GB2123693A - Sustained release device - Google Patents

Abstract

The device comprises a source of at least one trace chemical element (as defined) incorporated in a cement and releasable therefrom on contact with an aqueous medium. As examples, cements containing the trace element magnesium can be used in the prophylaxis or therapy of grass tetany in lactating ewes or cows and cements containing iron may be used for treating anaemia in sucking pigs. Other active agents can be present in the cement including pharmaceuticals. Many examples of suitable cements and active agents are listed.

Description

SPECIFICATON Release cement This invention relates to sustained release devices; more particularly, this invention relates to such devices which provide sustained release of active substances, especially substances having a medicinal effect. The invention is of particular, but not exclusive, relevance to animal husbandry.

During the last half-century it has become increasingly clear that, in order to maintain a complete, balanced metabolism, healthy livestock requires trace but sustained amounts of a number of chemical elements. Furthermore, ever more intensive systems of animal husbandry dictate that these requirements have to be rigorously adhered to.

In the Preliminary Table below, approximate minimum requirements, expressed in ppm. of dry dietry matter of certain chemical elements, are given (from "The Mineral Nutrition of Livestock" second edition, by E. J. Underwood published by the Commonwealth Agricultural Bureaux). It is to be understood that dietary requirements vary with the species and breed of animal, its age, its rate of growth or production and with the biological availability of the chemical element.

PRELIMINARY TABLE

LIVESTOCK CHEMICAL ELEMENT PIGS POULTRY SHEEP CATTLE Mg 325-500 200-600 700 7001 Fe 50-125 40-80 25 40 25 40 | 0.05-0.14 0.05-0.14 0.05-0.14 0.03-0.8 Cu 62 3-6 1-10 8-14 Co - - 0.7-1.1 0.7-1.1 Mn 12-40 25-108 10-40 10-25 Zn 35-46 35-65 17-33 30-50 Se 0.03-0.1 0.01-0.28 0.03-0.12 0.03-0.12 (1 If dietary magnesium (as presented) is available for metabolism only to the extent of 20%, then the magnesium requirements for a 40-litre cow can be as much as 24 g. day-1, especially in the spring.) ( Copper requirements are powerfully influenced by interaction with other dietary components, especially molybdenum and sulphur.) This invention seeks to provide a device which can give sustained release of one or more active substances, especially substances having a medicinal effect in a form preferably, but not necessarily, for oral administration or parenteral implant, not requiring frequent dosing and which can be susceptible of extempore preparation by a local veterinary surgeon.

Accordingly, the present invention provides a sustained release device which comprises a source of at least one trace chemical element, optionally with at least one active substance other than a trace chemical element, incorporated in a cement and releasable therefrom on contact with an aqueous medium. At least one trace chemical element may be an intrinsic component of the cement and/or at least one trace chemical element may be dispersed in the cement.

Such devices have also been found suitable for uses other than in oral administration or parenteral implant in livestock and where sustained release is desired, for example in the provision of one or more active substances in agriculture or horticulture. Examples include the sustained provision of magnesium for tomato crops or of copper as an antifouling agent for combating marine growth.

The term "active substance" as used herein includes any substance the administration of which to a locus imparts to that locus an effect which is beneficial to human resources. The effect imparted may be an enhancement of a desired effect (e.g. the improved health and/or rate of growth of livestock attained by correct provision of trace chemical elements) or the reduction or eradication of an undesired effect. The locus will be in vivo in the case of livestock but this need not be the case, for example, in agriculture or horticulture.

The term "substance having a medicinal effect" as used herein includes any active substance other than a trace chemical element the administration of which in vivo has a prophylactic or therapeutic effect.

By "trace chemical element" is meant herein at least one of As, B, Cd, Co, Cr, Cu, F, Fe, I, Mg, Mn, Mo Ni, Se, Si, Sn, V or Zn. This does not imply that the devices of this invention may only release these elements in trace amounts; on the contrary, magnesium needs to be released in substantial amounts in cattle, as noted above; furthermore, other elements, such as Cu, may be required to be released in substantial amounts in uses other than oral administration or parenteral implant to livestock.

The term "cement" as used herein means the coherent mass formed by reaction at a temperature below 2500C, preferably below 1000C, especially at ambient temperature, from at least one settable substance (but excludes covalently cross-linked organic thermoset materials) rather than the cementforming component(s) themselves. It is desirable that the settable substance is capable of adhesively binding solid particles by its setting about those particles though, in accordance with this invention, the solid particles need not always be or remain present.

The cement may be a hydraulic cement: that is, one in which the cement-forming component(s) are settable to form the cement by the action of water; for example, the various Portland cements (including ordinary, rapid-hardening, quick-setting and white) and pozzolanic cements. Preferably, however, the cement is a reaction cement: that is, one in which at least two cement-forming components other than water are reactable to form the cement. Preferably, the cement is an acid-base reaction cement: that is, one in which at least one cement-forming component is a Lewisor Bronsted acid and at least one other cement-forming component is a Lewis or Bronsted base. Examples include acid phosphate, phosphate, nitrate, sulphate, selenate, selenite, and oxychloride cements.

In the preferred case of acid-base reaction cements the cement is suitably formed from an acid cement-forming component which comprises a mineral acid, an acid salt, a Lewis acid, a polyfunctional organic carboxylic acid, a polyfunctional organic phosphoric acid, a polyfunctional phenol, a homo- or co-polymer of an unsaturated carboxylic acid, a homo- or co-polymer of an unsaturated sulphonic acid, or a hydrolysable precursor thereof. The term "hydrolysable precursor" as used herein includes any species, such as an anhydride or an acid chloride, which is transformed on hydrolysis to the required acid cement-forming component. Suitable examples of mineral acids include phosphoric acids such as orthophosphoric acid, pyro-phosphoric acid and meta-phosphoric acids, sulphuric acid, nitric acid, and hydrohalic acids, such as hydrochloric acid, with phosphoric acids being preferred.Examples of acid salts include the hydrogen and dihydrogen phosphates; bisulphates, and bifluorides, especially the alkali metal hydrogen and dihydrogen phosphates. Examples of Lewis acids include those metal halides which are Lewis acids, such as aluminium trichloride, aluminium tribromide, magnesium chloride, magnesium iodide, ferric chloride, zinc chloride, zinc iodide and copper chloride. Others are oxyacid salts, such as sulphates, selenates and selenites.Examples of polyfunctional organic carboxylic acids, polyfunctional organic phosphoric acids and polyfunctional phenols include the following polybasic acids: malonic, mesoxalic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic, malic, citric, tartaric, tartronic, tricarballylic, maleic, fumaric, citraconic, mesaconic, itaconic, glutaconic, muconic, aconitic, ortho-, iso- and tere-phthalic, gallic, tannic and mellitic acids, phytic acid, catechol, resorcinol, quinol, pyrogallol, hydroxyquinol and phloroglucinol. Other polyfunctional organic carboxylic acids and phenols which are not polybasic but are suitable as acid cement-forming components include hydroxycarboxylic acids and ketoacids.Examples are lactic, pyruvic, 2-hydroxyisobutyric, 2hydroxycyciohexane carboxylic, 2-hydroxy-2-phenyl propionic, diphenylhydroxyacetic, 2hydroxybenzoic, 3-hydroxybenzoic and 4-hydroxybenzoic acids, eugenol and salicylaldehyde. Examples of homo- or co-polymers of an unsaturated carboxylic acid include those prepared by the homopolymerisation or copolymerisation of aconitic acid, acrylic acid, citraconic acid, fumaric acid, glutaconic acid, itaconic acid, maleic acid, mesaconic acid, methacrylic acid, muconic acid and tiglic acid, and the copolymerisation of these acids with other unsaturated aliphatic monomers for example vinyl monomers, such as vinyl hydrocarbon monomers, vinyl ethers, acrylamide or acrylonitrile.

Particularly noteworthy are the homopolymers of acrylic acid and its copolymers, particularly copolymers of acrylic acid and itaconic acid, especially those described and claimed in UK 1484454.

Good results have also been obtained using a copolymer of vinyl methyl ether and maleic acid.

Examples of homo- or co-polymers of an unsaturated sulphonic acid include those prepared by the homopolymerisation or copolymerisation of ethylene sulphonic acid.

It is also possible to use a hydrolysable precursor of such polymers, for example a poly(carboxylic acid anhydride); furthermore, polyacrylic acids may be prepared by hydrolysis of corresponding polyacrylonitrile anhydride. The hydrolysable precursor of a poly(carboxylic acid) may be a homopolymer of an unsaturated carboxylic acids or a copolymer with an above mentioned other carboxylic acid or anhydride thereof, or a copolymer of an unsaturated carboxylic acid anhydride with an unsaturated aliphatic monomer, for example vinyl monomers, such as vinyl hydrocarbon monomers, linear or cyclic vinyl ethers, acrylamide or acrylonitrile, for example pyran copolymer. Good results may be obtained by using homopolymers of maleic anhydride or vinyl orthophthalic anhydride, or copolymers thereof, especially block copolymers thereof, with ethylene, propylene, butenes, styrene and vinyl methyl ether. Mixtures of such components may be used. Preferably, the acid cement-forming component is in aqueous solution.

The acid-base reaction cement is also suitably formed from a base cement-forming component which comprises a basic or amphoteric oxide or hydroxide, or a salt of a weak or volatile acid. There are many basic or amphoteric oxides or hydroxides which can form cements with at least one of the acid cement forming components defined above; examples include Li2O (other Group IA oxides or hydroxides tend to give materials which are too soluble in aqueous media, although they can be incorporated in minor amounts to facilitate release in other cements), Group IIA oxides, preferably calcined, such as MgO, "Tí(OH)4", "Zr(OH)4", V205, Foe203, Cm20, CuO, ZnO, preferably calcined, Al203 x H20 and SnO.

Salts of weak or volatile acids include carbonates, monocarboxylates, such as acetates, and halides, such as the halides of Mg, Ca, Ba, Th, Ti, Zr, Al and Sn. They also include the extensive class of monomeric and polymeric (alumino)silicates, (alumino)phosphates and (alumino)borates which include the acid-reactive natural and synthetic minerals and'ion-Ieachable glasses. By "(alumino)silicate" is meant herein a silicate or an aluminosilicate; by "(alumino)phosphate" is meant herein a phosphate or an aluminophosphate; by "(alumino)borate" is meant herein a borate or an aluminoborate.Examples of ion-leachable glasses include those glasses wherein the principal acidic oxide is silica (although the glass may also contain minor amounts of other anhydrides such as phosphorus pentoxide and boric oxide), and wherein the principal basic oxide in the glass is alumina which, although it has amphoteric properties, can be considered for the purposes of the present invention solely as a basic oxide.

Particularly preferred glasses fall within the composition range of 10 to 65% w/w silica and 1 5 to 50% w/w alumina. The glass desirably contains at least one other basic oxide, preferably calcium oxide, which may be present in the glass composition in an amount from 0 to 50% w/w. The calcium oxide may be partly or wholly replaced by sodium oxide or other basic oxide or a mixture of basic oxides. The presence of sodium oxide can be desirable in increasing the solubility of the resulting cement. Preferred glasses for use in the present invention containing alumina, silica and calcium oxide are the gehlenite and anorthite glasses, and in general glasses falling within the composition range 10 to 65% w/w silica, 15 to 50% w/w alumina and 0 to 50% w/w calcium oxide.

Other glasses suitable for use in the present invention may contain fluoride, suitably up to 15% by weight, preferably less than 10% by weight. A class of fiuoraluminosilicate glasses particularly suited to this invention are those wherein the ratio by weight of silica to alumina is from 1.5 to 2.0 and the ratio by weight of fluorine to alumina is from 0.6 to 2.5, or wherein the ratio by weight of silica to alumina is from 0.5 to 1.5 and the ratio by weight of fluorine to alumina is from 0.25 to 2.0.

Mixtures of such components may be used.

It is noted that, apart from cement-forming components of unequivocal acidity or basicity, certain components may react as acid cement-forming components under a given set of reaction conditions while reacting as base cement-forming components under a different set of reaction conditions.

The present invention is of broad applicability in the formulation of trace chemical elements releasable at a sustained rate.

This invention is particularly suited to sustained provision of sources of one or more of the following trace chemical elements: Mg, Fe, I, Cu, Co, Mn, Zn or Se, especially of at least one of Cu, Co, Se or I.

The source of trace chemical element may preferably be a phosphate, especially acid phosphate cement, a basic halide, a basic chalcogenate, or a carboxylate cement. Oxyhalide cements are of particular value in the sustained provision of halogen, especially iodine. Oxychalcogenate cements have values both in provision of cationic sources, for example of copper and cobalt in oxysulphate cements as well as anionic sources, for example, of selenium in oxyselenate cements.

Furthermore, it is possible to disperse one or more sources of trace chemical elements in cements which are themselves sources of one or more (or indeed no) other or the same chemical elements.

Where they are other chemical elements they need not be trace chemical elements. In this manner it is possible to get a multi-source device with all sources releasing a sustained, appropriate amount.

Moreover, it is also possible to vary the dosage, in accordance with this invention, to suit local conditions and also to incorporate at least one active substance other than a trace chemical element, especially one having a medicinal effect.

Examples of classes of active substance other than a trace chemical element which may be additionally incorporated in the sustained release devices of the present invention include pharmaceuticals, bacteriostats, viruscides, herbicides, pesticides such as insecticides, nematicides, and larvicides, fungicides, topical or dermatological agents, proteins, for example enzymes, peptides, vaccines, growth promoting factors used in agriculture, horticulture and animal husbandry, for example fertilisers, vitamins, for example nicotinamide and anabolic steroids. Of particular interest are compositions of the present invention comprising, as active substance, at least one substance having a medicinal effect.

Specific classes of substance having a medicinal effect which may be utilised in a sustained release device of the invention include hypnotics, sedatives, tranquilisers, antipyretics, antiinflammatory agents, antihistamines, antitussives, anticonvulsants, muscle relaxants, topical or dermatological agents, antispasmodics, anti-ulcer agents, preparations containing various substances for the treatment of infection by pathogens including anti-fungal agents, antiparasitic agents such as anthelmintics; for example avermectin and morantel tartrate, and other antimicrobials such as antibiotics: for example oxytetracycline, preparations containing hormones, for example androgenic, estrogenic and progestational hormones, notably steroids, such as progesterone, trenbolone, oestradiol and polypeptide hormones, sympathomimetic agents, hypoglycaemic agents, nutritional agents, preparations containing enzymes of various types of activity, for example chymotrypsin, preparations containing analgesics, for example aspirin and agents with many other types of action including nematocides and other agents of veterinary application. Mixtures of active substances may be incorporated into the sustained release devices of the invention which may suitably comprise a dosage from, especially one which is an integral body of cement.

In order to ensure retention of oral dosage sustained release devices of this invention in the reticulo-rumen of ruminant stock, it is desirable to incorporate therein a weighting agent to raise the density of the device, typically to about 3, although a somewhat lower density may be appropriate. The weighting agent may be dispersed throughout the device (e.g. as iron filings) or consolidated (e.g. as an essentially coaxially positioned steel rod).

The configuration of the sustained release devices of the invention is selected having regard both to the desired release characteristics and ease of administration. The devices are most often used in the form of a shaped body such as a hollow or blank cylinder, a sphere, a tablet or a slab and the nature of the shape and its dimensions may be selected appropriately. A primary target is to achieve a sustained release over appropriate time period, conveniently of a major proportion, for example 80 or 90%, of the active substance. Unusual release profiles may, however, be obtained by utilising devices which comprise open cavities, for example hollow cylinders or slabs with one or more holes or hollows in them. It is found that the release profiles of such devices can go through a maximum with time.Such geometric control of release profiles provides very useful additional means of obtaining and controlling improved release profiles. It is preferred, however, that the device is a cylindrical dosage form which may be mono- or bis- spherically capped. For administration orally to sheep this may be up to 20 mm in diameter and 50 mm long; for administration orally to cattle this may be up to 35 mm in diameter and 1 60 mm long. For parenteral administration either to sheep or cattle cylinders 3 mm in diameter and 5 mm long are very suitable. Up to 4 in sheep and 10 in cattle may be incorporated in one implant.

In accordance with a further aspect of this invention, there is provided a process for the preparation of a device of the invention, which process comprises preparing a cement-forming mixture in which is incorporated a source of at least one trace chemical element; investing a mould with the mixture; and permitting the cement-forming mixture to cure in the mould, preferably wherein the cement is subjected to a post-curing treatment at an elevated temperature.

However, it is also within the scope of the present invention to utilise the cement in powdered form, optionally in suspension in a liquid medium (for example as a subcutaneous depot).

In accordance with a further aspect of this invention, there is provided a particulate composition reactable in the presence of a polar liquid, suitably water, to form a device as herein defined.

This invention also provides a pack which comprises a particulate composition, a polar liquid, suitably water, reactable with the composition to form a device as herein defined, and separating means to prevent accidental reaction of the particulate composition with the polar liquid.

This invention further provides a source of at least one trace chemical element, optionally with at least one active substance other than a trace chemical element, incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in prophylaxis or therapy. In particular, the invention provides magnesium incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in the prophylaxis or therapy of grass tetany, especially in lactating cows and ewes. The invention provides iron incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in the prophylaxis or therapy of anaemia, especially in sucking pigs.The invention also provides iodine incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in the prophylaxis of goitre. The invention further provides copper incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, to facilitate anabolism in young pigs or ruminants. The invention provides cobalt incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in the prophylaxis or therapy of subclinical retardation or enzootic marasmus in sheep or cattle.The invention also provides manganese incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in the prophylaxis or therapy of perosis or nutritional chondrodystrophy in poultry or manganese deficiency in ruminants.

This invention provides livestock whenever administeredvwith a sustained release device or an active substance as herein defined.

This invention further provides a cement in which a plurality of trace metals is incorporated. The oxyselenate and acid phosphate cements are also novel products of the invention.

In a preferred embodiment, the invention provides a cement in which sources of Cu, Co and Se are incorporated. The invention also provides an integral body of a cement comprising at least one trace chemical element and, dispersed therein, at least one different trace chemical element and/or at least one active substance other than a trace chemical element.

The following Examples illustrate the invention. Parts are by weight unless otherwise stated. All numerical values given are the mean of two determinations.

EXAMPLE 1 This Example describes the preparation and testing of cylindrical devices of magnesium phosphate cement designed to release magnesium as prophylaxis or therapy for grass tetany in ruminant stock.

Two sources of base cement-forming component were used: (i) magnesium oxide calcined at 1 0000C (ex White Sea 8 Baltic Co.); and (ii) a magnesium aluminosilicate glass prepared by fluxing tqgether 180 parts magnesium carbonate, 180 parts silica and 100 parts alumina (all ex BDH Chemicals).

Three sources of orthophosphoric acid (ex Fisons, AR grade) solution as acid cement-forming component were used: (iii) 60% w/w aqueous orthophosphoric acid comprising 3.0% w/w aluminium; (iv) 50% w/w aqueous orthophosphoric acid comprising 2.5% w/w aluminium; and (v) 50% w/w aqueous orthophosphoric acid comprising no aluminium.

The components were mixed together at the ratio shown in Table 1 a below and were packed into cylindrical moulds 12 mm x 6 mm diameter. These were then sealed for 16 hours at 370C to form cylindrical devices. A pH = 5 buffer solution was next prepared from sodium acetate/acetic acid. The cylindrical devices were incorporated in the buffer solution and the in vitro release of magnesium was monitored with a Pye Unicam SP 1950 atomic absorption spectrophotometer. Results at pH = 5 are shown in Table 1 b.

TABLE 1A

setting compressive base acid time (h) strength component component powder:liquid 230C and after Cement (powder) (liquid) ratio (g/ml) 50% RH 24 h (MPa) 1 (i) (iii) 3.0 4 191 2 (i) (iv) 3.0 4 100 3 (i) (v) 3.0 1 71 4 (ii) (iv) 3.5 2 149 5 (ii) 4 (iii) 3.5 6.5 2 TABLE 1 B iB

Mg leached/day (% w/w of cement) after Cement id 2d 3d 4d 5d 6d 7d 14d 21d 28d 4 0.11 0.057 0.039 0.032 0.074 0.056 0.047 0.028 0.023 0.028 1 0.56 0.52 0.49 0.54 0.53 0.47 0.46 0.50 0.42 0.93 EXAMPLE 2 This Example describes the preparation and testing of cylindrical devices of magnesium oxychloride or magnesium oxysulphate cement.

Three sources of base cement-forming component were used: (i) magnesium oxide (heavy, ex Hopkin and Williams) heated at 4000C for 18 h; (ii) magnesium carbonate (ex BDH Chemicals) heated to 6500C for 6 h; and (iii) magnesium carbonate heated to 8500C for 6 h.

Two sources of acid cement-forming components were used: (iv) 30% w/v aqueous magnesium chloride (ex Fisons) solution; and (v) 22.4% w/v magnesium sulphate (ex Fisons) solution.

The components were mixed together at a powder:liquid ratio of 4 g : 5 ml; moulded; and tested at pH = 5 in essentially the same manner as described in Example 1. The results are shown in Table 2. TABLE 2

Mg leached/day (% w/w of cement) Average weight loss/ base acid after day (% w/w of Cement component component 1 d 8 d 15 d cement) 6 (i) (iv) 1.50 1.35 0.30 6.7 7 (ii) (iv) 1.76 1.38 0.74 6.3 8 (iii) (iv) 1.64 1.63 0.70 6.2 9 (i) (v) 2.03 2.18 - 9.1 10 (ii) (v) 3.72 1.88 - 8.0 11 (iii) (v) 2.56 1.64 - - 6.3 EXAMPLE 3 This Example describes the preparation of larger cylindrical devices comprising a weighting agent.

In this Example, components (i), (iv) and (v) of Example 2 and component (iii) of Example 1 were used. They were mixed, essentially as in Example 1 at a powder:liquid ratio of 4 g : 5 m!. Pure iron (99%) powder (ex Goodfellow Metals Ltd.) was also admixed as a weighting agent. The mixture was then packed into cylindrical moulds of 20 mm x 12 mm diameter and 20 mm x 20 mm diameter, cured and tested at the pH shown in essentially the same manner as described in Example 1. The results are shown in Table 3. Inter alia, they show that the rate of release of Mg is pH dependent with the rate increasing rapidly with decreasing pH.

TABLE

Mg leached/day (% w/w of cement) Magnesium pH of original wt. %av.

oxide: leaching after wt after weight Cement liquid:Fe solution 1 d 2 d 3 d 4 d 5 d 6 d 7 d 8 d (g) (g) loss 12 4:5 :15.5 5 1.203 0.864 0.717 0.673 0.647 0.557 0.502 0.489 20.206 11.560 5.35 6 0.454 0.106 0.094 0.086 0.058 0.056 0.055 0.052 20.086 19.406 0.423 5.5-6.06 0.368 0.219 0.133 0.087 - - - - 19.678 18.719 1.22 13 2.4:5 ::15.5 5 1.237 0.635 0.543 0.411 - - - - 20.070 14.585 6.83 6 0.389 0.118 0.089 0.060 - - - - 20.035 17.606 3.03 14 4:54:15.5 5 0.732 0.678 0.641 0.615 0.577 0.556 0.507 0.474 20.365 12.749 4.67 6 0.185 0.090 0.075 0.69 0.85 0.063 0.060 0.060 21.111 20.632 0.284 15 3.5:34::15.5 5 1.315 0.757 0.602 0.411 - - - - 17.909 12.688 7.29 6 0.476 0.163 0.131 0.097 - - - - 18.373 17.090 1.75 5.5-6.06 0.601 0.245 0.167 0.136 - - - - 18.003 16.109 2.63 16 3:15: :6.25 5 1.183 0.737 0.408 0.304 0.228 0.193 0.175 0.100 5.886 5.394 1.04 6 0.154 0.114 0.092 0.090 0.119 0.083 0.081 0.078 6.549 6.506 0.082 of dimensions 20 mm x 20 mm diameter of dimensions 20 mm x 12 mm diameter liquid (iv) of Example 2 4 liquid (v) of Example 2 5 liquid (iii) of Example 1 6 distitled demineralised water at a pH from 5.5 to 6.0 EXAMPLE 4 This example describes in vivo testing of the cements described in Example 3.

Cylindrical devices prepared as described in Example 3 and of the dimensions shown in Table 4, were simply inserted into the reticulum of a cow having a fistulated rumen. Periodically the devices were removed, weighed and replaced.

TABLE 4

% loss of original weight per day Cow J629 Cow K839 device dimensions initial after after Cement (mm) wt. (g) 10 d 20 d 30 d 10 d 20 d 30 d 12 20 x 20 18 2.01 2.10 2.04 2.53 2.29 2.21 9 2.39 2.38 - 3.08 2.66 7.5 2.80 - - 2.59 - 14 20 x 20 18 2.34 2.23 2.12 2.45 2.13 1.97 9 3.05 2.81 - 2.99 2.53 7.5 3.32 - - 3.48 - 16 20 x 12 8 0.39 0.31 - 0.43 0.35 (diam) 6 0.50 0.42 - 0.50 0.43 4 0.38 - - 0.38 - EXAMPLE 5 This Example describes the preparation and testing of cylindrical devices of copper phosphate and copper oxychloride cements, and also devices comprising copper (II) acetate and copper (i) chloride dispersed in copper phosphate cement.

Three sources of copper as base cement-forming component were used: (i) copper (II) oxide (ex Hopkin 8 Williams); (ii) copper (II) oxide calcined at 1 2000C; and (iii) copper (I) oxide (ex Hopkin # Williams).

Nine sources of acid cement-forming component were used: (iv) copper (il) chloride (ex Fisons) (saturated aqueous solution); (ix) 75% w/w aqueous orthophosphoric acid; (v) 90% w/w aqueous orthophosphoric acid; and (vi) 100% polyphosphoric acid (ex Aldrich); (xii) 50% w/w tannic acid; (xiii) 50% w/w phytic acid; (xiv) 50% w/w gallic acid; (xv) 50% w/w mellitic acid; (xvi) 50% w/w 1 ,3,5-pentanetricarboxylic acid.

Four sources of copper, dispersible in the cements formed from the above mentioned components by admixture with one or more thereof were used: (x) copper powder (vii) copper (I) chloride (ex Fisons) (xi) copper (II) formate (viii) copper (II) acetate (ex BDH) The components were mixed together at the ratio shown in Table 5a below and were packed into cylindrical moulds 12 mm x 6 mm diameter. These were then sealed for 24-48 hours at 370C to form cylindrical devices which were next incorporated in distilled demineralised water and the in vitro release of copper was monitored by atomic absorption spectrophotometry. Results are shown in Table 5b.

TABLE 5A

@@@@ @@@@ @@@@@@ Cement component component ratio temperature ( C) 17 (i) + (iii) (v) (i):(iii):(v)::1 37 18 (i) + (iii) (v) (i):(iii):(v)::1.5g:0.5g:1.0ml 37 19 (i) (vii) + (v) (i):(vii):(v)::1.5g:0.5g:1.0ml 37 20 (i) (viii) + (v) (i):(viii):(v)::l .5g:0.5g:1.0ml 37 21 (i) (iv) (i):(iv)::1.5g::1.0ml 37 22 (ii) (vii) + (iv) (ii):(vii):(iv)::l .5g:0.5g:1.0ml 37 23 (ii) (vii) |+ (vi) (ii):(vii):(vi)::1.5g:0.5g:1.0ml 37 24 (ii) (v) (i):(v)::1.5g:1.0ml 37 117 (i) (v) (i):(v)::1.27g:1.0ml 37 118 (i) (v) (i):(v)::1 .27g:1 .0ml 100 119 (i) (v) (i):(v)::1.27g:1 .Oml 250 120 (i)' (v) (i)':(v)::0.65g:1.0ml 100 121 (i)' (v) (i)':(v):: 0.65g:1.0ml 250 122 (i)' (v) (i)':(v)::0.65g:1.0ml 500 123 (i) (v) (i):(v)::0.96g:1.0ml 37 124 (i) (v) (i):(v)::0.96g:1.0ml 100 217 (i) (v) (i):(v)::0.96:1.0ml 250 218 (i) (ix) (i):(ix)::1.07g:1.0ml 37 219 (i) (ix) (i):(ix)::1.5g:1.0ml 37 220 (i) (x) + (v) (i):(v):0.96g:1.0ml 37 221 (i) (xi) + (v) (i):(xi):(v)::l .59:0.5g:1.0ml 37 222 (ii) (iv) (ii) (vi):: 1 .5g: 1.0ml 37 223 (i)' (xii) (i)' :(xii) .3g:1 1.0ml 37 224 (i)' (xiii) (i)':(xiii)::0.8g:1 .Oml 37 317 (i)' (xiv) (i)':(xiv)::1.0g:1.0ml 37 318 (i) (xv) (i):(xv)::3.0g:1.0ml 37 319 (i) (xvi) (i):(xvi)::3.0g::1.0ml 37 [(i)' is copper (II) carbonate-derived copper II) oxide.] TABLE SB Cu leached/day (% w/w of cement)

after 1 after 15 after22 after 29 after 36 after 43 Cement day days days days days days Comments 17 0.21 0.26 0.12 0.008 0.003 18 0.14 0.20 0.065 0.004 0.004 19 0.47 0.42 0.042 0.019 0.002 20 0.53 0.20 0.052 0.005 0.002 - 21 0.039 0.019 0.030 0.036 0.032 0.040 releasing 0.041% atday 71 22 0.58 0.081 0.057 0.063 - - 23 - 0.0143 0.071 0.067 0.047 0.037 releasing 0.037% at day 57 24 2.02 0.453 0.157 0.044 - - 117 0.24 0.31 0.15 0.015 0.001 0.001 uniform release in vivo 118 1.27 0.071 0.046 0.042 0.031 0.025 releasing 0.03% at day 100 119 0.083 0.017 0.012 0.015 0.020 0.022 releasing 0.008% at day 85 120 0.34 0.15 0.010 0.011 0.006 0.006 121 0.64 0.057 0.030 0.031 0.025 0.024 releasing 0.015% at day 92 122 0.14 0.019 0.015 0.016 0.013 0.009 123 0.70 0.36 0.12 0.034 0.032 0.025 releasing 0.013% at day 50 124 2.25 0.074 0.052 0.064 0.062 0.045 217 : 1.37 0.068 0.014 0.016 0.012 0.014 218 0.62 0.164 0.127 0.112 - 219 0.57 0.133 0.064 0.033 0.004 220 0.046 0.135 0.076 0.063 0.012 0.003 221 1.16 0.098 0.060 0.147 ~ ~ 222 0.049 0.015 0.011 0.011 0.009 - 223 0.051 0.016 0.017 0.021 0.023 0.024 releasing 0.020% at day 120 224 0.156 0.015 0.011 0.009 0.010 0.012 releasing 0.009% at day 92 317 0.080 0.032 0.024 0.026 0.026 0.026 releasing 0.021% at day 246 318 0.028 0.018 0.026 0.032 0.012 0.023 319 0.02 0.019 0.035 - 0.024 ,. 0.024 0.013 EXAMPLE 6 This Example describes the preparation and testing of cylindrical devices of cobalt cements, and also devices comprising cobalt phosphate dispersed in such cements.

Seven sources of base cement-forming component were used: (i) cobalt (II) carbonate (ex BDH); (ii) cobalt (II) carbonate heated at 4000 C; (iii) cobalt (II) acetate (ex BDH); (iv) cobalt (II) acetate, finely ground; (v) cobalt (II) hydroxide (exVentron GmbH) heated at 1 500C; (vi) cobalt (II) hydroxide heated at 1 500C and loaded with stainless steel (ex Goodfellow Metals) (at ratio 1:2); and (vii) zinc oxide (ex Fisons).

Thirteen sources of acid cement-forming component were used: (viii) 90% w/w aqueous orthophosphoric acid; (ix) 60% w/w aqueous orthophosphoric acid; (x) 50% w/w aqueous orthophosphoric acid; (xi) 50% w/w aqueous sodium dihydrogen phosphate (ex Fisons); (xii) 50% w/w aqueous sodium dihydrogen phosphate comprising 5% w/w cobalt (II) chloride (ex BDH); (xiii) 50% w/w aqueous cobalt chloride; (xvi) 50% w/w aqueous zinc chloride; (xiv) 50% w/w aqueous tannic acid (ex Hopkin s Williams); (xvii) 50% w/w aqueous L-malic acid; (xviii) 50% w/w aqueous mellitic acid; (xix) 50% w/w aqueous 1 ,3,5-pentanetricarboxylic acid; (xx) 50% w/w aqueous pyruvic acid; (xxi) 50% w/w aqueous tartaric acid.

One source of cobalt, dispersible in the cements formed from the above-mentioned components by admixture with one or more thereof, was used: (xv) cobalt (II) phosphate (ex BDH).

The components were mixed together at the ratio shown in Table 6a below and were packed into cylindrical moulds 12 mm x 6 mm diameter. These were then sealed for 24 hours at the curing temperature shown in Table 6a to form cylindrical devices which were next incorporated in distilled demineralized water and the in vitro release of cobalt was monitored by atomic absorption spectrophotometry. Results are shown in Table 6b.

TABLE 6A

base acid curing Cement component component ratio temperature ( C) 25 (i) (ix) (i):(ix)::2.0g:1.0ml 37 26 (i) (x) (i):(x)::2.0g:1.0ml 37 27 (i) (xi) (i):(xi)::2.5g:1.0ml 37 28 (i) (viii) (i):(viii)::2.5g:1.0ml 95 29 (iii) (viii) (iii) :(viii) ::2.5g :1.0ml 95 31 (iv) (viii) (iv):(viii)::3.Sg:1 .Oml 95 35 (v) + (xv) (xi) (v):(xv):(xi)::l .25g:0.25g:1.0ml 37 36 (vii) (xiii) (vii):(xiii)::1.0g::1.0ml 37 37 (vi) (xi) (vi):(xi)::3.0g:2.0ml 37 38 (ii) (xiv) (ii):(xiv)::1 .5g:1 .Oml 37 39 (i) (viii) (i) :(viii) ::2.Sg: 1 .Oml 37 40 (iv) (ix) (iv):(ix)::2.0g:1.0ml 37 125 (v) (x) (vi):(x)::2.5g:1.0ml 37 126 (v) (xi) (v):(xi)::1.25g:1.Oml 37 127 (i) (xvi) (i):(xvi)::2.0g:1.0ml 37 128 (v) (xvii) (i):(xvii)::2.0g:1.0ml 37 129 (v) (xviii) (v):(xviii)1.8g:1.0ml 37 130 (v) (xix) (v) :(xix)::2.0g:1.0ml 37 131 (v) (xx) (v):(xx)::2.0g1.0ml 95 132 (v) (xxi) (v):(xxi)::2.0g:1.0ml 37 133 (v) (xiv) (v):(xiv)::2.0g::1.0ml 37 TABLE 6B Co leached/day (% w/w of cement)

after after 15 after22 after29 after36 afterday Cement day days I days days days 43 Comments 25 0.012 0.031 0.036 0.036 0.036 0.038 releasing 0.038% at day 150 26 0.003 0.010 0.014 0.020 0.015 0.015 releasing 0.01 5% at day 190 27 0.004 0.010 0.018 0.017 0.019 0.024 releasing 0.024% at day 190 28 0.30 0.065 0.065 0.064 0.063 0.067 releasing 0.036% at day 148 29 6.7 0.033 0.021 0.031 0.020 0.024 releasing 0.020% at day 148 31 1.45 0.123 0.106 0.056 0.036 0.028 releasing 0.028% at day 85 35 0.006 0.028 0.019 0.026 0.023 0.028 releasing 0.028% at day 50 36 0.34 0.076 0.050 0.054 0.021 0.047 releasing 0.036% at day 50 37 0.0007 0.014 0.017 0.025 0.028 - 38 0.071 0.036 0.028 0.030 0.032 0.035 releasing 0.020% at day 148 39 0.48 0.048 0.047 0.067 0.038 0.035 40 1.00 0.049 0.037 0.029 0.028 0.018 releasing 0.010% at day 99 125 - 0.025 0.016 0.015 0.013 0.008 126 0.011 0.025 0.024 0.024 0.030 0.025 releasing 0.031% at day 57 127 4.81 0.027 0.016 - 0.017 0.016 releasing 0.018% at day 50 128 0.875 0.30 0.168 0.133 0.130 0.065 129 0.062 0.015 0.012 0.011 0.002 1 0.006 130 0.485 0.203 0.136 0.118 - - 131 1.44 0.139 0.049 0.043 0.047 0.032 132 0.227 0.081 0.065 0.070 0.077 0.061 133 0.195 0.084 0.051 0.057 0.054 0.041 @ releasing 0.052% at day 57 EXAMPLE 7 This Example describes the preparation and testing of cylindrical devices of copper-cobalt cements, and also devices comprising cobalt phosphate cement dispersed in copper phosphate cements.

Two sources of base cement-forming component were used: (i) copper (II) oxide; and (ii) cobalt (II) hydroxide heated at 1 500C.

Six sources of acid cement-forming component were used: (iii) 90% w/w aqueous orthophosphoric acid; (iv) 90% w/w aqueous orthophosphoric acid comprising 5% w/w cobalt phosphate; (v) 50% aqueous cobalt (II) chloride; (vi) saturated aqueous cobalt (ii) chloride; (vii) saturated aqueous copper (Il) chloride; and (viii) 75% w/w aqueous orthophosphoric acid comprising 6% cobalt (II) orthophosphate.

One source of cobalt, dispersible in the cements formed from the above mentioned components by admixture with one or more thereof, was used: (ix) cobalt phosphate cement (from cobalt (II) hydroxide and 60% orthophosphoric acid at a p:1 :1:1 g/ml); and (x) cobalt (II) phosphate.

The components were mixed together at the ratio shown in Table 7a below and were packed into cylindrical moulds 12 mm x 6 mm diameter. These were then sealed for 36 hours at the curing temperature shown to form cylindrical devices. The devices were next incorporated in distilled demineralized water and the in vitro release of cobalt was monitored by atomic absorption spectrophotometry.

Results are shown in Table 7b.

TABLE 7A

base acid curing Cement component component ratio temperature ( C) 41 (i) (vi) (i):(vi)::1.75g:1ml 37 42 (ii) (vii) (ii):(vii):2g:1 ml 37 43 (i) + (x) (iii) (i) :(x):(iii):: 1 .2g:O.2g:1 ml 37 44 (i) (v) (i):(v)::1.5g:1 ml 37 45 (i) (viii) (i):(viii) ::2g:1 ml 37 46 (i) + (ix) (iii) (i):(ix) :(iii) :1 .Og:0.2g: 1 ml 37 47 (i) + (x) (iii) (i) :(x) :(iii) :: 1 .2g :0.05g: 1 ml 37 48 (i) + (ix) (iii) (i):(ix):(iii)::1.0g:0.5g:1 ml 37 49 (i) (iv) (i):(iv)::1.2g:1 ml 37 50 (i) (viii) (i):(viii)::1.5g::1ml 37 TABLE 7B Cu and Co leached/day (% w/w of cement)

after 1 day after 15 days after 22 days after 29 days after 36 days after 43 days Cement Cu Co Cu Co Cu Co Cu Co Cu Co Cu Co Comments 41 0.005 0.094 0.005 0.041 0.020 0.37 42 0.004 0.52 0.002 0.022 43 1.43 0.49 0.27 0.042 0.182 0.016 0.037 0.002 44 0.016 0.12 0.012 0.021 0.017 0.022 0.028 0.022 0.043 0.027 0.036 0.023 reasonable Co release rate 45 0.070 0.042 0.080 0.041 0.002 46 2.13 0.64 0.059 0.018 0.090 0.024 0.168 0.037 0.128 0.022 0.081 0.018 47 1.19 0.042 0.40 0.018 0.26 0.007 0.003 0 48 0.99 1.03 0.026 0.020 0.056 0.025 0.107 0.031 49 1.02 0.71 0.29 0.011 0.25 0.005 0.031 0 50 0.42 0.256 0.028 0.006 EXAMPLE 8 This Example describes the preparation and testing of cylindrical devices of copper comprising selenites dispersed therein.

One source of base cement-forming component was used which was (i) copper (II) oxide; Four sources of acid cement-forming component were used: (ii) 90% w/w aqueous orthophosphoric acid; (iii) saturated aqueous copper (II) chloride; (iv) 90% w/w aqueous orthophosphoric acid comprising 5% w/w zinc selenite; and (v) 90% w/w aqueous orthophosphoric acid comprising 5% w/w copper (II) selenite; (viii) 90% w/w aqueous orthophosphoric acid comprising 5% w/w calcium selenite; (ix) 90% w/w aqueous orthophosphoric acid comprising 5% w/w calcium selenate.

Two sources of solid selenites, dispersible in the cement formed from the above mentioned components by admixture with one or more thereof, were used: (vi) copper (II) selenite (ex BDH); and (vii) zinc selenite (ex Fluka).

The components were mixed together at the ratio shown in Table 8a below and were packed into cylindrical moulds 12 mm x 6 mm diameter. These were then sealed for 36 hours at the curing temperature shown to form cylindrical devices. The devices were incorporated in distilled demineralized water and the in vitro release of selenium was monitored by heated graphite furnace atomic absorption spectrophotometry.

Results are shown in Table 8b.

TABLE 8A

base acid curing Cement component component ratio temperature (OC) 51 (i) + (vi) (ii) (i) :(vi):(ii)::1.29 :0.05g:1 ml 37 52 (i) + (vi) (ii) (i):(vi):(ii)::1 .2g:O.2g:1 ml 37 54 (i) + (vii) (iii) (i):(vii):(iii)::1 .5g:O.1 g:1 ml 37 55 (i) + (vi) (iii) (i):(vii):(iii)::1.5g:0.1g:1ml 37 56 (i) (iv) (i):(iv)::2g:1 ml 37 57 (i) (v) (i):(v)::2g::1 ml 37 58 (i) + (vi) (iii) (i):(vi):(iii)::1.5g:0.2g:1ml 37 59 (i) + (vii) (iii) (i):(vii):(iii)::1.5g:0.2g:1 ml 37 62 (i) + (vi) (ii) (i):(vi):(ii)::4g:1 g:1 ml 37 63 (i) + (vi) (ii) (i):(vi):(ii)::2g:0.2g:1 ml 37 151 (i) (viii) (i):(viii)::1 g:1 ml 37 152 (i) (ix) (i):(ix)::1 g:1 ml 37 153 (i) (iv) (i):(iv)::1 g:1 ml 37 1 54 (i) + (vii) (ii) (i):(vii):(ii)::1 .2g:O.2g: :1 ml 37 155 (i) + (vi) (ii) (i):(vi):(ii)::2g:O.2g:1 ml 37 TABLE 8B Cu and Se leached/day (% w/w of cement)

after 15 day after 22 days after 29 days after 36 days after 43 days Cement Cu Se Cu Se Cu Se Cu Se Cu Se Comments 51 0.29 0.007 0.23 0.007 0.21 0.005 52 0.082 0.011 0.24 0.026 0.23 0.021 54 0.018 0.006 0.011 0.006 0.007 0.006 0.006 0.005 55 0.016 0.002 0.015 0.002 0.014 0.010 0.012 0.003 56 0.22 0.007 0.15 0.007 0.062 0.003 57 0.23 0.010 0.15 0.005 0.071 0.004 58 0.001 0.001 0.008 0.001 59 0.014 0.003 0.010 0.003 0.007 0.005 62 1.02 0.004 0.003 0.001 63 0.15 0.012 0.062 0.012 151 0.30 0.016 0.19 0.009 0.146 - 0.170 0.006 152 0.43 0.012 0.28 153 0.46 0.016 0.29 0.009 154 0.42 0.042 0.30 0.063 0.39 0.062 more stable; higher Se release 155 0.32 0.026 0.20 0.023 0.19 0.028 stable Se releas EXAMPLE 9 This Example describes the preparation and testing of cylindrical devices of, in the main, oxyhalideand oxychalocogenate cements.

Six sources of base cement-forming component were used: (i) zinc oxide; (ii) cobalt (II) hydroxide; (iii) cobalt (II) carbonate; (iv) copper (II) oxide, finely ground; (v) copper (II) oxide, calcined at 1 2000C; The following other cement-forming components were used:: (vi) saturated (60% w/w) zinc sulphate aqueous solution; (vii) saturated (50% w/w) zinc iodide aqueous solution; (viii) saturated (65% w/w) cobalt (II) sulphate aqueous solution; (ix) saturated (50% w/w) cobalt (II) iodide aqueous solution; (x) saturated (65% w/w) copper (II) sulphate aqueous solution; (xi) 90% w/w aqueous orthophosphoric acid; (xii) copper (II) iodate; (xiii) saturated (75% w/w) copper (II) chloride aqueous solution; (xiv) saturated (50% w/w) zinc chloride aqueous solution.

The components were mixed together at the ratio shown in Table 9a below and were packed into cylindrical moulds 12 mm x 6 mm diameter. These were then sealed for 36 hours at the curing temperature shown to form cylindrical devices. The devices were incorporated in distilled demineralized water and the in vitro release of cobalt, copper, zinc and iodine was monitored by atomic absorption spectrophotometry.

Results are shown in Table 9b.

TABLE 9A

base acid curing Cement component component ratio temperature (OC) 65 (i) (viii) (i):(viii)::2g:1 ml 37 66 (ii) (iv) (ii):(iv)::2.4g:1 ml 37 67 (i) (ix) (i):(ix)::1.0g:1 ml 37 68 (ii) (vii) (ii) :(vii) :1.0g:1 ml 37 69 (iii) (vii) (iii):(vii):1 .Og:1 ml 37 70 (i) (x) (i):(x)::2.2g:1 ml 37 71 (iv) (vi) (iv):(vi)::4.0g::1 ml 37 72 (iv) (xii) + (xi) (iv):(xi):(xii)::1 .5g:1 ml:0.5g 37 73 (v) (vii) (v):(vii)::1 g:1 ml 37 74 (i) (ix) (i):(ix)::1 g:1 ml 37 75 (i) (xiii) (i) (xiii) ::1 g: 1 ml 37 76 (ii) (xiv) (ii):(xiv)::2g:1 ml 37 TABLE 9B Trace elements leached/day (% w/w of element)

after 1 day after 15 days after 22 days after 29 days after 36 days after 43 days Cement Zn Co Zn Co Zn Co Zn Co Zn Co Zn Co 65 0.034 0.086 0.022 0.053 0.015 0.035 0.015 0.028 0.015 0.023 0.010 0.019 66 0.013 2.47 0.011 0.017 0.002 0.011 0.002 0.015 0.001 0.011 0.001 0.009 67 1.54 2.18 0.011 0.019 0.038 0.010 68 0.025 2.31 0.090 0.060 0.007 0.026 0.006 0.021 0.005 0.019 0.004 0.015 69 1.16 2.03 0.011 0 0.010 0 0.012 0 0.013 0 0.003 0.020 Zn Cu Zn Cu Zn Cu Zn Cu Zn Cu Zn Cu 70 0.094 0.003 0.026 0 0.018 0 0.017 0 0.013 0 0.012 0 71 0.153 0.008 0.031 0.007 0.020 0.011 Cu I Cu I Cu I Cu I Cu I Cu I 72 0.184 0.116 0.120 0.120 0.064 0.118 0.056 0.069 73 0.048 0.012 0.020 0.015 0.012 Co I Co I Co I Co I Co I Co I 74 2.18 0.019 0.105 0.010 0.060 0.050 Cu Zn Cu Zn Cu Zn Cu Zn Cu Zn Cu Zn 75 0.004 1.19 0.004 0.053 0.005 0.092 0.005 0.066 0.005 0.040 0.006 0.025 Co Co Zn Co Zn Co Zn Co Zn Co Zn 76 1.36 0.086 0.055 0.021 0.038 0.012 0.023 0.011 0.018 0.009 0.019 0.009 EXAMPLE 10 This Example describes the preparation and testing of cylindrical devices of a copper phosphate cement comprising nicotinamide.

The components were mixed together in the ratio 1.3 g CuO: 1.0 ml of 90% phosphoric acid: and 0.2 g nicotinamide; and were then packed into cylindrical moulds 12 mm x 6 mm diameter. These were then sealed for 36 hours at 370C.

The devices were next incorporated in distilled demineralised water and the in vitro release of the nicotinamide was monitored by UV absorption spectrophotometry.

The results are shown in Table 10.

TABLE 10

Time (days) % nicotinamide released 1 17.6 2 25.5 3 31.4 6 43.0 7 45.9 8 49.0 9 52.1 10 55.3 13 64.6 15 671 EXAMPLE 11 Proceeding in essentially the same manner as in Examples 5 to 9 a variety of cements were prepared; their compositions, preparation and release rates are shown in the following Tables 11 to 13 inclusive.

TABLE 11 Trace elements leached/day (% w/w of cement)

Ratio Day 16 Day 22 Day 29 Day 36 Day 43 of Cement components Cu Zn/Mg Se Cu Zn/Mg Se Cu Zn/Mg Se Cu Zn/Mg Se Cu Zn/Mg Se CuO(fine) + 50% Galllc Acid + ZnSeO3 3g:1ml:0.5g 0.004 0.015 0.03 0.004 0.020 0.024 0.005 0.014 0.023 0.005 0.013 0.0257 0.003 0.0105 0.022 CuO(fine) + 50% Mellitic acid + ZnSeO3 3g:1ml::0.5g 0.013 0.012 0.03 0.009 0.014 0.026 0.011 0.009 0.026 0.008 0.008 0.016 0.009 0.007 0.014 CuO(fine) + 50% Phytic Acid + ZnSeO3 3g:1ml:0.5g 0.0027 0.0029 0.015 0.002 0.005 0.011 0.003 0.002 0.008 0.001 0.002 0.012 0.0007 0.002 0.008 CuO(fine) + 50% Pentan (COOH)3 + ZnSeO3 3g:1ml:0.5g 0.019 0.014 0.023 0.016 0.019 0.021 0.014 0.011 0.023 0.007 0.009 0.014 0.009 0.008 0.011 CuO(fine) + 50% Tannic Acid + ZnSeO3 3g:1ml::0.5g 0.001 0.008 0.015 0.002 0.009 0.010 0.001 0.007 0.017 0.002 0.006 0.013 0.004 0.006 0.006 MgO + CuSeO4 (satd. (25%)) 1.2g:1ml 0 0.055 0.093 0 0.036 0.069 0 0.029 0.041 0 0.028 0.035 0 0.026 0.028 ZnO + CuSeO4 " " 2g:1ml 0 0.035 0.018 0 0.019 0.015 0 0.015 0.012 0 0.011 0.012 0 0.012 0.010 CuO + ZnSeO4 " (50%) 4g::1ml 0.007 0.027 0.046 0.015 0.005 0.062 - - - - - - - - CuO + 90% H3PO4 + BaSeO4 (fine) 3g:1ml:1g - 0.024 0.004 - 0.023 0.002 - 0.021 0.001 - 0.020 0.002 - 0.018 CuO + 90% H3PO4 (fine) + ZnSeO3 (95 C) 1.2:1ml:0.4g 0.013 - 0.026 0.012 - 0.022 0.053 CuO + 90% H3PO4 (fine) + ZnSeO3 (95 C) 1.2:1ml:0.2g 0.105 - 0.037 0.057 - 0.021 0.041 TABLE 12 Trace elements leached/day (% w/w of cement)

Ratio Temp. Day 16 Day 22 Day 29 Day 36 Day 43 of of Cement components cure Co Zn/Mg Se Co Zn/Mg Se Co Zn/Mg Se Co Zn/Mg Se Co Zn/Mg Se Cu(OH)2 + 50% Malic Acid + ZnSeO3 2g:1ml:0.2g 37 0.135 0.003 0.017 0.127 0.003 0.012 0.078 0.002 0.007 0.057 0.002 0.006 0.038 0 0.005 Co(OH)2 + 50% Mellitic Acid + ZnSeO3 1.6g:1ml::0.2g 37 - - 0.004 0.001 0 - 0.006 0 - - - - - - Co(OH)2 + 50% Pentan (COOH)3 + ZnSeO3 2g:1ml:0.2g 37 - - 0.003 0.101 0 - 0.07 0 - - - - - - Co(OH)2 + 50% Pyruvic Acid + ZnSeO3 2g:1ml:0.2g 37 0.053 0.002 0.013 0.05 0.002 0.009 0.038 0.001 0.014 0.043 0.001 0.014 0.036 0.001 0.012 Co(OH)2 + 50% m-Tartaric Acid + ZnSeO3 2g:1ml::0.2g 37 0.201 0.016 0.028 0.21 0.015 0.018 0.116 0.007 0.026 0.144 0.009 0.028 0.097 0.006 0.016 Co(OH)2 + 50% Tannic Acid + ZnSeO3 2g:1ml:0.2g 37 0.061 0.004 0.027 0.047 0.004 0.021 0.040 0.003 0.020 0.048 0.003 0.017 0.038 0.023 0.024 Co(OH)2 + CoSeO4 (A) 2g:1ml 95 0.069 - 0.103 0.067 - 0.114 0.056 - 0.085 0.043 - 0.062 0.041 - 0.052 MgO + CoSeO4 (A) 1.3g: :1ml 37 0.016 0.049 0.114 0 0.031 0.104 0 0.031 0.070 0 0.025 0.058 0 0.026 0.052 ZnO + CoSeO4 (A) 2g:1ml 37 0.017 0.016 0.046 0.014 0.014 0.045 0.012 0.090 0.03 0.007 0.086 0.027 0.010 0.010 0.028 Co(OH)2 + ZnSeO4 (A) 2.4g::1ml 37 0.022 0.0017 0.023 0.013 0.0001 0.02 0.010 0 0.012 0.007 0.001 0.013 0.007 0 0.009 A = 50% solutions TABLE 13 Trace elements leached/day (% w/w of cement)

Ratio Temp of of Day 16 Day 22 Day 29 Cement components cure Mg Zn Se Mg Zn Se Mg Zn Se MgO + MgSeO4 (A) 1:2g:1ml 37 - - 0.0988 0.059 - 0.119 0.050 - 0.114 MgO + ZnSeO4 (A) 1.0g::1ml 37 - 0 0.110 0.031 0.004 0.115 0.034 0 0.083 ZnO + ZnSeO4 (A) 2.0g:1ml 37 - 0.0 0.053 - 0.031 0.056 - 0.025 0.046 Cu Co Se Cu Co Se Cu Co Se Co(OH)2 + CuSeO4 (B) 2.0g:1ml 37 0 0.029 0.013 0 0.025 0.006 0 0.017 0.004 Day 36 Day 43 Mg Zn Se Mg Zn Se MgO + MgSeO4 (A) 1:2g:1ml 37 0.051 - 0.096 0.054 - 0.098 MgO + ZnSeO4 (A) 1.0g::1ml 37 0.029 0 0.074 0.030 0 0.067 ZnO + ZnSeO4 (A) 2.0g:1ml 37 - 0.021 0.041 - 0.021 0.040 Cu Co Se Cu Co Se Co(OH)2 + CuSeO4 (B) 2.0g:1ml 37 0 0.020 0 0.024 0.002 TABLE 13 (Continued) Trace elements leached/day (% w/w of cement)

Ratio Temp of of Day 16 Day 22 Cement components cure Cu Co Zn Se Cu Co Zn Se CuO(fine) + 1.2g: Co3(PO4)2 + 0.2g: ZnSeO3 + 90% H3PO4 0.2g::1ml 95 0.138 0.195 0.03 0.04 0.099 0.044 0.026 0.033 Day 29 Day 36 Cu Co Zn Se Cu Co Zn Se CuO(fine) + 1.2g: Co3(PO4)2 + 0.2g: ZnSeO3 + 90% H3PO4 0.2g:1ml 95 0.091 0.033 0.023 0.033 0.062 0.018 0.013 0.019 A = 50% solutions B = 25% solutions EXAMPLE 12 Fourteen cylindrical devices (20 mm x 12 mm) of cement 11 7, mean weight 4.78 g (ranging from 4.60 g to 5.25 g), were provided.Two devices were dissolved in hydrochloric acid for analysis of initial copper content (by atomic absorption spectrophotometry) and the remainder were placed, in groups of four devices, into three polypropylene mesh bags which were then inserted into the reticulum of a cow having a fistulated rumen. The devices were removed at regular intervals, weighed, and replaced save that, at each such weighing, one device was dissolved in hydrochloric acid for analysis of the remaining copper content.

Over the 72 day period of the experiment the mean weight of the devices was found to decrease approximately linearly by 0.26%/day (ranging from 0.18 to 0.38%/day), although extrapolation to zero time suggests an initial weight increase of approximately 3%. The copper content of the devices was found to decrease from an initial 33.8% to a mean of 32.7% by weight (ranging from 30.7 to 35.0%). All of the devices maintained their cylindrical geometry in vivo.

EXAMPLE 13 Ten cylindrical devices (20 mm x 12 mm) of cement 119, mean weight 4.35 g, were treated in essentially the same manner as in Example 12. The mean weight of the devices was found to decrease approximately linearly by 0.4%/day with an initial weight increase of approximately 15%. The copper content of the devices was found to decrease from an initial 37.7% to a mean of 32.8% by weight. The geometry of the devices became irregular in vivo.

EXAMPLE 14 Fourteen cylindrical devices (20 mm x 12 mm) of cement 118, mean weight 8.9 g, comprising 50% by weight of stainless steel as filler were provided. These were treated in essentially the same manner as those of Example 12. Apart from a 14 day period (days 14 to 28) (in which the host cow had a jaw infection and was not eating), the devices lost weight at an approximately linear rate of 7 mg/day (2.3 mg Cu/day). After day 70 the rate increased to 9.5 mg/day (3.2 mg Cu/day).

EXAMPLE 15 Twenty cylindrical devices (18 mm x 45 mm) of cement 117 comprising 50% by weight stainless steel as filler, mean weight 39.9 g, were provided. One was retained for analysis of initial copper content and the remainder were given, one each, by mouth to 1 9 sheep. The sheep were then X-rayed; and it was confirmed that each device resided in the host's reticulum. Four sheep were slaughtered after 1 month, 5 after 2 months,5 after 4 months and the last 5 were slaughtered after 6 months.

The devices were recovered at slaughter, as was each host liver, and both were analyzed for copper content. Results are shown in Table 14.

TABLE 14

Liver Cu content Months in Mean wt. devices (g) Mean Cu content (ppm. wet wt.) reticulum ~ ~ wet dessicated of device (g) mean range 0 39.9 1 39.6 37.0 5.38 97 47-174 2 39.6 36.8 5.61 93 50-148 4 38.7 36.4 5.64 114 59-151 6 39.6 37.0 5.54 182 127-287 All of the devices retained their geometry in vivo but were coated in a thin layer of black material. All remained in the reticular of the respective hosts.

EXAMPLE 16 Eight cylindrical devices (20 mm x 20 mm) of cement 47, mean weight 13.58 g, were provided.

Two devices were analysed for initial copper and cobalt content in essentially the same manner as in Example 12 and the remainder were placed in the reticulum of a cow having a fistulated rumen. The devices were weighted at intervals for 64 days. Analytical results were shown in Table 1 5.

TABLE 15 Cu Co Initial content (%) . 33.5 0.60 After 64 days in reticulum (% initial weight) 31.8 0.44 % dissolved 5 27 g released 0.22 0.22 The results suggest that this cement has limited solubility in vivo.

EXAMPLE 17 Six cylindrical devices (20 x 20 mm) of cement 43, mean weight approximately 14 g, were provided. Two devices (A and B) were analysed for initial copper and cobalt content and the remainder were placed in the reticulum of a cow having a fistulated rumen. Two devices (1 and 2) were removed for analysis after 21 days and the last two (3 and 4) after 41 days. Analytical results are shown in Table 16.

TABLE 16 Copper and cobalt contents of devices after incubation in reticulum Initial Days in Weight Cu Original Cu loss Co Original Co loss Device wt. (g) reticulum change (g) Cu (g) (g) (mg) Co (mg) (mg) A 13.772 0 0 2.51 2.51 351 351 B 13.720 0 0 2.34 2.34 350 350 1 13.920 21 +0.812 2.23 2.45 0.22 332 355 23 2 13.593 21 +0.639 2.21 2.39 0.18 328 347 19 3 14.127 41 +0.243 2.07 2.49 0.42 328 360 32 4 14.248 41 +0.165 2.08 2.51 0.43 324 363 39 It will be seen from Table 16 that although the devices have not lost weight nonetheless they have been releasing copper and cobalt at an approximate rate, respectively, of 10 mg Cu/day and 0.9 mg/Co/day.

EXAMPLE 18 Eighteen cylindrical devices essentially the same as those of Example 1 7 were provided. Six devices were analysed for initial copper and cobalt content and the remainder were given, one each, by mouth to 12 three month old Finn x Dorset sheep. Ten similar sheep were used as control animals. All the sheep grazed pasture until their slaughter between 98 and 133 days after administration of the device. Blood samples were taken for Cu analysis before dosing and at slaughter. All the devices and the livers were recovered at slaughter and analysed for Cu content.

The mean content of original devices was 36.7% Cu and 2.2% Co. There were no significant differences in the weight of the pellets resulting from incubation in the reticula but the Cu and Co content decreased resulting in an average loss of 3.9 mg Cu/ (ranging from 1.7 mg to 8.2 mg Cut and 0.32 mg Co/ (ranging from 0.05 to 0.67 mg Co/) day.

These rates are similar to those determined in the cow in Example 1 7. No significant differences could be detected between treated and untreated sheep with respect to blood or liver copper concentration; but none of the sheep could be considered to be copper deficient.

EXAMPLE 19 Eight cylindrical devices (20 mm x 20 mm) of cement 154 were provided. Two devices were analysed for initial copper content while the remainder were placed in the reticulum of a cow having a fistulated rumen. Two devices were removed for analysis after 28 days, 2 after 56 days and 2 after 87 days.

Weight changes were erratic. When the devices were analysed those which had not been in the reticulum were compietely soluble but an insoluble orange-red residue, which increased in amount with incubation time in the reticulum, formed within the remainder.

Copper analyses (duplicate) gave release rates of: 8 and 0 mg Cu per day over 28 days 6 and 9 mg Cu per day over 56 days 6 and 0 mg Cu per day over 87 days EXAMPLE 20 Nine cylindrical devices (24 mm x 12 mm) of the cement shown on page 47 were provided. Three devices (A, B, C) were analysed for initial copper and cobalt content and the remainder (D to I) were placed in the reticulum of a cow having a fistulated rumen.

The results are shown in Table 17.

TABLE 17

Cu content Co content Weight Device (g) (9) (%) (mg) (%) A 15.63 5.10 32.6 30 & 1.96 B 15.84 5.24 33.0 288 1.82 C 15.51 5.08 32.7 290 1.87 Cu loss Co change Device Days Wt. change (g) (mg/day) (mg) (mg/day) D 29 +4% 0.50 17.2 -37 -1.3 E 29 +2% 0.06 2.1 -28 -1.0 F 63 +6% 0.23 3.7 +32 +0.5 G 63 +8% 0.11 1.7 +6 0 H 106 +5% Q46 4.3 +1 0 I 106 +4% 0.23 2.2 +3 0 EXAMPLE 21 Seven cylindrical devices 24 mm x 12 mm of the cement shown on page 47 but comprising Co58 were given, one each, by mouth to sheep. The sheep were radiocounted at intervals after administration. One was then slaughtered after 29 days; another after 93 days.In both cases the device was recovered and the radioactivity of the carcass, recovered device, liver and gastrointestinal tract was measured. Approximately 1% of the total radioactivity remained after removal of the device: one third in the carcass and two thirds in the gastrointestinal tract.

Initial results are shown in Table 18.

TABLE 18 Cobalt loss from pellets 29 days 93 days Loss by in vivo count 26% 23% Loss by in vitro count 25% (0.79 mg/kg) 23% (0.33 mg/day) Loss by analysis (at. Abs.) 9 (gain of 12 mg) 20% (0.29 mg/day) Loss of Cu (by analysis) 0.25 g (13%) 0.65 g (39%) mg Cu/day 6.4 7.0 Weight loss 12% '4% Continuing experimentation has shown an approximately constant rate of release of cobalt to a maximum of 1 60 to 210 days (depending on host) with a release of up to 65% of the cobalt. An average rate of release was approximately 0.5 mg Co/day.

EXAMPLE 22 In this Example, livestock of Warren Farm, Lambourn, Berkshire, an area naturally deficient in selenium and copper, was divided into four groups, the first being a control and receiving no trace element supplement; the second receiving injected trace element supplement; the third receiving a proprietary preparation; and the fourth receiving devices of the invention as used in Example 21 but also comprising kaolin. The livestock comprised yearling Hereford x Friesian steers.

A significant increase in carcass weight, up to 20 kg in the cattle, was found in the cattle.

Claims (38)

1. A sustained release device which comprises a source of at least one trace chemical element incorporated in a cement and releasable therefrom on contact with an aqueous medium.

2. A sustained release device according to Claim 1 wherein at least one trace chemical element is an intrinsic component of the cement.

3. A sustained release device according to Claim 1 or 2 wherein at least one trace chemical element is dispersed in the cement.

4. A device according to any preceding claim wherein the cement comprises a hydraulic cement.

5. A device according to any preceding claim wherein the cement comprises a reaction cement.

6. A device according to Claim 5 wherein the cement comprises an acid-base reaction cement.

7. A device according to Claim 6 wherein the cement is formed from an acid cement-forming component which comprises a mineral acid, an acid salt, a Lewis acid, a polyfunctional organic carboxylic acid, a polyfunctional organic phosphoric acid, a polyfunctional phenol, a homo- or Co- polymer of an unsaturated carboxylic acid, a homo- or co-polymer of an unsaturated sulphonic acid, or a hydrolysable precursor thereof.

8. A device according to Claim 7 wherein the acid cement-forming component is in aqueous solution.

9. A device according to any of Claims 5 to 8 wherein the cement is formed from a base cementforming component which comprises a basic or amphoteric oxide or hydroxide, or a salt of a weak or volatile acid.

10. A device according to any of Claims 5 to 9 wherein the cement comprises a phosphate cement.

11. A device according to any of Claims 5 to 9 wherein the cement comprises a basic halide, basic chalcogenate, or a carboxylate cement.

12. A device according to any preceding claim wherein the trace chemical element comprises at least one of Cu, So, Se or I.

1 3. A device according to any preceding claim which also comprises at least one active substance other than a trace chemical element.

1 4. A device according to Claim 1 3 wherein the at least one active substance other than a trace chemical element is a substance having a medicinal effect.

1 5. A device according to any preceding claim which comprises a dosage form.

16. A device according to any preceding claim which is an integral body of cement.

1 7. A device according to any preceding claim which comprises a weighting agent.

1 8. A device according to any preceding claim which is a cylindrical dosage form.

1 9. A process for the preparation of a device according to any preceding claim, which process comprises preparing a cement-forming mixture in which is incorporated a source of at least one trace chemical element; investing a mould with the mixture; and permitting the cement-forming mixture to cure in the mould.

20. A process according to Claim 1 9 wherein the cement is subjected to a post-curing treatment at an elevated temperature.

21. A particulate composition reactable in the presence of a polar liquid to form a device according to any of the preceding claims.

22. A particulate composition according to Claim 21 wherein the polar liquid comprises water.

23. A pack which comprises a particulate composition, a polar liquid reactable with the composition to form a device according to any of Claims 1 to 18, and separating means to prevent accidental reaction of the particulate composition with the polar liquid.

24. A device prepared from a particulate composition defined in any of Claims 21 to 23, or prepared by the process defined in Claim 1 9 or 20.

25. A source of at least one trace chemical element, optionally with at least one active substance other than a trace chemical element, incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in prophylaxis or therapy.

26. Magnesium incorporated in a cement, or a particulate composition reactablein the presence of, or with, a polar liquid to form the same, for use in the prophylaxis or therapy of grass tetany, especially in lactating cows and ewes.

27. Iron incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in the prophylaxis or therapy of anaemia, especially in sucking pigs.

28. Iodine incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in the prophylaxis of goitre.

29. Copper incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, to facilitate anabolism in young pigs or ruminants.

30. Cobalt incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in the prophylaxis or therapy in sub-clinical growth retardation or of enzootic marasmus in sheep or cattie.

31. Manganese incorporated in a cement, or a particulate composition reactable in the presence of, or with, a polar liquid to form the same, for use in the prophylaxis or therapy of perosis or nutritional chondrodystrophy in poultry or manganese deficiency in ruminants.

32. Livestock, whenever administered with a sustained release device according to any of Claims 1 to 18Or24.

33. Livestock, whenever administered with an active substance according to any of Claims 25 to 31.

34. A cement in which a pluraiity of trace metals is incorporated.

35. An acid oxyselenate cement.

36. An acid phosphate cement.

37. A cement in which sources of Cu, So and Se are incorporated.

38. An integral body of a cement comprising at least one trace chemical element and, dispersed therein, at least one different trace chemical element and/or at least one active substance other than a trace chemical element.