

In particular, it is known to provide a bolus with a central core including graphite material and an outer coaxial hollow cylindrical shell of a magnesium rich alloy. The graphite ensures that the core as a whole is conductive and provides a cathode electrically coupled with the magnesium alloy shell to form a galvanic cell. Liquor in the rumen serves as an electrolyte to cause galvanic corrosion of the magnesium alloy shell.

Thus the application of water impermeable materials such as waxes, synthetic or naturally occurring resins or paints and varnishes, may result in corrosion being initially confined to the ends or particular areas of the bolus. 2 In an alternative bolus construction (EP-A-0243111), an active agent is present in the core and the magnesium alloy shell is externally surrounded by a coaxial sheath of plastics material which confines corrosion, caused by rumen liquor, of the magnesium alloy shell to its axial ends. In one embodiment, the coaxial sheath of plastics material is a series of close fitting rings applied to the exterior of the bolus. The magnesium alloy shell, covered with the plastics sheath, serves as a timing device, the corrosion and consequent shortening in length of which accurately controls release of the active agent present in the core. In place of graphite, the conductive material may be a powder of any metal which is lower in the electro-chemical series than magnesium, for exampie, iron, copper, nickel or zinc. In commercial examples of this type of bolus, the active agent is present as an ingredient in a series of weighted tablets made electrically conductive by the presence of graphite. A large potential difference exist between the graphite bearing tablet and the magnesium alloy tube e.g. 1 volt and corrosion proceeds galvanically. The device may have a life extending up to 140 days.

In another bolus construction, disclosed in WO-A-98/056347, a core, again consisting of a plurality of weighted tablets containing an active agent and rendered conductive and electropositive by the presence of graphite, is surrounded by an outer coaxial hollow cylindrical shell of a magnesium alloy. Likewise, in GB-A-2186291, a core comprises a magnesium alloy containing at least 40% magnesium, at least 30% zinc and at least.5% aluminium and from 0 - 5% copper. In addition, the core 3 includes a weighting component such as iron shot or zinc powder. In each of the boli of WO-A-98/056347 and GB-A-2186291, the magnesium alloy shell is much larger and thicker than that of the bolus construction disclosed in EP-A-0243111. Corrosion proceeds mainly parasitically on the outside of the tube and galvanically at the ends where the tablets are exposed. The corrodible metal alloy shell serves as a source of the beneficial trace element magnesium.

However the known methods described above may be inappropriate for use on reactive magnesium containing alloys for the following reasons: a. Boli having too thick a shell have too low a density to allow sinking of the bolus within the rumen of an animal and therefore require the presence in the core of unwanted weighting materials. b. Moreover such boli having a thick shell may not afford the required rate of dissolution to allow the desired rate of release of the active ingredients of the core. c, Boli having the organic coatings referred to above require careful and expensive surface preparation of the bolus prior to the application of the coating if they are to have good adherence and perform adequately. Their performance in protecting the bolus is subject to variations in coating thickness and variable permeability to water. 4 d. The application of plastic rings to metallic cylindrical boli demands a high degree of surface finish and precision. Particular grades of plastic must be used if seepage of corrodant between the interface of plastic 5 and metal is to be avoided, Apart from the expense of fitting plastic rings the density of the resultant composite boli may be too low to avoid regurgitation by the animal.

Moreover, the cost of such boli is always an important factor governing their use and this is particularly the case with sheep. As explained above, many known constructions tend to be expensive.

As to the particular active component of the core of a bolus, this depends upon the particular disease to be treated or prevented/ see, for example, EP-A-0243111 (supra), which discloses a bolus comprising a tube which serves as a carrier for drugs such as anthelmintics or 20 antibiotics.

A particular disease which represents a major animal health problem in New Zealand is facial eczema, which has also been observed in South Africa and the USA. The 25 disease is caused by the toxin sporidesmin carried by the spores of the saprophytic fungus Pithomyces chartarum which proliferates on pasture in warm and humid weather conditions. Perennial ryegrass is frequently associated with facial eczema. The toxin damages the livers of 30 sheep, cattle and goats when ingested by the animal. The animal becomes photosensitive and develops the facial lesions characteristic of the disease.

A well established protection against facial eczema in sheep and young cattle is the regular dosing of the animal with zinc compounds and in particular zinc oxide; see Munday et al, New Zealand Veterinary Journal, (1997), 45, 93-98.

To be effective the animal should receive a daily dose of elemental zinc in excess of 20 mg/kg/day over a 10 period of up to five weeks. It is generally impracticable to administer zinc compounds as repetitive drenches and alternative methods such as dressing the pasture with zinc oxide are inefficient and expensive. Sustained release boli with adequate reserves of zinc and a 15 sufficient lifespan are hence a particularly attractive means of controlling facial eczema. This requirement has resulted in the development and commercial exploitation of sustained release boli based on compacted zinc oxide.

However, even such commercially available zinc oxide boli may not provide particularly high zinc serum levels, at least over a period of a few weeks. Furthermore, they require surface protection with a waterproof coating e.g. paraffin wax, to control the erosion rate arid are 25 relatively fragile. Care is hence needed during transport and administration to the animal to avoid damage.

GB-A-2186291 (supra) describes magnesium rich alloys for the manufacture of boli intended for the control of 30 magnesium deficiency disease (hypomagnesaernia) in ruminants. The alloys so described form part of the magnesium-aluminium-copper-zinc constitutional system. In 6 this system, magnesium is the major constituent as an animal dietary supplement.

We have found, surprisingly, that a neat, simple 5 bolus construction which is easy and therefore economical to produce, can, at one and the same time, provide the desired pattern of sustained release of a sufficient quantity of zinc for treatment of diseases, especially facial eczema, and yet have a sufficiently high density 10 for the bolus to sink in the rumen without the addition of otherwise undesirable weighting material such as iron shot.

Thus, according to one aspect, the present invention 15 provides a release device comprising an inner, core portion and an outer portion comprising a thin shell portion, which outer shell portion at least partially covers the inner, core portion, each of the said inner and outer portions comprising 20 respective metal alloy compositions, the metal alloy composition of the inner portion comprising at least 35 wt.% of zinc, by weight of the total metal alloy composition of the inner portion, and the metal alloy composition of the outer 25 portion comprising at least 60 wt.% of magnesium, by weight of the total metal alloy composition of the outer portion.

According to another aspect, the invention provides 30 a method of preparing a release device comprising the steps of IPONZ 1 7 NOV 2003 7 preparing a shell portion of the release device, in the form of a thin hollow cylindrical tube or segment thereof, from a metal alloy composition comprising at least 60 wt.% thereof of magnesium, having dimensions 5 such as to provide a close fit in a die cavity of a die; inserting the shell portion into the die; pouring into the die cavity a molten metal alloy composition comprising at least 35 wt.% thereof of zinc; and allowing the metal alloy composition poured into the die cavity to solidify, thereby providing an inner, core portion of the release device.

Thus, a zinc alloy core is at least partially covered by a corrodible magnesium alloy shell.

Typically, the release device is a cylindrical bolus, the core portion of which may be produced by casting, especially die casting.

The shell portion has a wall thickness of up to 5 mm and preferably has a thickness of from 1-4 mm, more preferably 1.5 - 3 mm.

The shell portion may then be a thin tubular shell or segment of such a shell which partially covers the exterior of the core portion. The shell may be conveniently and economically made from an extruded tube or strip.

A preferred bolus construction embodying the invention allows the use of a thin unprotected magnesium 8 base alloy sleeve as a shielding tube to shield and galvanically protect a reactive zinc alloy bolus and hence control the rate of zinc release in the rumen.

Thus, an unprotected magnesium alloy sleeve may serve as an anode affording cathodic protection to the bolus, while the use of a thin magnesium alloy sleeve avoids reducing the density of the bolus, allows minimum cost by reducing the amount of material required and may corrode away at a desired corrosion rate, leaving no residue in the rumen. Moreover, such a construction allows economical manufacture of a composite bolus by casting molten zinc alloy into the sleeve, as described below.

Thus, surprisingly, it is found that a bolus having, in combination, a thin magnesium alloy shell or segment thereof containing at least 60 wt% magnesium which at least partially covers a zinc alloy core containing a large proportion of zinc, in particular, at least 35 wt% zinc, especially at least 50 wt% zinc, may (a) have a sufficient density, a,e. at least 2.2 g/ml, especially at least 2.5 g/ml, to allow it to sink within the rumen of an. animal, (b) provide a sufficient quantity of zinc to the animal to combat diseases such as facial eczema (for which we find surprisingly that administration of zinc to an animal is particularly effective) and foot rot and (c) allow dissolution of the shell or segment thereof at a rate suitable for obtaining a desired rate of release of the zinc in the case for sustained effective treatment of an animal.

In order to prepare the bolus, the shell, or a segment thereof, may be provided with exterior dimensions 9 such that it is a close fit in a die cavity used to produce a die cast bolus. In particular, the shell or segment may first be cut to the appropriate size and then inserted into the open die, The molten zinc alloy of the core may be prepared by melting zinc in ferrous or refractory crucibles and dissolving the requisite amounts of other components of the alloy such as magnesium and copper in the molten 10 metal. The alloy is inflammable in the molten state and the surface must be protected with inert gas e.g. argon or a fluid cover flux to avoid excessive oxidation. 9 After insertion of the shell or segment into the 15 open die, the die containing the shell, or segment thereof, may then be closed and the molten zinc alloy poured into the die cavity in the usual way.

In particular, the molten zinc alloy may be 20 introduced into the mould cavity by the usual gravity, low pressure or high pressure casting techniques. Alloys of the more zinc-rich composition of release devices embodying the invention may exhibit brittle tendencies due to their high content of the intermetallic compounds 25 which comprise the zinc rich regions of the zinc-magnesium equilibrium system.

The castings may advantageously be heat treated at temperatures of 200-300°C for a period of e.g. 2-16 hours. 30 This stress relieves the castings and modifies their corrosion characteristics.

After solidification, the composite bolus is extracted from the die and any riser or feed gate removed. After removal of any flash and smoothing or areas of the bolus not covered by the shell or segment 5 the bolus is in a finished condition.

Alternatively the shell may be applied mechanically to the cast bolus rather than as described above. In this case the shell may be designed to be an interference ]0 fit on the exterior surface of the bolus.

The zinc alloy composition of the core portion contains at least 35 wt.%, and may contain at least 40 wt.%, zinc.

A first preferred zinc alloy composition of the core portion contains aluminium and the total amount, in the composition, of zinc and aluminium is, more preferably, at least 45 wt.%. Still more preferably, the composition 20 contains from 35 - 40 wt.% zinc, from 4 5 - 55 wt.% magnesium, from 5 - 15 wt.% aluminium and from 0-6 wt.%, more preferably up to 6 wt.%, especially, from 1 -6 wt-%, more especially from 2 - 5 wt.% copper.

Particularly effective alloys (1) and (2) consist, by weight of the total weight of the alloy, of: (A) (B) Zinc 38% 37% Magnesium Aluminium 48% 50% 12% 8% Copper 2% % 11 A second preferred zinc alloy composition of the core portion contains at least 50 wt.% zinc, preferably 50-70, more preferably 50-65, wt.% zinc and preferably 5 additionally contains from 30-49, more preferably 30-45, wt.% magnesium and preferably also contains up to 6 wt.%, more preferably 1-6, still more preferably 2-5, wt.%, especially 3, wt.%, copper.

Particularly effective second preferred alloys (A) and (B) consist, by weight of the total weight of the alloy, of: (A) (B) Zinc 52% 65% Magnesium 4 5% 32% Copper 3% 3% In the zinc-magnesium-copper system provided by the second preferred zinc alloy core of a bolus in accordance with the invention, the zinc is at least the main active ingredient, whilst the magnesium and copper serve to control the rate of corrosion of a pellet or bolus in the 25 rumen juices.

Furthermore, for any zinc alloy core composition embodying the invention, the magnesium content may provide a valuable function in aiding the prevention of 30 the deficiency disease "Grass Staggers" (hypomagnesaemia) . Similarly the copper content may be advantageous in combating copper deficiency diseases 12 which may also be occasioned by large zinc inputs to the animal.

In addition, a preferred zinc alloy composition of 5 the core portion may comprise elements additional to zinc, magnesium and copper.

Prominent among these are the beneficial trace elements selenium and cobalt. Thus, the composition may 10 also additionally contain up to 0.02 wt.%, preferably up to 0.015 wt.%, selenium and/or up to 1 wt.%, preferably up to 0.7 wt.%, cobalt. Typical additions of these alloys amount to: Selenium - 0.015 wt% Cobalt - 0.75 wt%.

In addition, as indicated above, the abovementioned first preferred zinc alloy core composition contains aluminium. Here, the aluminium plays a stabilizing role 20 in reducing the tendency, associated with alloy compositions containing a higher zinc content, to fragment.

On the other hand, elements additional to zinc, 25 magnesium and copper may be preferably absent. In particular the abovementioned second preferred zinc alloy composition is preferably free from aluminium. Such compositions may provide the bolus with an improved corrosion pattern and improves physical properties.

In a zinc alloy of a core of a bolus in accordance with the invention, it is preferred that the total weight 13 of zinc and magnesium is at least 94 wt%, by weight of the total weight of the alloy.

The composition of the magnesium alloy from which 5 the shell or segment is extruded is determined by the following factors: a. It should have a higher melting point than the casting temperature of the bolus alloy in order to avoid risk of fusion and collapse of the shell on casting. b. It should be capable of economical extrusion by an extrusion process. c. It will generally be more electronegative than the zinc base bolus alloy and hence potentially capable of exerting a degree of cathodic protection to the bolus. However it must also be capable of corrosion in the rumen fluid and degrade in the required time so leaving the 20 underlying zinc alloy exposed. d. It must be non-toxic to the animal.

Favoured alloy systems complying with the above are 25 magnesium based alloys containing zinc and/or aluminium with additions of copper to promote corrodibility, i.e. magnesium alloys containing at least 60 wt,%, preferably at least 65 wt.%, more preferably at least 70 wt.%, magnesium, still more preferably at least 70 wt%, 30 especially at least 80 wt%. Such favoured alloys also preferably additionally contain up to 20 wt.% zinc or aluminium or up to 20 wt.% of aluminium plus zinc, 14 preferably together with up to 10 wt.% of copper.

Typically, the magnesium alloy of the outer shell or segment may contain from 80 - 95, more typically 85 - 95 wt% magnesium, from 5-20 wt% of aluminium or zinc or a 5 mixture thereof and from 0-5, more typically 1-5 wt! copper. Particularly suitable examples are 86 wt.% magnesium - 12 wt.% aluminium - 2 wt.% copper; 92 wt.% magnesium - 6 wt.% aluminium - 2 wt.% copper; and 93.75 wt.% magnesium - 6 wt.% zinc - 0.25 wt.% copper. Where 10 extended shield tube or segment life is required, manganese, e.g. up to 1,6 wt.%, may be incorporated in the above alloys.

A release device embodying the invention allows 15 greater flexibility in controlling the corrosion pattern and corrosion rate of the core portion especially of the above cylindrical type of bolus, than has hitherto been V the case. The size, location and shape of the shell or segment thereof providing a shielding tube or part 20 thereof may all be varied. The thickness of the shell may also be varied up to a maximum of 5 mm. However, a preferred thickness is from 0.5-5 nun, more preferably from 1-4 mm, especially from 1.5-3 mm. Bolus alloys (i.e. core alloys) can be selected which would normally 25 corrode at too fast a rate to give the required bolus life. Partial shielding of such a bolus however delays the onset of corrosion and so not only extends bolus life but also allows immediate delivery of a substantial dose of active agent. This is a feature which is of 30 particular value in the treatment of racial Eczema where, conventionally, an up front dose of zinc compound, e.g. used in the form of a drench, is frequently given together with a bolus. By administration of a bolus embodying the invention, such an additional dosage may be dispensed with.

Moreover, since the magnesium shell is particularly thin, the overall density of the bolus is not significantly reduced by the shell, so that this decreases the risk of regurgitation by the animal. In addition, when desirable, for example, in order to 10 improve core stability by incorporation into the core alloy of aluminium, this allows a reduction in the amount of zinc present in the core, as for example, in the abovementioned first preferred zinc alloy core composition.

On the other hand, particularly when treating lambs of less than 40kg weight there is a limit to the size of ^ bolus which can be accommodated by the animal. There may .therefore be a further difficulty with core alloys 20 containing such lower amounts of zinc in achieving a sufficiently high zinc content in the bolus to meet the minimum daily requirement of the animal for avoiding facial eczema. Whereas this may be compensated for by dosing with more than one bolus this is not an economical 25 solution. In such a case a second preferred zinc alloy composition of the core containing a larger amount of zinc may be employed. Such alloys have especially favourable densities.

However, although zinc-magnesium-copper alloys of a core containing substantially more than 70 wt% zinc have favourable densities in excess of 3.5, their dissolution 16 and/or physical characteristics may render them unsuitable for use in boli where the core is in the cast form. Alloys containing very high zinc e,g, 85 wt% and over may be insoluble in the rumen liquor. Alloys of 5 intermediate zinc contents e.g. 70-85 wt% are only sparingly.soluble and are excessively brittle and fragment when exposed to corrodant. Accordingly, core alloys having a zinc content higher than 70 wt.% are les preferred.

It is preferred to cover, with the shell portion, at least 10%, more preferably at least 20%, of the surface area of the core portion. However, the shell portion may cover the core portion in its entirety. Typically, for a 15 cylindrical core portion of a bolus, the shell portion may cover the entire length of the core portion but leave open the two axial ends.

It is especially preferred that the shell of a 20 segment of the magnesium alloy be uncovered so as to allow immediate contact of the magnesium alloy with rumen juices on administration.

A bolus suitable for administration to young lambs 25 of up to 30 kg weight may have dimensions about 17 mm diameter x 80 mm long whereas a bolus for young cattle, e.g. 150 kg weight, may have dimensions of approximately 25 mm diameter x 75 mm length.

The suitability of a bolus for administration is governed by its ability to meet the following criteria. In particular, to be effective the animal should receive 17 a daily dose of elemental zinc in excess of 20 mg/kg/day over a period of several weeks. Boli given to sheep should have a relatively high density to avoid regurgitation and be of a size sufficiently small for 5 ease of oral administration. The requirements for a zinc bolus suitable for lambs weighing 30-40 kg may hence typically be listed as follows: Available zinc content, 40 gm.

Bolus life, 40 days.

Density, 3.0 gm/ml.

Dimensions, 20 mm diameter x 80 mm long.

A further requirement is that at the end of the bolus life no substantial residue should remain in the 15 rumen and in particular no hard masses such as the weights sometimes employed to augment the density of intraruminal boli. The latter may damage the blades of carcass processing machinery. It is also necessary that the bolus should be economical to manufacture 20 particularly in the case of lambs due to the comparatively low value of the animal.

Preferred embodiments of the invention will now be described with reference to the accompanying drawings, 25 which illustrate various design features, and with reference to the following Examples, which illustrate various zinc and magnesium alloy compositions of the core and shell portions respectively and results achieved.

Examples of shield tube design features which are of particular value are illustrated as follows: 18 Fig. 1 shows a cylindrical zinc 52% - magnesium 46% - copper 2% alloy bolus 1 suitable for administration to a ewe of 40kg weight. The bolus 1 has dimensions of 21mm dia. x 80mm long. A shield tube segment 2 is provided during the die casting process and is located towards one axial end of the bolus. It has a wall thickness of 1.5mm. It is extruded from 92 wt% magnesium - 6 wt% zinc - 2 wt% copper alloy. The tubular shield segment exerts a galvanic effect on the zinc alloy bolus the protective value of which diminishes towards the bolus end remote from the ring. The initial corrosion rate of the bolus in the animal is hence reduced.

Fig, 2 shows a bolus 3 similar to that of Fig. 1 15 with, however, a shell 4 extending along the length of the bolus but so as to provide a longitudinal gap 5 wherein the core remains uncovered by the shell throughout its entire axial extent. The width of the gap may be varied at will, thus facilitating control of the 20 initial dose rate and subsequent life of the bolus.

Fig. 3 shows a cross section of a zinc alloy bolus 6 fitted with a hemispherical shell segment 7. The thickness of the shell segment may be varied from a 25 minimum value at the edges to a greater value at the base 9 of the hemisphere. This variation in wall thickness gives additional control of the corrosion rate of the bolus. As shown in Fig. 3, the shell 7 has a longitudinal rib 10 extending from one axial end of the shell 7 to the 30 other and projecting radially inwardly from the internal periphery of the shell within the core of the bolus. The rib 10 forms an integral part of the, preferably, 19 extruded, shell 7 and, during manufacture by casting, molten zinc alloy may freeze and contract around it, so anchoring the sleeve 7 to the core casting providing the bolus 6, thus ensuring that the shell 7 is securely 5 anchored to the bolus 6.

Fig, 4 shows a zinc alloy bolus 11 similar to that depicted in Fig. 1 but with a tubular shell 12 applied mechanically to the bolus after casting. The bolus core 10 has a reduced diameter towards one end and the shell is pressed on with a small interference fit.

As can be seen from Figs. 1-4, the shell or shell segment need not cover either the entire circumferential, 15 nor the entire longitudinal, extent of the core.

Test Example 1 Table 1 lists the results of experiments to determine the solution potentials of various magnesium 20 base alloys, containing at least 60 wt.% magnesium compared with a 52 wt.% zinc base alloy. The corroding potential of all the magnesium base alloys against the reference 4B zinc alloy is quite small, e.g. about 0.1 volt and less, but nevertheless surprisingly effective 25 (see Test Example 2). This is a small fraction of the 0.7 - 1.2 volt which has been exploited hitherto in Intraruminal Devices, using iron and graphite bearing cathodes to promote and control the corrosion of magnesium alloys (see, for example, EP-A-0243111). The 30 corroding potentials of the aforementioned magnesium alloys against pure zinc is approximately 0.7 volt, illustrating that the electrochemical behaviour of the 4B alloy more closely resembles that of magnesium rather than zinc.

Table 1 Comparative Example Reference (4B)** Ex 1* Ex 2 Composition Wt% Ex 3 Ex <3 Ex 5 Ex 6 Ex 7 Ex 8 Ex 9 Ex 10 (MftBI)** (Optimag)* + (AZ91)** (AZ31)** Zn Co 52 30 20 12 3 6 1 1 Al Mn 2 2 2 2 2 2 0.25 12 6 9 3 0.6 0.2 0.2 Mg 46 68 78 86 86 92 91.4 93.75 89.8 95.8 99.9 Solution Potential Volt 0 0.038 0.045 0.062 0.070 0.070 0.087 0.088 0.094 0.099 0.129 ♦Experimental alloy ^^Commercially available alloys It follows from the above data that all the magnesium rich alloys of Examples 1-11 listed above may be expected to provide a degree of cathodic protection to the Reference (4B) alloy when exposed to an aqueous 15 chloride bearing corrodant.

Test Example 2 In a preliminary test merely to determine the extent of protection from corrosion afforded to a zinc alloy 20 bolus by a magnesium alloy anode, respective anodes were simply inserted into corresponding recesses formed in respective extreme axial ends of each of three cylindrical boli. In particular, the anodes were of AZ91 21 and were plugs of 2, 4 and 6mm diameter respectively and 10mm long and each of the boli was of 4B alloy boli and was 20mm diameter x 80mm long. As a control, one bolus having no anodes inserted was also tested. The boli were immersed in 0.1% sodium chloride solution maintained at 30°C. The samples were weighed after 5 weeks immersion with the following results.

Table 2 Immersion test results on duplex boli diameter of anode insert, mm _ * 2 4 6 *Control (no anode inserted) Loss in weight gm. 61. 6 40.8 11. 3 8.4 It can be seen that under these test conditions, the cathodic protection provided by the AZ91 anode is very effective in reducing the parasitic corrosion of the 4B boli.

Test Example 3 Indeed, surprisingly, the test data shown in Table 2 above indicates that even a potential difference as small as 0.1 volt can be effective in galvanically protecting the 4B alloy in a chloride bearing environment.

In contrast to the small diameter inserts used in the above tests, shield tubes as illustrated in Fig. 1 22 above provide a greater degree of mechanical protection by initially shielding the bolus from both abrasive and corrosive attack by the rumen contents.

Four similar ewes of average weight 45 kg were each dosed with a 4B alloy bolus. Each bolus measured 85mm long x 21mm diameter arid weighed approximately 77gm. One bolus had no protective sleeve and the others had sleeves of varying length. The sleeve tubes were extruded from a 10 93.75 wt.% magnesium, 6 wt.% zinc, 0.25 wt.% copper alloy. The tubes had a wall thickness of 2mm. The sheep were grazed on winter pasture and regular blood samples taken and analysed for serum zinc levels using an atomic absorptiometer with the results shown in Table 3.

Table 3 In Vivo Test Results on Duplex Boli.

Sleeve length mm Uncovered Bolus Length mm Serum Zinc Level, pmol/litre, Time (days). 0 5 10 15 20 25 30 35 40 50 0 85 9.5 27.5 22.5 17.5 14 11 ' 50 7 16.5 26 12 11 12.5 13 65 8 9.5 17 34 .5 24 19 17 14 Serum zinc levels reflect the rate of zinc release from the bolus. It is evident from these results that both the 50mm and 65mm long sleeves reduce the initial rate of zinc release. In the case of the 65mm long 25 sleeve the time to maximum zinc release is extended to 20 days as opposed to 10 days for the unprotected bolus. In addition the bolus life has been increased from approximately 25 to 40 days. 23

Claims (36)

1. A release device comprising an inner, core portion and an outer portion comprising a shell portion, which 5 outer shell portion at least partially covers the inner, core portion and has a wall thickness of up to 5 mm, each of the said inner and outer portions comprising respective metal alloy compositions, the metal alloy composition of the inner portion 10 comprising at least 35 wt.% of zinc, by weight of the total metal alloy composition of the inner portion, and the metal alloy composition of the outer portion comprising at least 60 wt.% of magnesium, by weight of the total metal alloy composition of the outer portion. 15

2. A release device according to claim 1, wherein the metal alloy composition of the outer portion contains at least 70 wt.% thereof of magnesium. 20

3. A release device according to claim 2, wherein the metal alloy composition of the outer portion contains at least 75 wt.% thereof of magnesium.

4. A release device according to claim 3, wherein the 25 metal alloy composition of the outer portion contains at least 80 wt.% thereof of magnesium.

5. A release device according to any one of claims 2 to 4, wherein the metal alloy composition of the outer 30 portion additionally contains up to 20 wt.% thereof of zinc or aluminium or up to 20 wt.% thereof of aluminium plus zinc. 24

6. A release device according to any one of claims 2 to 5, wherein the metal alloy composition of the outer portion additionally contains up to 10 wt.% thereof of 5 copper.

7. A release device according to any one of claims 2 to 6, wherein the metal alloy composition of the outer portion additionally contains up to 1,6 wt.% of 10 manganese.

8. A release device according to claim 2, wherein the metal alloy composition of the outer portion contains at least 65 wt.% thereof of magnesium; 15 up to 20 wt.% thereof of zinc and/or aluminium; and up to 10 wt.% thereof of copper.

9. A release device according to claim 8, wherein the metal alloy composition of the outer portion contains:- 20 8 6 wt.% magnesium; 12 wt.% aluminium; and 2 wt.% copper.

10. A release device according to claim 8, wherein the 25 metal alloy composition of the outer portion contains 92 wt.% magnesium; 6 wt.% aluminium; and 2 wt.% copper. 30

11. A release device according to claim 8, wherein the metal alloy composition of the outer portion contains:-93.75 wt.% magnesium; 25 6 wt.% zinc; and 0.25 wt.% copper.

12. A release device according to any one of the 5 preceding claims, wherein the metal alloy composition of the inner portion additionally contains aluminium and the total amount thereof of zinc and aluminium is at least 45 wt. %. 10

13. A release device according to any one of the preceding claims, wherein the metal alloy composition of the inner portion contains from 50 - 70 wt.% thereof of zinc. 15

14. A release device according to claim 13, wherein the metal alloy composition of the inner portion contains from 50 - 65 wt.% thereof of zinc.

15. A release device according to claim 13 or claim 14, 20 wherein the metal alloy composition of the inner portion additionally contains from 30 - 49 wt% thereof of magnesium.

16. A release device according to claim 15, wherein the 25 metal alloy composition of the inner portion contains from 30 - 4 5 wt.% thereof of magnesium.

17. A release device according to any one of claims 12 to 16, wherein the metal alloy composition of the inner 30 portion additionally contains up to 6 wt.% of copper. 26

18. A release device according to claim 17, wherein the metal alloy composition of the inner portion contains from 1-6 -wt. I thereof of copper. 5

19. A release device according to claim 18, wherein the metal alloy composition of the inner portion contains from 2 - 5 wt.% of copper.

20. A release device according to any one of claims 12 10 to 19, wherein the metal alloy composition of the inner portion additionally contains up to 0.015 wt.% thereof of selenium and/or up to 0.75 wt.% thereof of cobalt.

21. A release device according to claim 12, wherein the 15 metal alloy composition of the inner portion contains from 35 - 4 0 wt.% thereof of zinc; from 45 - 55 wt.% thereof magnesium; from 5 - 15 wt.% thereof of aluminium; and up to 6 wt.% copper. 20

22. A release device according to claim 21, wherein the metal alloy composition of the inner portion contains 38 wt.% zinc; 4 8 wt.% magnesium; 25 12 wt.% aluminium; and 2 wt.% copper.

23. A release device according to claim 21, wherein the metal alloy composition of the inner portion contains 30 37 wt.% zinc; 50 wt.% magnesium; 8 wt.% aluminium; and 27 5 wt.% copper.

24. A release device according to claim 13, when claim 13 is appended to any one of claims 1 to 11, wherein the metal alloy composition of the inner portion contains from 50 - 70 wt.% thereof of zinc; from 30 - 49 wt.% thereof of magnesium; and up to 6 wt.% thereof of copper.

25. A release device according to claim 24, when claim 13 is appended to any one of claims 1 to 11, wherein the metal alloy composition of the inner portion consists of 52 wt.% of zinc; 45 wt.% of magnesium; and 3 wt.% of copper.

26. A release device according to claim 24, when claim 13 is appended to any one of claims 1 to 11, wherein the metal alloy composition of the inner portion consists of 65 wt.%) of zinc; 32 wt.%) of magnesium; and 3 wt.% of copper.

27. A release device according to any one of the preceding claims which takes the form of a cylindrical bolus.

28. A release device according to claim 27, wherein the shell portion is a tubular shell or segment thereof which partially covers the exterior of the core portion.

29. A release device according to claim 28, wherein the thickness of the shell is from 0.5 - 5 mm.

30. A release device according to claim 29, wherein the thickness of the shell is from 1-3 mm. INTELLECTUAL PROPERTY OFFICE OF N.Z. 19 DEC 2003 RECEIVED [R:\LIBLL] 14985.doc:TCW 28

31. A release device according to any one of the preceding claims, wherein the shell portion covers at least 10 wt.% of the surface area of the core portion. 5

32. A release device according to claim 31, wherein the shell portion covers at least 20 wt.% of the surface area of the core portion. 10

33. A release device according to any one of the preceding claims, wherein the shell portion covers the entire longitudinal end.

34. A method of preparing a release device comprising 15 the steps of preparing a shell portion of the release device, in the form of a hollow cylindrical tube or segment thereof having a wall thickness of up to 5 mm, from a metal alloy composition comprising at least 60 wt.% thereof of 20 .magnesium, having dimensions such as to provide a close fit in a die cavity of a die; inserting the shell portion into the die; pouring into the die cavity a molten metal alloy composition comprising at least 35 wt.% thereof of zinc; 25 and allowing the metal alloy composition poured into the die cavity to solidify, thereby providing an inner, core portion of the release device. 29 526 9 3 9

35. A release device substantially as hereinbefore described with reference to any one of the figures of the accompanying drawings.

36. A method of preparing a release device, the method substantially as hereinbefore described with reference to any one of the figures of the accompanying drawings. Castex Products Limited By Attorneys for the Applicant SPRUSON & FERGUSON Per: [R:\LIBLL] 14608.doc:TCW Release Devices for Veterinary Use ABSTRACT A release device (1, 3, 6, 11) comprises an inner, core portion and an outer portion (2, 4, 7, 12) comprising a thin shell portion, which outer shell portion (2, 4, 7, 12) at least partially covers the inner, core portion, each of the said inner and outer portions comprising respective metal alloy compositions. The metal alloy composition of the inner portion comprises at least 35 wt.% of zinc, by weight of the total metal alloy composition of the inner portion, and the metal alloy composition of the outer portion comprises at least 60 wt.% of magnesium, by weight of the total metal alloy composition of the outer portion. Thus, a zinc alloy core is at least partially covered by a thin corrodible magnesium alloy shell. [R:\LIBLL] 14608.doc:TCW