GB2340395A

GB2340395A - Implants for the delivery of vitamin B12 compounds

Info

Publication number: GB2340395A
Application number: GB9917757A
Authority: GB
Inventors: Donald George Mclaren; Syed Ziauddin Hashmi; Ian George Tucker; Majid Hamid Abdul-Razzak; Ms Li Xiahong
Original assignee: Bomac Laboratories Ltd
Current assignee: Bomac Laboratories Ltd
Priority date: 1998-07-30
Filing date: 1999-07-29
Publication date: 2000-02-23
Anticipated expiration: 2019-07-29
Also published as: AU753759B2; GB9917757D0; GB2340395B; AU4239099A; GB2340395B8; NZ331201A

Abstract

An implant for the gradual long term release of vitamin B12 compounds comprising an insoluble polymeric material which includes a network of cavities and channels to form a porous network. The vitamin B12 compounds are uniformly distributed throughout the porous network and gradually leach from the implant when implanted, preferably subcutaneously.

Description

2340395 IMPROVEMENITS IN AND RELATING TO IMPLANTS FOR DELIVERING B 12

COMPOUNDS

TECHNICAL FIELD

The present invention is directed to the use of implants containing active components, and which are particularly suitable for vitamin B 12 compounds.

These implants may be used to address deficiencies, or to ensure an animal receives an adequate supply of an active component, such as vitamin B 12.

Preferred implants are injectable subcutaneously. Implants allow sustained release, while preferred B 12 embodiments release vitamin B 12 for extended periods exceeding 60 days.

BACKGROUND ART

Vitamin B 12 is essential to living animals. Its deficiency affects livestock health and performance and may be exhibited as various physiological disorders. In New Zealand, vitamin B 12 deficiency can be associated with cobalt deficiencies, and when symptoms are exhibited may be variously known as Bush Sickness, Morton Mains Disease, or Mairoa Dopiness.

While all animals will experience problems if subjected to a B12 deficiency, young growing lambs are particularly susceptible to vitamin B 12 deficiency. B 12 deficient lambs usually show mild to severe unthriftyness. Reduced growth rates are commonly seen and can lead to marked wasting and even death. Reduced growth rates usually appear from 3 to 4 months of age, though not all the lambs in the flock may be affected. In contrast, ewes running on similar country and feedstock during the same period may withstand this level of deficiency, and show no symptoms of a deficiency at all.

When newly bom, lambs are largely incapable of producing vitamin B 12. While colostorum in ewe's milk provides some B 12 immediately after lambing, this falls off and little B 12 is then provided by the milk. Vitamin B 12 production only begins to reach a sustainable level as the lamb develops ruminant abilities and is weaned from the mother's milk. While this explanation is somewhat of a simplification, it is during this early period that lambs are particularly susceptible to vitamin B 12 deficiency.

2 The prior art addresses this problem, as it does B 12 deficiencies in other livestock. One method is to address cobalt intake, either by addressing the dietary feedstuff or by the administration of cobalt compounds. This may include dosing pasture with cobalt - though this is of no use to pre-ruminant lambs and other animals - or by regular (usually weekly) dosing with cobalt compounds such as cobalt sulphate. Other dosing options exist such as cobalt bullets. However, while this represents at least part of an effective remedy for animals able to produce their own vitamin B 12, these solutions are not necessarily of any great effectiveness for new-bom animals such as lambs.

The prior art also addresses vitamin B 12 deficiency by the administration of vitamin B 12 directly to the animal. The most effective form of administration is by injection, though once again the effects are relatively short term due to rapid excretion from the system and regular injection is still required. For a farmer having other tasks, monthly or regular administration of remedies to flocks of lambs and other new-born animals is time intensive.

Accordingly, there are a number of problems associated with the prior art. The requirement for repeated and regular dosing is one of the greatest disadvantages. In addition, dosage forms such as cobalt bullets can be lost by the animal, while injections do not always elevate serum vitamin B 12 levels to the required degree.

An article by John A. Smart is VetednM Continuing Education - Proceedings of the 28h Seminar, The Sociey of sheep and Beef Cattle Vetednarians NZVA, PubIn. 180 pp 123-135, summarises these problems of the art. Another article entitled 7he Efficacy of Animal Remedies to Prevent Codeficiency in Sheep" appears in the same publication at pp 137 - 143 and also summarises the benefits and problems of remedies known in the art.

Reference is also made to a long-acting injectable vitamin B12 though which is the subject of as yet unpublished NZ patent application No. 329447, and published Australian specification No. AU 98229198. This technology comprises biodegradable microparticles consisting of vitamin B12 in a biodegradable

Claims

material. Claims are made for B 12 release over extended periods of in excess of 360 days as the biodegradable composition slowly lets out incorporated vitamin B12. In some respects there are similarities (except in the size of the particles) with the well known and less advanced slowrelease bolus. 3 The art has also considered methods for the slow release of various substances over time. The slow-release bolus, which gradually dissolves over time, has been popular, particularly for the release of zinc in ruminants. However, significant variations in release profiles can be experienced when placed in different environments. The inability to accurately predict the dissolution rate of a dissolving matrix over periods measured in months generally eliminates this technology for accurate long-term controlled release. The prior art also includes other release methods. For instance US4900556 describes the use of liposomes within semipermeable Microcapsules. However the release rate of this method is measured in days with 90% release within 500 hours, and 100% release within 1000 hours, being typical. The duration is insufficient to provide an effective means of long term sustained release. The reliance on capsule and liposome construction for release also imposes high requirements on quality control to ensure that release can be reliably predictable over a long period, and also increases the cost and complexity of the final product. Coating technology is the focus of AU 601443 (75134/87) which provides a polymeric coating of a tablet. While this can achieve long term release profiles for the actives they have considered, coating technologies have some potential drawbacks. Firstly, release rate is highly dependent upon the coating and thus any damage or fluctuations in coating thickness or integrity (if the coating process is not tightly controlled, for instance) can substantially affect the release rate. While this may be of little consequence in quick release products, it may mean a significant variation for an article designed to last 6 months. Secondly, manufacturing requires at least 2 discrete steps - tablet manufacture, followed by coating. This means not only additional manufacturing steps, but inflexibility in manufacturing processes. For instance, a different dose article for use in different animals either requires altering the composition from which the tablets or formed, or attempting to change the size of the tablet. These can only be done at the manufacturing stage. Compare this to preferred embodiments of the present invention in which the dose can be altered by merely altering the size of the article by trimming, and which is something that even the end user can achieve with a pair of scissors. This increases the versatility of the product. WO 87/06129 describes biodegradable microcapsules containing an active which 4 has been dispersed in a biodegradable polymeric matrix. Again consideration needs to be given of the different rates of biodegradation in different environments. As for the preceding prior art example, any alteration in dose size needs to be performed at the manufacturing stage. WO 91/04052 describes a solid vaccine composition which includes an antigenic substance combined with a polycationic adjuvant for longevity, and dispersed in a solid matrix filler of a water insoluble compound such as calcium phosphate. However, the primary role of this invention is to present antigenic materials to generate an antibody response in an animal. This involves different considerations, and a saponin combined with a polycationic adjuvant is used to promote longevity of the antigenic material within the animal system. Erodability of the filler matrix is used to control release of the antigenic material, with coatings being optional. This invention is essentially a modification of the previously mentioned prior art techniques and suffers sin-Lilar handicaps. Accordingly, it is an object of the present invention to provide a dosage form suitable for long term release of active components. Desirably also, embodiments will address limitations or problems associated with techniques reliant upon the gradual dissolution of fillers or coatings. Increased versatility of the resulting product for the user, and flexibility in manufacturing processes for manufacturing differently sized or dosed articles, are also desirable. In response to these problems, the applicant diagnosed a need for a product which could address the problems and disadvantages of the prior art or which could at least provide a useful alternative. It was determined that it would be useful for there to be a product which could be administered once and would be effective for an extended period of time, avoiding the need for repeated and regular dosing. It would be also desirable that the product was easily manufactured and according to a process which offered the, flexibility to readily produce dosage forms with different levels of included active components. It would also be desirable that the discharge characteristics were consistent and reproducible between different articles from the manufacturing process. However, a solution to these problems were not as straightforward as originally thought, as will become apparent from the general description of the invention given later. It is sufficient to say, however, that neither the proposed invention presented herein to address the prior art problems, nor the pathway to the present invention, was straightforward or obvious. It is therefore an object of the present invention to address the foregoing problems or at least to provide the public with a useful choice. Further aspects and advantages of the present invention will become apparent from the ensuing description which is given by way of example only. DISCLOSURE OF INVENTION According to one aspect of the present invention there is provided an implant including: at least one active component including a B 12 compound dispersed substantially uniformly throughout a polymeric material. According to another aspect of the present invention there is Provided an implant, substantially as described above, in which a polymeric material is a plastics material. According to another aspect of the present invention there is provided an implant, substantially as described above, in which the structure of the implant is such that the polymeric portion alone includes a substantially interconnected network of cavities and channels affording a substantially porous support structure. According to another aspect of the present invention there is provided an implant, substantially as described above, in which active component is present, in an unused implant, within the cavities and channels of the polymer. According to another aspect of the present invention there is provided an implant, substantially as described above, in which the presence of nondissolved active component assists formation of said interconnected network within the polymer portion during formation of the implant. According to another aspect of the present invention there is provided an implant, substantially as described above, in which during its formation, the proportion of non-dissolved active component is selected to achieve a minimum desired level of porosity. 6 According to another aspect of the present invention there Is provided an implant, substantially as described above, whose release profile of B 12 compound over time in aqueous media comprises an initial burst profile levelling off to a plateau. According to another aspect of the present invention there is provided an implant, substantially as described above, in which the daily release rate of a single implant of included B 12 compound remains above 5pg/24hr for at least 60 days. According to another aspect of the present invention there is provided an implant, substantially as described above, in which the daily release rate of a single implant of included B 12 compound preferably remains above 5gg/24hr for at least 150 10 days. According to another aspect of the present invention there is provided an implant, substantially as described above, in which the daily release rate of a single implant of included B 12 compound remains above 1Ogg/24hr for at least 60 days, and more preferably for at least 150 days. According to another aspect of the present invention there is provided an implant, substantially as described above, configured to be insertable subcutaneously. According to another aspect of the present invention there is provided an implant, substantially as described above, suitable for insertion by injection. According to another aspect of the present invention there is provided an implant, substantially as described above, sufficiently rigid to penetrate the dermal layers at a designated or predetermined point of insertion on an animal. According to a further aspect of the present invention there is provided an implant manufactured according to a method comprising: - dissolution of a polymer in a solvent portion in which chosen B 12 compound to be included is substantially insoluble; - dispersing chosen active components throughout the polymer solvent mix; - fonning the combination into a desired configuration, and - removing solvent, and optionally further forming into the desired configuration of the implant. According to a further aspect of the present invention there is provided an implant, substantially as described herein, when inserted as an implant into an animal. 7 According to a further aspect of the present invention there is provided a method of manufacture of an implant including steps of: - dissolution of a polymer in a solvent portion in which chosen active component to be included is substantially insoluble; 5 - dispersing chosen B 12 compound throughout the polymer solvent mix; - forming the combination into a desired configuration, and - removing solvent. According to another aspect of the present invention there is provided a method of manufacture, substantially as described above, in which the chosen solvent portion is non-aqueous and either or both substantially hydrophobic and immiscible with water. According to another aspect of the present invention there is provided a method of manufacture, substantially as described above, comprises at least one member of a solvent group comprising: dichloromethane, xylene, carbon tetrachloride, and chloroform. Other halogenated solvents can also be considered. According to another aspect of the present invention there is provided a method of manufacture, substantially as described above, in which active component loading is sufficient to ensure a porous structure allowing release of a substantial proportion of the included B 12 compound. According to another aspect of the present invention there is provided a method of manufacture, substantially as described above, in which a substantial proportion is 75 % or greater of included B 12 compound, such that at least 75 % of included B 12 compound is available for release. According to another aspect of the present invention there is provided a method of manufacture, substantially as described above, in which the method of forming comprises extrusion. According to a further aspect of the present invention there is provided a method of use of an implant, substantially as described herein, comprising its insertion into an animal. 8 According to another aspect of the present invention there Is provided a method of use, substantially as described herein, inserted into new-born lambs when less than 60 days old. According to another aspect of the present invention there is provided a method of use, substantially as described herein, inserted into lambs prior to weaning. According to a further aspect of the present invention there is provided a method for addressing B 12 deficiency in animals comprising the implantation of at least one implant, substantially as described above, into an animal. According to another aspect of the present invention there is provided a method for addressing B12 deficiency, substantially as described herein, in which the animal is a newly born animal, and the implantation occurs within one month of birth. According to another aspect of the present invention there is provided a method for addressing B 12 deficiency, substantially as described herein, in which the inserted implants, in total, release at least an average daily amount of 5pg/24hr for at least 60 days after insertion. According to another aspect of the present invention there is provided a method for addressing B 12 deficiency, substantially as described herein, in which the inserted implants, in total, release at least 5pg/24hr at at least day 60 after insertion. According to another aspect of the present invention there is provided a method for addressing B 12 deficiency, substantially as described herein, in which the inserted implants, in total, release at least an average daily amount of 10pg/24hr for at least during days 90-150 after insertion. According to another aspect of the present invention there is provided a method for addressing B12 deficiency, substantially as described herein, in which the inserted implants, in total, release at least 10pg/24hr at at least day 150 after insertion. According to another aspect of the present invention there is provided a method for addressing B12 deficiency, substantially as described herein, in which the aforesaid release rates are determined by extrapolating accelerated bench tests. 9 According to a further aspect of the present invention there is provided a kit for addressing B12 deficiency including one or more implants, substantially as described above, in a form suitable for implantation by injection, said kit being suitable for a range of animal species and/or animal sizes/ages of an individual species; said kit including at least one implant containing a predetermined minimum dose for an animal such as a new bom infant, and containing sufficient further implants to adequately dose other intended animals, sizes, or ages for which the kit is intended to cover, either by the inclusion of alternate dosage implants or by the combination of included implants to achieve the required total dosage. The present invention seeks to address the problems associated with the prior aft by providing an implant which will address or contribute in addressing the daily requirements of an active component such as vitamin B12 compound in a biosystem, i.e. an animal. Other active components may also be included, such as for instance selenium compounds, though for simplicity the present invention will focus primarily on the B 12 active portion. While a number of vehicles are available for the slow release of active components inserted into a biological system, the applicants shied away from the common practice of a slowly dissolving matrix. It was considered desirable that embodiments of the present invention should have a relatively long duration over which the active component is slowly released. Preferably this period is 60 days or more, though the preferred embodiment will slowly release active component over a period of up to 150 - 180 days or greater. It was considered that at the desired periods for which the implant must remain active, existing prior art slow dissolution matrices were not necessarily reliable, consistent nor appropriate. Accordingly, it was considered that dispersing the active component in a nonsoluble matrix or body was desirable. This need not be biodegradable if it could be located such that it did not create physiological problems for the animal, and would not appear in the edible carcass after slaughter. Preliminary work lead to consideration of a plastics material as a carrier/support for the B 12 in an implant. However, there is difficulty associated with the combination of the active component with such a carrier/support material. As a consequence, early embodiments of the present invention were not particularly successftil, or were considered to be in need of further refinement. For instance, EVA is typically provided as a granular, particulate material which possesses a rubbery nature which does not make it amenable for grinding or comminution. This was one problem experienced in early attempts to produce an implant. A further problem is that vitamin B 12 is sensitive to temperature. The duration at which it can withstand elevated temperatures is dependent on the temperature itself. By way of example, it can typically withstand 120'C for 20 - 30 minutes or 75'C for several days, with little appreciable degradation. This will have a 10 bearing on how it is incorporated into the carrier/support material. A wide range of suitable plastics materials are suitable for the present invention. Early work made use of an EVA (ethylene vinyl acetate) plastics polymer having a melting point of approximately 55'C. Further work was based on this plastic material, and for simplicity the majority of the description is also with reference to this plastics material. However, this is not intended to be limiting, and it is envisaged that other suitable plastics materials (the criteria of which will be given later) can be used in substitution for, or in conjunction with, an EVA plastic. It was recognised that it is desirable for the B12 active components to be evenly dispersed throughout the polymer support. This makes release more uniform and predictable, which are desirable in a long term slow release implant. In addition, the relatively small size of the implants means that uniform distribution and dispersion is necessary to avoid a situation where some implants have high activity while others have negligible activity. Initial development of the present invention focused on the dissolution of the B 12 component in a solvent miscible with a solvent for the plastic support material. The chosen solvent for B 12 was ethanol, while dichloromethane was used for the plastics material. Near saturated solutions of each were prepared and combined, and the resulting mixture formed into sheets of material. However, the problem was that B 12 loadings of only several per cent were possible. This was considered too low, and also gave rise to problems with a significant proportion of the B12 component being retained i.e. unavailable for release. The relationship between B 12 retention and B 12 loading will be discussed further herein. This initial work highlighted that the plastics material itself is not porous nor permeable to water or bodily fluid. Hence, much of the retained B 12 was due to its encapsulation within the plastic matrix. Accordingly, the next phase involved the introduction of polyethylene glycol to increase the solubility of the resulting implant, and to also possibly slowly leach from the implant device to leave pathways for the entrained B 12 compound. In this instance polyethylene glycol (PEG1000) was introduced into the ethanol solution of B 12 before incorporation with the dissolved plastic mixture. This method affords a higher drug loading of approximately 10%, and improves the release of B 12, though was still considered too low a B 12 loading for acceptable commercial embodiments of an implant. Accordingly, this represents a lesser preferred embodiment of the present invention. In these embodiments the trialled proportion of EVA to PEG was 80:20 by weight, though embodiments comprising about 70% EVA, 20% PEG, 10% B12 were also prepared. It is envisaged that the ratio of PEG to EVA can be altered significantly outside of these values, though it is also to be appreciated that at a particular point what will be obtained will be a less than rigid implant which may be unsuitable for many implantation techniques into a biological system. Accordingly, these embodiments represent among the least preferred embodiments of the present invention. Further to this work, while it was recognised that the introduction of B 12 into the manufacturing mix within a solvent can afford excellent dispersion of that component, the difficulty remained that while it was uniformly dispersed it could not be easily released and the retention values were still too high. In addition, such solvent methods introduced too high an amount of solvent which led to further problems of solvent removal - especially when lab tests were extrapolated to what was required on a commercial or industrial scale. Accordingly, it was decided to progress to alternative methods in which B 12 components were not introduced as part of a solvent mixture. At this point, it was decided to capitalise on the relatively low melting point of EVA plastics which is 55"C for the type used in the trials. Crystalline powdered cyanocobalamin is air stable and is not melted at 3000C though is understood to undergo degradation at elevated temperatures over time. It was determined that the vitamin B 12 component could safely withstand temperatures of up to 75'C for at 12 least three days, and temperatures up to 120'C for 20 - 30 minutes. These periods may be extended, and it is anticipated that the period at 120C could be doubled without concern though there is increasing risk of degradation as time increases. A degree of degradation may be acceptable, particularly if it facilitated implant manufacture. Accordingly, these values are used as guidelines, with some preliminary trial suggested to determine the optimum parameters for a particular manufacturing set-up. Early trials progressed on the basis of melting the plastics material and blending in solid B 12 component. Unfortunately, the viscosity of the plastic mix, even at temperatures up to around 100C, was too great and it was not possible to readily achieve anything approaching uniform dispersion of the B 12 material except with exceptionally extensive stirring and mixing. However, from a commercial point of view this was impractical, and even at the laboratory level only met with partial success. Subsequent work has shown that cyanocobalamin is sufficiently heat stable to produce a usable implant by combining the cyanocobalarrLin and hot EVA in an extruder. The implants for the trials of example 4 were produced in this manner. It was considered that it may be possible to improve the process by reducing the size of the B 12 particles, though this in itself posed a problem due to the rubbery nature of the vitamin B 12. Grinding and milling at room temperature was difficult, though increased success was found by freezing the B 12 in liquid nitrogen and quickly comminuting the frozen compound. However, even with the finer particulate matter, dispersion within a melted plastics mixture was found to be difficult and impractical under most circumstances. Finally, the next stage of development lead to a more preferred embodiment of the present invention which will be described in more detail herein. In this system, the preferred method is to dissolve the plastics material in a solvent. Ideally this should be a solvent which is not only a good solvent for the plastics material (thereby minimising the amount of solvent required) but also a volatile solvent which can be readily removed from the final product after forming. Further, it was also determined that it was desirable that the B 12 component did not dissolve within this solvent mixture. The earlier work suggested that B 12 introduced by dissolution, ended up being substantially retained within the 13 resulting product. Accordingly, it was recognised that it is desirable for the B12 component to remain in a particulate form. This will be discussed in greater detail later herein. Accordingly, the solvent chosen for the plastics material should also be such that it is not a good solvent for the B 12 compound i.e. the vitamin B 12 component is substantially insoluble therein, or at least when the preferred plastics material has been dissolved therein. This therefore opens the possibility that solvents, in which the B12 component does dissolve, may be used providing that they preferentially dissolve the chosen plastics material to the exclusion of, or in substantially greater preference to, the B 12 component. Preferred embodiments of the present invention are thought to attain their release characteristics by having a plastic support structure which is riddled with a number of cavities and channels. These cavities and channels are considered, in a newly formed implant, to be filled with other included components such as the actives. It is when these components are removed by leaching (through use) that the porous structure becomes evident. However for simplicity, reference made to the porous network is intended to be a reference to the polymer portion alone, and as if the components which fill these cavities are temporarily removed from consideration. It is also noted that such a network may in reality not necessarily be totally accurate or overly simplistic, though initial trial data based on drug loadings suggests such a structure for the polymeric material. This arrangement should provide a substantially open cell structure allowing any component trapped within a cavity or channel to eventually be able to find a path to the outside of the plastic support structure. It is believed that in practice what occurs is that as particles of B12 components near the outside of the implant slowly dissolve, they open up channels allowing particles further inward to slowly dissolve as well. This in turn opens up further pathways allowing further dissolution of particles closer to the interior. Accordingly, a preferred embodiment of the present invention could be likened to a matrix comprising a soluble portion and an insoluble portion with respect to the tissue fluid in which the implant is intended to be placed. Over time the soluble components dissolve and leach from the implants leaving a substantially porous structure. In such embodiments a plastic polymeric component represents the insoluble portion, 14 while the B 12 and other active components represent the soluble portions. At this point it is appropriate to mention drug loading, or more specifically the loading of the B 12 and/or other active components. It has been found that there is a relationship between drug loading, the rate of release of active components, and the amount of retention of active components (i.e. active components which will never be released). Observations suggest that, in a very simple sense, a drug loading above a particular level is required in order to form an effective network of cavities, channels and other internal features. If the drug loading is too low, the result is an increasing proportion of closed cells containing active components which can never be released without disintegration of the encapsulating plastics structure. Observations suggest that for B 12 only (i.e. ignoring considerations for any other included components) useful embodiments in which a significant proportion of the included B 12 component is available for release, occurs when the B 12 loading is around 30% or greater by weight. B 12 loadings of approximately 20% or below give little useful results for most embodiments which are to be of any commercial use. Such low drug loadings are currently considered useful only when used in conjunction with other techniques for ensuring the presence of sufficient cavities, channels and features to provide what is considered to be a desirable open network within the plastics structure. This may include the use of other soluble active components. As can be appreciated, higher levels of drug loading will increase the porosity and openness of the resulting network as a consequence of more particles touching or being in close proximity to each other. However, one will also reach a point at which the structural integrity of the resulting implant will be affected. This may not be immediately apparent as an unused implant will still tend to be substantially rigid and solid even at very high drug loadings as all of its components are present and in asolid form. However, as the active components are removed, the structural integrity may decrease to the extent of eventual implosion or disintegration. Even in preferred embodiments described later this may ultimately occur, though it is desirable that this does not occur during the period in which predictable release characteristics are to be exhibited. For instance, once disintegration occurs, substantially the remainder of any contained active components are released and further slow release is not possible. In addition, exceptionally high drug loadings may normally accelerate disintegration as structural integrity may have reduced to the point of collapse when only a small percentage of the active components have been released. Accordingly, there is a compromise in the relationship between active component loading, and the nature 5 of the chosen plastics material. A wide range of possible combinations of active components and plastics materials are available, though it has been found in preliminary trials that (for an active component only comprising B12 compound) loadings of 40 10%,and more preferably 40 5% are most preferred. For usable embodiments it is envisaged that a loading of total active components (based on B 12) of at least 20% is desirable, this typically representing the lowermost limit for such types of compounds. Particle size will also have a bearing. A preferred embodiment restricts the maximum particle size to 63pm, though it is envisaged that most sustained release embodiments will utilise particles whose mean size is within the range 15 125pm inclusive, though this does not exclude the use of particle sizes outside of this range for some embodiments - especially if burst release is of importance. The active components of the present invention may vary though vitamin B 12 is a preferred choice. By this is meant not only vitamin B 12 in the form of cyanocobalamin, but also other analogues (see for instance International Application No. PCT/AU86/00299), and in various commercial forms. Typically however it should be soluble or releasable in tissue fluid in the intended biosystem. Early trials have focused on the use of EVA as a polymeric material. Various EVAs are known and may be used providing they fulfil the requirements of being soluble in a solvent in which the vitamin B12 is substantially insoluble (at least when there is dissolved plastics material present). It is also envisaged that other plastics may be used with the present invention. One possibility currently envisaged is polycaprolactone. Some other possibilities include methyl acrylates 30 and other alkyl acrylates, methyl methacrylates and other alkyl methacrylates. It is also envisaged that mixtures and blends of different plastics materials may be used. Typically the primary plastics material is not water soluble to any appreciable degree. Various solvents may be used with the present invention. Ideally these should be an effective solvent for the plastics material(s) selected for use with the present invention. Apart from high solubility, a chosen solvent should also be relatively volatile or otherwise readily removable from the final product. The relationship between the solvent and the B 12 compound has also been discussed previously. Various means of solvent removal may be practised, including reduced pressures, elevated temperatures etc. In practice the amount of plastics material to be dissolved in the solvent will be such that the resulting mixture is not so viscous as to prevent the ready distribution of included active components throughout. This was a problem with the melted plastics materials and it is desirable that this situation is avoided in the resulting solutions of plastics material. Various active components may be introduced into the plastics mixture. While vitamin B 12 is the prefer-red component for addressing B 12 deficiencies, it is also envisaged that the present technology may also be used as a vehicle for introducing other active components. It is envisaged that the principles described herein may also be applied to other components for slow release as part of an implant. It is envisaged that the same manufacturing techniques will be used, and it is noted that the salts of many compounds which are ionic in nature will not be soluble in commonly selected solvents for the plastics material. Focusing once again on B 12 containing embodiments, other components may also be present. These may be components which show little activity and are merely there to increase the non-plastics loading ratio so as to enhance the network of cavities. These may merely comprise ionic compounds such as sodium chloride, though it is perhaps preferable to also introduce compounds which may be of some benefit or assistance to the animal, particularly those which only need to be present at small amount, such as the trace elements. Accordingly, soluble salts of trace elements may be included in various embodiments of the present invention. For an implant intended to address B 12 deficient and related disorders, a desirable choice of other components include sodium selenate or selenite and cobalt salts, such as cobalt sulphate, (though it is envisaged that this will be present more to assist animals with the requisite gut flora to produce vitamin B 12). 17 It is also envisaged that according to one method of use, rather than manufacturing and using single implants comprising both B 12 and other active components, separate specific implants are manufactured e.g. one containing B 12, and one containing a selenium compound etc. These may then be co-administered as needed. An implant according to the present invention may take many forms. To a large extent this would depend how it is to be used. It is envisaged that most embodiments of the present invention will be implanted subcutaneously and preferably located in an area where there is sufficient tissue fluid to aid dissolution of the active components over time. Where any components are included which have a localised effect, then implantation in that area would be a likely preference. However, for vitamin B 12, and cobalt, most locations in the body of an animal (providing there is not rejection or ejection) are suitable. Considerations for non biodegradable plastics have been mentioned earlier. It is envisaged that a common insertion place for embodiments of the present invention will be subcutaneously. For new-born lambs, a preferred position is near the base at the rear of the ear. Here an implant is located in an area between the cartilage and the skin and in which there is a small amount of loose skin also signifying the presence of tissue fluid desirable for extraction of the active components. In such a case, injection is a preferred method of implantation, relying on the use of a cannula or hypodermic needle to position and inject the implant. Such methods of implantation may be used for implanting the present invention at other locations in an animal. Alternatively, the invention may be adapted for use with other methods of subcutaneous penetration, including forming an implant into a shape which is able to pierce and be pushed under the skin with the aid of a suitable backing piece. As a consequence, most embodiments of the present invention will be relatively small. By way of example, an implant for a new-born lamb would typically be of around 1.2 - 3.Omm average diameter, and preferably 2. 1 mm or less. Typically the length may be of the order of 3 - 6 mm. at these diameters. For larger animals and body sizes, larger implants may be used. For instance, on 18 cattle it is known to use needles of 3 SWG, and hence diameters which can be accommodated in such a needle can also be considered. Where larger needles are possible, larger sizes may be used, though it is envisaged that from a practical point of view average diameters of 5 mm or less will often be used. It is also envisaged that embodiments will often be substantially cylindrical, ellipsoidal or elongate in shape, though it is also possible that other configurations may be adopted. Total size will depend upon a particular application. For most livestock it is envisaged that embodiments of the present invention will typically be of a mass of 750 mg or less. By way of example, for new-bom lambs, a preferred embodiment is around 25 - 45 mg, while it is envisaged that a typical range for most common livestock will be in the range 10 - 125 mg. The amount of active component in an implant is also a consideration. Typically a lower limit of 2mg B 12 is envisaged for implants treating a B 12 deficiency, though 5mg is perhaps more typical, and with preferred embodiments for lambs being around 10mg. Larger animals may require greater doses in an implant, or the administration of multiple implants. Usual dosage ranges per implant are envisaged in the range 5 - 25mg B 12 inclusive. The release characteristics of an implant will vary upon the conditions and location in which it is implanted. However, for a typical implantation point it is intended that an implant will be able to be able to provide sustained release of a primary active component for at least 60 days. This will often be determined by the needs of the user, and for an application such as addressing deficiencies of B 12 in infant lambs, sustained release periods of 150 - 180 days or greater are more preferable. During this sustained period, the implant should be able to sustain an average daily release rate, at least towards the end of the desired period of time, above a certain minimum level. For most applications this will be at least 5pg/24 hr. For smaller animals this minimum threshold may be lower, though could perhaps be achieved by the use of smaller implants, or trimming other implants to size. However, taking once again the case of a new-bom lamb, it is desirable that 5lig/24 hr is a minimum average daily release rate towards the end of the intended 19 life of the implant, while lOpg/24hr would be more preferable. Higher release rates may be achieved by increasing the size and/or loading of the implant, while the use of multiple implants is also envisaged. The release profile of the implant is also worth considering. Typically the average release profile will be an initial burst, represented by a rapid rise in release rate over time which peaks and descends to tail off into a relatively consistent plateau. This plateau may be substantially flat and horizontal on a release rate versus time graph though may also slowly decay over time. However, at no point should this exhibit any prolonged or significant dip below the desired release rate during a period of time corresponding to the intended life in situ of the product. It is noted that factors such as drug loading, and the nature of the included components, will have a bearing on both the height of the plateau, the duration of the plateau (before all available active components are consumed) and also the shape and size of the initial burst portion. These characteristics may be altered by varying the proportions and components used in the manufacture of an implant. Some trial and experimentation will be necessary to tailor user variables to achieve a specific characteristic or profile, though it is envisaged that this can be readily achieved by a skilled addressee of the art with the description and specific examples given herein. It is noted however that it is not an objective of the present invention to provide for every possible release profile, but rather to provide for useful implants which can provide for sustained release over a useful duration, and may provide further benefit by the provision of an initial burst release to at least compensate for any existing deficiency before helping to regulate or maintain internal levels of active component in the chosen biological system over the lifetime of the implant. BRIEF DEsCREMON OF DRAWINGS Further aspects of the present invention will become apparent from the following description which is given by way of example only and with reference to the accompanying drawings in which: Figure I is a typical release graph over time for an embodiment of the present invention; Fiy-ure 2 is a perspective diagrammatic view of a preferred embodiment of the present invention; Figjre 3 is a diagrammatic view indicating a preferred method of implantation in a lamb of implantation in a lamb of an embodiment such as illustrated in Figure 2; Figure 4 is a graph of vitamin B 12 concentrations in blood serum from the Mosgiel trial; Figure 5 is a graph of mean vitamin B 12 concentrations in blood serum from the Otautau tria.1; Figgre 6 is a graph of mean lamb body weight from the Otautau trial; Figure 7 is a graph of vitamin B12 concentrations in blood serum from the Balclutha trial; BEST MODES FOR CARRYING OUT THE INVENTTON By way of example only, several examples of preferred examples of the present invention will now be given. It is not intended that these examples be limiting, but rather illustrative of some potential applications and embodiments of the invention. Example I EVA co-polymer was dissolved in dichloromethane to form a 20% (w/v) solution. The co-polymer was an ELVAXTm resin manufactured by Du Pont, CAS number 108-05-4. Vitamin B12 in the form of a Cyanocobalamin powder meeting the requirements of Japanese, European, British and US Pharmacoepia, such as is available from Roussel, Roche Products - was sieved to obtain particle sizes of a maximum of 63pm. This was weighed and introduced to the co-polymer solution in a proportion such that the final ratio of B 12 component to EVA is 40:60 i. e. a B 12 loading of 40%. The mixture was then vortexed to yield a uniform suspension. The resulting matrix was dried for two hours at -15'C then transferred to -20'C for 12 hours then 20'C for 12 hours. A laboratory glass syringe was utilised to contain the 21 polymer under heat (65'C) and which was then extruded into long strings 2 mm in diameter. Example I As a variation the B12 loading is reduced down to 30% and up to about 10% sodium selenate is included as a second active. The sodium selenate is sieved to substantially the same particle size as the B 12 in this example. The remainder of the procedure is as for Example 1. As can be appreciated the forming of the product may be accomplished in a number of different ways. In the above example, solvent was initially evaporated to give a product which was later extruded into a final shape. Solvent evaporation may be accomplished in a number of different ways, such as usually practised in the plastics industry. In the present invention this may include casting the solvent mixture into sheets or other forms, evaporating the solvent, and then using these obtained intermediate forms to form the final implant. For the casting of sheets, it is typically desirable that the sheets are relatively thin to aid solvent extraction. Sheets and other forms thus obtained may also be shredded or comminuted into other particles which can then be melted or pressure formed as desired. Final forming may take place in a number of manners, also commonly practised in 20 the plastics industry. One preferred method is extrusion, though casting or pressure casting (e.g. injection moulding) are other possibilities. Example 2 In the above described procedure of Example 1, the strings of 2 mm diameter were trimmed into small rods of approximately 3 - 4 mm in length, and approximately mg weight (see Figure 2, (10)). These implants had a total B12 content of around 5-15 mg. It is envisaged that a commercial embodiment for lambs would be preferably centred around 10- 12 mg. These were then cut and used in subsequent in vitro release studies. Previous 30 experiments conducted to determine the diffusion co-efficient of Cyanocobalamin 22 through EVA membranes indicated that the bio-active does not diffuse through the membrane of a pure polymer. However, release from the pellets with higher drug loadings thus obtained were substantial. This supports the theory that release occurs through a porous network of channels and cavities. Accelerated release studies indicated that 50% of included cyanocobalamin was released within 24 hours. In practice this would indicate a relatively high burst release, though less than 50% of the available cyanocobalarnin. In some instances it may not be required to have a high initial burst proportion and thus coating the implant can be considered to at least partially address this problem. One proposed solution is to coat the pellet with an additional EVA layer, such as by dipping the pellet into a 5-10% EVA solvent solution. Figure I illustrates a typical extrapolated release profile from embodiments prepared according to the above method. As can be seen in representative example [A] there is an initial peak due to a burst release of the B 12 actives, though this tails off to a slowly decreasing plateau. Representative example curve [B] illustrates a lesser initial burst though still tailing to a plateau. It is noted that the curves and characteristics of this graph were extrapolated from initial trials and it has been found that this is supported by blood serum (B 12 level) data obtained from the Mosgiel, Balclutha, and Otautau Field trials (see example 4). Reference is also made that the scale of the axes in figure I was arbitrary. The earlier work extrapolated that the plateau would remain above the lower threshold of 10 pg/24 hour release rate for at least 120 days, and preferably for at least 180 days. This is also supported by the Field trial data. Figure 2 illustrates a rod manufactured according to the present invention, while reference will shortly be made to Figure 3 illustrating its use. Example 3 A method of use of a preferred embodiment of the present invention comprises the injection of a rod, such as illustrated in Figure 2, into the ear of a new-born lamb, preferably around the time of docking - typically 10 - 14 days after birth. The preferred method of insertion is by injection, in which a hypodermic syringe is used to insert and deliver the implant to the intended location. Typically a carrier fluid is used to propel the rod which is positioned within the needle. 23 With reference to Figure 3, the needle (1) is inserted at site (2) into the back of the lamb's ear (3) and inserted along a pathway (4) intermediate the cartilage (5) and skin. This leads to the preferred delivery site (6) positioned near the base of the ear as it meets the cranium (7). There is a loose portion of skin here which is able to accommodate the implant (8) without any recognised physiological problem. There is also sufficient tissue fluid here to assist release of the actives. Example 4 Long term trials (Mosgiel, Balclutha and Otautau Field trials) were performed using an implant, administered into the car as described in example 3. The pilot batches used in these trials were hot-melt extruded by hand, using a syringe to shape the EVA/cyanocobalamin mixture which was then cooled and coated with EVA (or left uncoated) and cut into 3 mm lengths. It is envisaged that commercial embodiments will be formed from a commercial extruder and a rotary cutter. The implant contains 40% of cyanocobalamin in the form of a dry powder bound with 60 % of Ethylene vinyl acetate copolymer. In sealed plastic pouches, the Vitamin B 12 of the implant should have a similar stability to that of the powder, which is highly stable over a wide temperature range. Crystalline, hydrated cyanocobalamin is stable in air. In the following in vitro studies, the pattern of release of Vitamin B 12 from the 20 polymer implant was studied in a group of stall-fed lambs, and in field trials under pastoral grazing conditions. I - Mosaiel Field Trial Twenty four Romney-cross lambs were used for the study. At approximately four weeks of age they were tailed and the males castrated using rubber rings (Elastratoro). They were then weighed, tagged, blood sampled and assigned to three equal groups by sequential allocation from a weight ordered list. The first group received an implant made with cyanocobalamin powder granules that had been through a 45 im gauge sieve. The second group received an implant made with cyanocobalamin powder granules that had been through a 63 gm gauge sieve and the remaining eight lambs received implants without cyanocobalamin (negative controls). All the implants were injected at the base of the ear using a 24 Ralgro @ implanting gun. Lambs were fed a cobalt deficient diet of hay and barley and were maintained on a pad of cobalt deficient straw. Blood was collected at approximately monthly intervals and the lambs were weighed weekly. At approximately 7 months of age, lambs were slaughtered and liver biopsies collected. Mean serum vitamin B 12 concentrations from the Mosgiel field trial (pmol/L) Liver Sample 1 2 3 4 5 6 7 (serum) Baseline runol/k 9 Date 19/10/98 17/11/98 15/12/98 8/1/99 2r2199 813/99 8/4/99 20/5/99 Uncoated >1500 4847.5 1385.71 2338.75 1941.25 1702.5 2505 550 implant 45 (Means, n = 8 Uncoated >1500 9280 4051.43 3487.5 1756.25 1087.5 1697.5 646.25 implant 63 (Means, n = 8) Controls > 1500 2560 1041.67 1435.71 497.14 480.0 1115.71 374.29 (Means, n = 8) From one month post implantation and for the subsequent four months, lambs implanted with the '63' implant maintained scrum Vitamin B12 levels significantly higher than those of the control lambs. Vitamin release from the '45' implant was variable and serum levels of Vitamin B 12 did not differ significantly from serum levels of control lambs at two and three months after implantation. See Fig 4. Conclusion: Both implants released sufficient Vitamin B 12 over the course of the experiment to ensure that treated lambs had an adequate vitamin B 12 status at the conclusion of the trial, based on liver Vitamin B 12 concentrations. In contrast, 11 ver biopsies showed control lambs to be marginally Vitamin B 12 deficient. The sustained release of even a small amount of Vitamin B 12 was shown to promote hepatic storage of the vitamin in this trial. 2 - Otautau Field Tria,21 Sixty paired twin lambs were implanted two to four weeks after tailing on a farm selected because of a history of cobalt deficiency. One twin of each pair (thirty lambs) was implanted with an EVA/cyanocobalamin uncoated implant. Half of this group (fifteen lambs) received an implant made with cyanocobalamin powder granules that had been through a 45 pm gauge sieve. The other half received an implant made with cyanocobalarnin powder granules that had been through a 63 gm gauge sieve. The remaining thirty lambs received a placebo implant (EVA without cyanocobalamin). A Ralgro@ implanting gun was used to place one implant under the skin at the base of the ear of each lamb. Blood samples for Vitamin B 12 analysis were taken prior to implanting and each lamb was weighed and tagged. The lambs were returned to pasture and grazed together. Lambs were weighed and blood sampled monthly up to 6 months of age. Mean serum vitamin B 12 concentrations from the Otautau field trial (pmol/L) Sample 1 2 3 6 Baseline Date 22/10/99 23/11/99 21/12/99 25/1/99 22/2/99 2213/99 22/4/99 Uncoated implant 746.15 1593.33 584.67 439.33 591.33 542.67 677.33 (Means, n = 15 Uncoated implant 746.15 2870.67 934.67 767.33 834 626 856 63 (Means, n = 15) Controls 746.15 358.33 218.90 226.13 282.53 360.90 489.31 (Means, n = 30) Results showed that the Vitamin B 12 implant released active rapidly in the first 2 - 3 months following implantation. The release then slowed over a period of a further 3-4 months. 26 Body weights of lambs in both treatment groups gained weight faster than those in the control group, and reached a higher body weight by the conclusion of the trial. These differences were significant at the 0.05 level at months 3 and 4, and at the 0. 1 probability level at months 5 and 6. Conclusion: The '63' implant was successful in protecting lambs in the treatment group from cobalt deficiency in the face of inadequate cobalt intake for a period of six months. With the information gained from this trial, further implants were developed to slow the release of the active. These were then secretly trialled. on a property at 10 Balclutha. Balclutha Field TriaI22 The efficacy of three slightly different implants was compared in a trial in Balclutha. Sixty Romney-cross, pre weaned lambs were individually ear tagged, weighed and blood sampled for Vitamin B 12 analysis. Lambs were then assigned to one of four groups of fifteen animals by sequential allocation. The first group of lambs received an uncoated implant made with cyanocobalamin powder granules that had been through a 45 tm gauge sieve prior to manufacture. Tlie second group also received an implant made with cyanocobalamin powder granules that had been through a 45 [tm gauge sieve, but was coated and a third group received a coated implant made with cyanocobalamin powder granules that had been through a 63 im gauge sieve. The remaining lambs served as untreated controls. The implants differed only in the size of the cyanocobalamin particles used in the manufacture (<45 or <63 jim) and whether the implant was coated/uncoated with EVA prior to cutting. These variables were anticipated to alter the release characteristics of the implant. All implants were placed in a Ralgro(b cartridge for implantation which was sterilised using ethylene oxide gas before placement under the skin on the caudal surface of the pinna of the ear, one third way up from the base with a Ralgro@ implanting gun. Lambs were blood sampled for Vitamin B 12 analysis at monthly intervals for the duration of the trial (December 1998 - May 1999) and weighed at alternate blood sampling times. 27 The uncoated implant rapidly released high levels of Vitamin B 12 for a period of two months. From the third month of the trial, the recorded serum Vitamin B 12 of sheep implanted with the uncoated implant did not differ significantly from that of control sheep. The coated implants showed a relatively constant release profile over the five month period. The serum Vitamin B 12 of lambs implanted with coated implants were not significantly different at the 5% level at any time and the results have therefore been combined. Mean serum Vitamin B 12 concentrations of lambs from the Balclutha field 10 trial (pmol/L) SampIe 1 2 3 4 5 6 Baseline Date 2112/98 11/m 14/2t99 15/3/99 13/4/99 11/5/99 Controls 902.2 866.7 812.0 976.0 632.0 844.0 (Means, n = 15) Uncoated implant 902.2 5290.0 1165.0 1222.14 790.0 1059.29 (Means, n = 15) Coated implant 902.2 2006.3 2096.7 2284.0 1456.7 1510.3 (Means, combined data, n = 30) This study, which is still in progress, shows that coating the implant successfully slowed the rate of Vitamin B 12 release. The coated implants maintained serum B 12 concentrations > 500 gmol/1 greater than that of control lambs for the duration of the five month trial. At the end of the trial, the lambs treated with the coated implants had a mean serum Vitamin B12 of almost twice that of control sheep. The coated implants were still releasing the active and liver Vitamin B 12 in treated lambs will provide 28 protection from Vitamin B 12 deficiency beyond the 5 month trial period. This trial supports the six month claim for this product. Field Trials Overview- Pharmacokinetics The active component of the implant, cyanocobalamin, is an analogue of hydro x ocobalamin, which is marketed widely in New Zealand for the treatment and control of Vitamin B 12 deficiency in sheep. Vitamin B 12 is the name generally used for a group of related cobalt containing compounds, known as cobalamins, of which cyanocobalamin and hydroxocobalamin are the principle forms in clinical use. Parenteral cyanocobalamin has been shown to be efficacious in the treatment of Vitamin B 12 deficiency in sheep and in humans. Hydroxocobalamin is an analogue of cyanocobalamin. Hydroxocobalamin is retained in the body for a longer period than cyanocobalarnin and is the currently preferred form of treatment for young sheep at pasture. NewZealand field experience and recent experimental data suggests that an injection of a recommended dose (1-2 mg) of Vitamin B12 (hydroxocobalamin) in lambs provides for the liver storage of Vitamin B 12 sufficient for only 3 - 4 weeks. The release rate of cyanocobalan-dn from the implants was sufficient to maintain an adequate vitamin B 12 status for a period of six months in lambs. Following release from the implant, cyanocobalarnin is rapidly absorbed. Vitamin B12 is known to become extensively bound to specific plasma proteins transcobalan-iin 1 and 11. Transcobalamin H appears to be involved in the rapid transport of the cobalamins to tissues. Aqueous cyanocobalamin in excess of serum protein binding capacities is rapidly excreted. In humans, up to 70% of a 1 mg injection of cyanocobalamin (aqueous) will be lost in urinary excretion in the first 72 hours. It has also been shown by others that rabbits receiving intramuscular radio-labelled Vitamin B12 as an aqueous formulation of cyanocobalamin, exhibited rapid absorption with 60% being subsequently excreted in urine in the first 24 hours. Vitamin B 12 diffuses across the placenta and reaches milk. Unlike other water soluble B group Vitamins, Vitamin B 12 is stored in the body, principally in the liver, where it is utilised and excreted in bile. The distribution of injected radio labelled Vitamin B12 in a study in sheep resembled that of other species. Liver 29 (storage) and kidney (excretion) were the main sites of Vitamin B 12 retention. Although intestinal resorption of Vitamin B 12 following excretion in bile is very effective, the major excretion route of Vitamin B 12 released from tissues is faeces. Cobalt deficient individuals retain a greater proportion of the Vitamin B 12 dose. A sheep on a low cobalt diet, under conditions where hepatic stores of Vitamin B 12 were depleted, has been given 25 p/g radiolabelled cyanocobalamin daily, for 20 days. Only 13.3% of the dose was excreted in urine, 19.9% excreted in faeces. The net retention in deficient animals in this and similar studies was high. Slow release formulations of Vitamin B12 promote replenishment of hepatic stores. The Mosgiel Field Trial showed that even small amounts of Vitamin B 12, when released slowly over a period of six months, result in significant vitamin storage. This storage has also been illustrated by a study in rabbits: After intramuscular injection, the absorption from the injection site, the extent of liver storage and excretion in urine and faeces, of 6OCo-cyanocobalamin (aq) or one of six Vitamin B 12_60CO long acting preparations was compared. The long acting dosage forms of Vitamin B 12 were absorbed slowly and were minimally excreted. As Vitamin B 12 was released slowly, it was available for hepatic storage over a longer period of time. Rabbits injected with the slowest release dosage form stored a considerably greater amount of Vitamin B 12 compared to controls. The in vitro testing of pilot implants supported a preferred matrix design for prolonged, linear release of the active by 40% loading with a cyanocobalamin particle size of < 63 tm. Other Considerations Pertaining to ImRlant Use The tissue biocompatability of EVA has been demonstrated in experimental animals. Histological evaluation of tissue sections around a subcutaneous EVA implant in rat tissue showed no inflammatory cell reaction after a period of 7 months. EVA was shown.to be inert in rabbit corneal implants. EVA is safe, biocompatible and heat stable. It is FDA approved and is used in human implants and drug delivery systems. Ear implants identical in dimensions to our B 12 implant (of the Field trials) have been used in lambs for many years (Ralgro(P Schering Plough Corp.) and have not been associated with significant problems. None of the lambs in any of the field trials showed any evidence of irritation or 5 pain following placement of the implant. No swelling or infection at the site was observed subsequently. Apart from a thin fibrous capsule, which formed over the implant within a month of implantation, the site of implantation was devoid of inflammation or granulation tissue reaction. There are no residue concerns with respect to Cyanocobalamin. Hydroxocobalarnin is used widely in New Zealand and products carry a nil withholding time. Cyanocobalamin is more rapidly excreted than Hydroxocobalamin. Aspects of the present invention have been described by way of example only and 15 it should be appreciated that modifications and additions may be made thereto without departing from the scope thereof as defined in the appended claims. 31 THE CLAIMS DEFINING THE INVENTION ARE:

1 An implant for the slow release of one or more active components, the implant comprising a form of an insoluble polymeric material, the polymeric material including a network of cavities and channels forming a porous network; said active components being present within said porous network and substantially uniformly distributed throughout the form; and wherein there is present as an active component at least one B 12 compound as herein defined.

2. An implant as claimed in claim I in which the polymeric material is a plastics material.

3. An implant as claimed in claim 2 in which the plastics material is an EVA polymer.

4. An implant as claimed in claim I in which release is accomplished by the gradual dissolution of active components from the porous network.

5. An implant as claimed in claim I in which the release profile over time includes an initial burst profile followed by a decay levelling to a plateau.

6. An implant as claimed in as claimed in claim I in which the daily release rate of active components comprising B 12 compounds is above 5pg/24hr for at least 60 days.

7. An implant as claimed in claim I in which the daily release rate of active components comprising B 12 compounds is above 5pg/24hr for at least 150 days.

8. An implant as claimed in claim I which, when implanted, will maintain the serum vitamin B 12 level above 500pmolAitre for at least 6 months from the date of implant in new lambs.

9. An implant as claimed in claim I which has been manufactured by an extrusion process.

32

10. An implant as claimed in claim 1 which has been cut or trimmed from a rod, sheet, or length of polymeric material.

11. An implant as claimed in any one of claims 1 through 3, manufactured from a method comprising:

- dispersing active components throughout a polymer with solvent mixture; - forming the combination into forms of the desired shape; - allowing firming of the forms by solvent evaporation.

12. An implant as claimed in claim 1 which has been coated with a material exhibiting any one or more of the following properties:

- substantially non-dissolving and acting as a permeable membrane controlling the rate of leaching of active components therethrough; slowly dissolving in pre-determined environments.

13. An implant as claimed in claim 1 in which at least 75% of the included B 12 compounds, by weight, is available for release.

14. A bulk article in the form of a sheet, rod, or coil, which can be cut or trimmed to form an implant as claimed in any one of the preceding claims.

15. A method for the long term controlled release of a B 12 compound by the implantation of an implant as claimed in claim 1 into a target subject.

16. The method of claim 16 in which the implantation is subcutaneous by injection.

17. The method of any one of claim 16 in which the implant is inserted into new-bom lambs when less than 60 days old.

18. A method of manufacture of an implant for long term controlled release of a B 12 compound which includes steps of:

- dissolution of a polymer in a solvent portion in which chosen active component to be included is substantially insoluble; - dispersing chosen B 12 compound throughout the polymer solvent mix; - forming the combination into a desired configuration, and - removing solvent.

33

19. A method of manufacture as claimed in claim 18 in which the chosen solvent portion is non-aqueous and either or both substantially hydrophobic and immiscible with water.

20. A method of manufacture as claimed in claim 19 in which the solvent portion comprises at least one member of a solvent group comprising: dichloromethane, xylene, carbon tetrachloride, chloroform or other halogenated solvent.

21. A method of manufacture as claimed in claim 18 in which the active component loading is sufficient to ensure a porous structure allowing release of at least 75% of the included B 12 compound.

22. A method for addressing B 12 deficiency in animals comprising the implantation of at least one implant, as claimed in claim 1, into an animal and in which the inserted implants, in total, release at least an average daily amount of 5gg/24hr of B 12 compounds for at least during days 90-150 after insertion.

23. A method for addressing B 12 deficiency, as claimed in claim 22, in which the animal is a newly born animal, and the implantation occurs within one month of birth.

24. A kit for addressing B 12 deficiency including one or more implants, substantially as described above, in a form suitable for implantation by injection, said kit being suitable for a range of animal species andlor animal sizeslages of an individual species; said kit including at least one implant containing a predetermined minimum dose for an animal such as a new born infant, and containing sufficient further implants to adequately dose other intended animals, sizes, or ages for which the kit is intended to cover, either by the inclusion of alternate dosage implants or by the combination of included implants to achieve the required total dosage.

Bomac Laboratories Limited