GB2123690A - Sustained release device - Google Patents

Abstract

The device has at least one active substance incorporated in a cement and releasable therefrom on contact with an aqueous medium. The active substance may be a chemical element needed in plant or animal metabolism or other substance having a medicinal effect, e.g. a pesticide or a drug. Many examples of suitable "cements" and active substances are listed.

Description

21. 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.

22. 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.

23. 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.

24. 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.

25. 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 subclinical growth retardation or of enzootic marasmus in sheep or cattle.

26. 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.

27. Livestock, whenever administered with a sustained release device according to any of Claims 1 to 15 or 19.

28. Livestock, whenever administered with an active substance according to any of Claims 20 to 26.

SPECIFICATION Sustained release device 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 require trace but sustained amounts of a number of chemical elements. Furthermore, ever more intensive systems of animal husbandry dicatate that these requirements have to be rigorously adhered to.

In the Preliminary Table below, approximate minimum requirements, expressed in ppm. of dry dietary 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 both 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 1 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 ') 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-l, especially in the spring.) 2? 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 at least one active substance incorporated in a cement and releasable therefrom on contact with an aqueous medium. At least one active substance may be an intrinsic component of the cement and/or at least one active substance may be dispersed in the cement.

Such devices have also been found suitable for other uses 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 herbicides at a locus; of magnesium for tomato crops or of copper as a fungicide; and in the sustained provision of antifouling agents 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 trace provision of chemical elements) or the reduction or eradication of an undesired effect (e.g. the removal of fungi at a locus attained by provision of copper). 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 the administration of which in vivo has a prophylactic or therapeutic effect.

The term "cement" as used herein means the coherent mass formed by reaction from at least one settable substance (but excludes covalently cross-linked organic thermoset materials) rather than the cement-forming 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 Lewis or Bronsted acid and at least one other cement-forming component is a Lewis or Bronsted base. Examples include acid phosphate, nitrate, sulphate, oxyphosphate 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.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 hydroxy-carboxylic acids and ketoacids.Examples are lactic, pyruvic, 2- hydroxyisobutyric, 2-hydroxycyclohexane carboxylic, 2-hydroxy-2-phenyl propionic, diphenylhydroxyacetic, 2-hydroxybenoic, 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 polyacrylonitriles. The hydrolysable precursor of a poly(carboxylic acid) may be a homo-polymer of an unsaturated carboxylic acid anhydride 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 acidcement 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, "Ti(OH)4", "Zr(OH)4", V2O5, Fe2O3, Cu2O, CuO, ZnO, preferably calcined, AI2O3 xH2O 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-leachable 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 with 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, 1 5 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 fluoraluminosilicate 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 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 active substances releasable at a sustained rate. Examples of classes of active substances which may be incorporated in the sustained release devices of the present invention include pharmaceuticals, bacteriostats, viruscides, herbicides, pesticides such as insecticides, nematicides, molluscicides and larvicides, fungicides, topical or dermatological agents, proteins, for example enzymes, peptides, veterinary formulations for the trace provision of chemical elements, and other growth promoting factors used in agriculture, horticulture and animal husbandry, for example fertilisers, anti-anaemic preparations and anabolic steroids. Of particular interest are compositions of the present invention comprising, as active substance, at least one substance having a medicinal effect.

The compositions of this invention thus find wide application in veterinary contexts.

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 and other antimicrobials, preparations containing hormones, for example androgenic, estrogenic and progestational hormones, notably steroids such as oestradiol, sympathomimetic agents, hypoglycaemic agents, nutritional agents1 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 verterinary application. Mixtures of active substances may be incorporated into the sustained release devices of the invention.

It is particularly preferred, however, that the active substance comprises a source of chemical element, especially of one or more of the following: Cr, Mn, Fe, Co, Ni, Cu, Zn, Mo, Se and I. Magnesium is also an element which can be provided from a device in accordance with this invention. This invention is particularly suited to sustained provision of sources of one or more of the following chemical elements: Mg, Fe, I, Cu, Co, Mn, Zn or Se.

The source of 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 chemical elements in cements which are themselves sources of one or more (or indeed no) other or same 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 substance (other than a chemical element) having a medicinal effect.

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 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. 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 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 an active substance 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 prophylaxi's 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 administered with a sustained release device or an active substance as herein defined.

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 s Baltic Co.); and (ii) a magnesium aluminosilicate glass prepared by fluxing together 1 80 parts magnesium carbonate, 1 80 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 alumina; (iv) 50% w/w aqueous orthophosphoric acid comprising 2.5% w/w alumina; and (v) 50% w/w aqueous orthophosphoric acid comprising no aluminium.

The components were mixed together at the ratio shown in Table la below and were packed into cylindrical mounts 12 mm x 6 mm diameter. These were then sealed for 36 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 Ib.

TABLE la

\ compressive | base acid setting time (h) strength component component powder:liquid 23 C and 50% after Cement (powder) (liquid) ratio (g/ml) 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) (iii) 3.5 6.5 2 TABLE 1b

Mg leached/day (% w/w of cement) after Cement 1d 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 base acid after weight loss/day Cement component component 1 d 8d 15d (% w/w of 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 were used. They were mixed, essentially as in Example 1 at a powder:liquid ratio of 4 g:5 ml. 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 3

Magnesium pH Mg leached/day (% w/w of cement) oxide: leaching after original wt wt after % av.weight Cement liquide: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 5.5-6.04 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' 4:5::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 0.186 0.090 0.075 0.69 0.85 0.063 0.060 0.069 21.111 20.632 0.284 15' 3.5:3:15.5 5 1.315 0.757 0.602 0.411 --- --- --- --- 17.909 12.688 7.29 6 0.478 0.163 0.131 0.097 --- --- --- --- 18.373 17.090 1.75 5.5-6.04 0.601 0.245 0.167 0.136 --- --- --- --- 18.003 16.109 2.63 16' 3:1 ::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 liquid (iii) of Example 1 4 distilled demineralised water at a pH from 5.5 to 6.0 of dimensions 20 mm x 12 mm diameter of dimensions 20 mm x 20 mm 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 5629 Cow K839 device dimensions initial after after Cement (mm) wt.(g) lOd 20 d 30 d 10d 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 t Williams); (ii) copper (II) oxide calcined at 12000C; and (iii) copper (I) oxide (ex Hopkin # Williams).

Three sources of acid cement-forming component were used: (iv) copper (II) chloride (ex Fisons) (saturated aqueous solution); (v) 90% w/w aqueous orthophosphoric acid; and (vi) 100% polyphosphoric acid (ex Aldrich).

Two sources of copper, dispersible in the cements formed from the above mentioned components by admixture with one or more thereof were used: (vii) copper (I) chloride (ex Fisons) (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

base acid Cement component component | ratio 17 (i) + (iii) (v) (i):(iii):(v)::1.5 g:0.2 g:1.0 ml 18 (i) + (iii) (v) (i):(iii):(v)::1.5 g:0.5 g:1.0 ml 19 (i) (vii) + (v) (i):(vii):(v)::1.5 g:0.5 g:1.0 ml 20 (i) (viii) + (v) (i):(viii):(v)::1.5 g:0.5 g:1.0 ml 21 (i) (iv) (i):(v)::1.5 g:1.0 ml 22 (i) (vii) + (iv) (i):(iv):(v)::1.5 g:0.5 g:1.0 ml 23 (i) (vii) + (vi) (i):(iv):(viii):::1.5 g0.5 g:1 .0 ml 24 (ii) (v) (ii):(vii)::1.5 g:1.0 ml TABLE 5b

Cu leached/day (% w/w of cement) Cement l after 1 d afterl5d after29d 17 0.21 0.26 0.008 18 0.14 0.19 0.005 19 0.47 0.42 0.035 20 0.53 020 0.005 21 0.039 | 0.019 0.036 22 0.57 0.08 0.063 23 0.14 0.067 24 2.0 0.45 0.045 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 400 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).

Seven 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; and (xiv) 50% w/w aqueous tannic acid (ex Hopkin s Williams).

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

curing base acid temperature Cement component component ratio ( C) 25 (i) (ix) (i):(ix)::2 9:1 ml 37 26 (i) (x) (i):(x)::2.5 g:1 ml 37 27 (i) (xi) (i):(xi)::2.5 9:1 ml 37 28 (i) (viii) (i):(viii)::2.5 9:1 ml 95 29 (iii) (viii) (iii):(viii)::2.5 g:1 ml 95 30 (i) (x) (i):(x)::2 g:1 ml 37 31 (iv) (viii) (iv):(viii)::3.5 g::1 ml 95 32 (v) (x) (v):(x)::1.25g:1 ml 150 33 (v) (xii) (v):(xii)::1.25 g:1 ml 37 34 (v) + (iii) (xi) (v):(iii):(xi)::1.0 9:0.2 g:0.8 ml 37 35 (v) +(xv) (xi) (v):(viii):(xi)::1 .0 g:O.2 g:0.8 ml 37 36 (vii) (xiii) (vii):(xiii)::1.0 g:1 ml 37 37 (vi) (xi) (vi):(xi)::3.0 9:2 ml 37 38 (ii) (xiv) (ii):(xiv)::1 .5 9::1 ml 37 39 (i) (viii) (i):(viii)::Z.5 9:1 ml 37 40 (iv) (viii) (iv):(viii)::3.5 g:1 ml 95 TABLE 6b

Co leached/day (% w/w of cement) Cement after 15 d 22d 29d 36d 43d 50 d 25 0.031 0.036 0.036 0.036 0.038 0.036 26 0.010 0.014 0.020 0.015 0.015 0.018 27 0.016 0.018 0.017 0.019 0.024 0.024 28 0.065 0.065 0.064 0.063 0.067 0.064 29 0.033 0.021 0.031 0.020 0.024 0.022 30 0.007 0.014 0.020 0.015 0.015 0.018 31 0.123 0.106 0.056 0.036 0.028 0.022 32 0.009 0.011 0.013 0.023 0.020 0.018 33 0.009 0.012 - - - 34 0.017 0.011 disintegrated 35 0.028 0.019 0.026 0.023 0.028 0.028 36 0.076 0.050 0.054 0.021 0.047 0.036 37 0.014 0.017 0.025 0.028 disintegrated 38 0.036 0.028 0.030 0.032 0.035 0.026 39 0.048 0.047 0.067 0.038 0.035 40 0.049 0.037 0.029 0.028 0.018 0.014 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 150"0.

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 (II) chloride; and (viii) 75% w/w aqueous orthophosphoric acid comprising 6% cobalt.

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 in the in vitro release of cobalt was monitored by atomic absorption spectrophotometry.

Results are shown in Table 7b.

TABLE 7a

curing base acide temperature Cement component component ratio ( C) 41 (i) (vi) (i):(vi) .75 g:1 ml 37 42 (ii) (vii) (ii) :(vii) :2 g: 1 ml 37 43 (i) + (x) (iii) (i):(x):(iii)::1.2 g:O.2 g:1 ml 37 44 (i) (v) (i):(v)::1 .5 g:1 ml 37 45 (i) (viii) (i) :(viii) ::2 g 1 ml 37 46 (i) + (ix) (iii) (i):(ix):(iii)::1.0 g:2.0 g:1 ml 37 47 (i) + (x) (iii) (i):(x):(iii)::1.0 g:0.05 g:1 ml 37 48 (i) + (ix) (iii) (i):(ix):(iii)::1.0 g:0.5 g::1 ml 37 49 (i) (viii) (i):(viii)::1.5 g:1 ml 37 50 (i) + (ix) (iii) (i):(ix):(iii)::1.2 g:O.04 g:1 ml 37 TABLE 7b

Co leached/day (% w/w of cement) Cement after 1 d 15d 18d 22d 29d 41 0.094 0.041 - 0.037 disintegrated 42 0.52 0.022 - - 43 0.50 0.042 0.027 0.016 V. low release 44 0.121 0.0 0.022 0.022 0.022 45 0.042 0.041 0.019 0 46 0.64 0.018 0.019 0.024 0.037 47 0.042 0.016 0.011 0.007 0 48 1.03 0.020 0.023 0.018 0.018 49 0.071 0.012 0.008 0.005 0 50 0.26 0.005 - - 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 copper (II) oxide; Four sources of acid cement-forming component were used:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (1)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   TABLE 7a

   curing base acide temperature Cement component component ratio ( C) 41 (i) (vi) (i):(vi) .75 g:1 ml 37 42 (ii) (vii) (ii) :(vii) :2 g: 1 ml 37 43 (i) + (x) (iii) (i):(x):(iii)::1.2 g:O.2 g:1 ml 37 44 (i) (v) (i):(v)::1 .5 g:1 ml 37 45 (i) (viii) (i) :(viii) ::2 g 1 ml 37 46 (i) + (ix) (iii) (i):(ix):(iii)::1.0 g:2.0 g:1 ml 37 47 (i) + (x) (iii) (i):(x):(iii)::1.0 g:0.05 g:1 ml 37 48 (i) + (ix) (iii) (i):(ix):(iii)::1.0 g:0.5 g::1 ml 37 49 (i) (viii) (i):(viii)::1.5 g:1 ml 37 50 (i) + (ix) (iii) (i):(ix):(iii)::1.2 g:O.04 g:1 ml 37 TABLE 7b

   Co leached/day (% w/w of cement) Cement after 1 d 15d 18d 22d 29d 41 0.094 0.041 - 0.037 disintegrated 42 0.52 0.022 - - 43 0.50 0.042 0.027 0.016 V. low release 44 0.121 0.0 0.022 0.022 0.022 45 0.042 0.041 0.019 0 46 0.64 0.018 0.019 0.024 0.037 47 0.042 0.016 0.011 0.007 0 48 1.03 0.020 0.023 0.018 0.018 49 0.071 0.012 0.008 0.005 0 50 0.26 0.005 - - 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 copper (II) oxide; Four sources of acid cement-forming component were used:

   (i) 90% w/w aqueous orthophosphoric acid; (ii) saturated aqueous copper (II) chloride; (iii) 90% w/w aqueous orthophosphoric acid comprising 5% w/w zinc selenite; and (iv) 90% w/w aqueous orthophosphoric acid comprising 5% w/w copper (II) selenite.

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

   curing base acid temperature Cement component component ratio ( C) 51 (i) + (vi) (ii) (i):(vi):(ii)::1.2 g:0.05 g:1 ml 37 52 (i) + (vi) (ii) (i):(vi):(ii)::1.2 g:0.2 g:1 ml 37 53 (i) + (vii) (ii) (i) :(vii) :(ii) :: 1 .2 g:0.2 g: 1 ml 37 54 (i) + (vii) (iii) (i):(vii):(iii)::1.5 g:0.1 g:1 ml 37 55 (i) + (vi) (iii) (i):(vi):(iii)::1.5 g:0.1 g:1 ml 37 56 (i) (iv) (i):(iv)::2 g:1 ml 37 57 (i) (iv) (i):(v)::2 g:1 ml 37 58 (i) + (vi) (iii) (i):(vi):(iii)::1.5 g:O.2 g:1 ml 37 59 (i) + (vii) (iii) (i):(vii):(iii)::1.5 g:O.2 g:1 ml 37 60 (i) (v) (i):(v)::3 g: :1 ml 37 61 (i) (v) (i):(v)::4 g:1 ml 37 62 (i) + (vi) (ii) (i):(vi):(ii)::4 g:1 g:1 ml 37 63 (i) + (vi) (ii) (i):(vi):(ii)::2 g:0.2 g:1 ml 37 64 (i) + (vi) (ii) (i):(vi):(ii)::4 g:0.4 g:1 ml 37