Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/28—Compounds containing heavy metals
  • A61K31/30—Copper compounds

Definitions

• This invention relates to compositions and their administration, for addressing zinc responsive disorders. More specifically, the invention seeks to establish a lasting zinc depot in an animal, so as to increase its resistance to zinc responsive disorders such as facial eczema. The establishment of a lasting zinc depot also appears to infer resistance to other disorders. In addition, various aspects of the present invention may also be used as a therapeutic or remedial treatment for an animal inflicted with these disorders.
• facial eczema is a disorder rising through the ingestion of the spores of Pithomyces chartarum, which are found in great numbers on dead plant litter during warm, damp weather conditions.
• Present in the spores is the toxin sporidesmin which causes liver damage in an animal if ingested.
• Symptoms of facial eczema include photo- sensitivity and a tendency for animals to mutilate themselves by rubbing against standing objects. However not all animals exhibit these symptoms, and it is generally accepted that when 5% of a flock of lambs exhibit photo-sensitivity during an outbreak, about 50% will exhibit liver damage at slaughter.
• facial eczema occurs predominantly among grazing animals including sheep, catde, deer, goats and more exotic animals such as alpacas.
• New Zealand it has been recently stated that facial eczema costs New Zealand's farmers between NZ$80- 120 million each year, while the effective cost to the nation when the inability to farm sheep effectively in many areas, is in excess of NZ$500 million.
• Facial eczema which is not specific to New Zealand, can be addressed.
• One technique is to adopt farm management practices which reduce proliferation of the fungus. Spore counting to identify hazardous pastures and areas, serve to warn farmers to routinely transfer stock to safer sites to limit their total spore intake.
• Spore counting to identify hazardous pastures and areas, serve to warn farmers to routinely transfer stock to safer sites to limit their total spore intake.
• some control of facial eczema may be obtained through the regular administration of zinc to animals.
• the effectiveness of this control relies on regular administration and to date there has been no treatment or preparation discovered which is able to impart long term, or even short term, resistance or immunity to the condition by the animal.
• a solution addressing the disorder has eluded scientists.
• a method for addressing zinc responsive disorders in animals by providing a depot of zinc through the administration of a zinc substance exhibiting slow-release characteristics within the said animal, by its introduction via a non-digestive route.
• a method of treating zinc-responsive disorders comprising the administration of an effective yet non-lethal amount of one or more zinc substances having a low aqueous solubility, via a non- digestive route.
• composition of fluid or paste-like consistency for use in addressing zinc-responsive disorders in animals other than humans, comprising a zinc substance exhibiting slow release characteristics within said animal, disbursed in a pharmacologically acceptable carrier.
• compositions as described above which includes at least one of: i) a selenium containing compound or mineral; ii) a magnesium containing compound or mineral; iii) a fatty acid or a solution or dispersion thereof; iv) a plant derived oil; v) sulphur or sulphide compound; vi) a vitamin.
• a bolus for administration by introduction into at least one of i) the bloodstream, ii) muscle, and iii) subcutaneous tissue, of an animal other than a human, said bolus comprising a zinc substance and at least one of: i) a selenium containing compound or mineral; ii) a magnesium containing compound or mineral; iii) a fatty acid or a solution or dispersion thereof; iv) a plant derived oil; v) sulphur or sulphide compound; vi) a vitamin.
• composition for addressing zinc-responsive disorders comprising, in percentage by weight and to a total of 100%:
• a magnesium containing compound or mineral 0-20% a magnesium containing compound or mineral; 0-80% a fatty acid;
• a method of treatment and or prevention substantially as described above, comprising the incorporation of a substance enhancing the activity of the zinc, with the zinc compound.
• a method of treatment and/or prevention substantially as described above, directed to address facial eczema and/or fading elk disease.
• a method of administering zinc for addressing facial eczema, fading elk disease and or zinc-remediable afflictions comprising the subcutaneous, non-oral, non-anal administration of a substantially insoluble zinc releasing substance.
• 'zinc substance' is defined as being any zinc containing substance including, for example, zinc metal, zinc complexes, zinc minerals and salts, zinc organic and organozinc compounds.
• the zinc substance chosen should not be excessively toxic to an animal or else its use reduced to less than toxic levels.
• a 'preferred inorganic-zinc compound' is a member of the group comprising zinc aluminate, zinc carbonate, zinc fluoride, zinc iodate, zinc oxide, zinc hydroxide, zinc orthophosphate, other zinc phosphates having a solubility of O.Olg ml (H 2 O at 35°C), zinc selenate, zinc selenide, zinc silicate, and zinc sulphide.
• a 'zinc organic salt' comprises a compound of zinc with an organic acid, though their method of synthesis need not be from an acid-base reaction.
• members of this group include zinc acetate, zinc benzoate, zinc butyrate, zinc citrate, zinc rfWactate, zinc laurate, zinc oleate, zinc oxalate, zinc salicylate, zinc stearate, zinc tartrate, and zinc valerate. It should be appreciated that this list is not exhaustive and many other salts which could be said to be compounds of zinc with an organic acid are also envisaged.
• fatty acid' shall be used in its normal sense though it is envisaged that readily available acids such as linoleic acid and linolenic acid which occur in many vegetable oils will be used for convenience.
• 'alkaline earth element wherever used throughout this specification shall refer to a member of Group II of the periodic table, though more preferably Magnesium and Calcium.
• 'zinc responsive disorder' shall refer to any affliction, disease, condition or deficiency which responds favourably, or may be treated with, zinc or zinc substances.
• An 'enhancer' is a substance which increases or enhances the activity or increases the effectiveness of zinc with respect to the condition it has been applied to treat. This does not necessarily mean improving the release of zinc from the compound used in the preparation - for instance, a soluble zinc compound would more readily release zinc to the animal but at the detriment of long term slow release, and possible toxic zinc effects. According to the present invention it appears that some compounds and substances, such as those of magnesium, enhance the effectiveness of the zinc in some instances. These 'enhancers' should be substantially non-toxic at the proportions and quantities administered and not normally be totally insoluble in the blood stream or animal tissue. Examples of some compounds include the sulphates, carbonates, oxides, chlorides etc. of alkaline earth metals such as calcium and magnesium.
• Chelated forms may also be suitable. Trials have indicated that administrations of the present invention are more effective when the animal is not suffering from some other form of mineral or vitamin deficiency. For instance, selenium is deficient in many New Zealand soils and the co- admininstration of selenium appears to increase the effectiveness of the invention in some instances.
• the administration of 'enhancers' may be simultaneous (site and timing) with administration of a zinc composition or administered separately. The site may be different or nearby and the timing may be, for instance, at the same time, within a given period (e.g.
• the preferred main active component of the present invention is a zinc substance.
• the chosen substance should exhibit slow release characteristics at the introduced site.
• the choice of site will have a bearing - for instance a substance introduced into the bloodstream may be more likely to dissolve than when subcutaneously located.
• the animal itself, and its environment will affect its physiology which can indirectly affect the rate of release of zinc and other minerals.
• the solubility of the chosen zinc substance can be used. Typically, this should be a solubility of less than or equal to lOg per 1 litre water at 35°C, or more preferably less than or equal to lg per litre at 35°C.
• a remedial/treatment preparation having a relatively high initial zinc release (e.g. a more soluble or active zinc compound) may be included to provide an initial boost for animal already afflicted with a disorder.
• An intermediary zinc-release compound may also be included to ensure a therapeutically high zinc level for a short-medium term to help the animal recover while a third long-life, slow release zinc compound may be used to continue a low level of zinc release for the continuing treatment and some immunity from recurrence of the affliction.
• the profile of zinc release and/or activity may be altered with respect to time. This may be useful in determining pre-season, mid-season or late-season formulations for addressing certain disorders such as facial eczema. It can also be useful in customising preparations for the needs of individual species or animals. It is likely that several preparations, according to the present invention, may be provided which are combined according to the requirements of the animal, before its administration. Furthermore, the chemistry and biological activity (notably in the blood stream of different species of animals) can vary and thus different formulations may be desirable to 'fine tune' a preparation to an animals specific requirements.
• the zinc substance used for a particular embodiment should be relatively non-toxic at the normal dosage rates to be described below. Mild toxicity at these dosages may also be acceptable if a useful treatment results.
• Zinc oxide is one zinc compound useful in the present invention, being aqueously insoluble, plentiful and relatively non-toxic other than possible zinc toxicity through over-administration. It is also amphoteric and likely to slowly release into alkaline or acid environments. Other possibilities include hydroxides, carbonates, selenides and sulphides of zinc, preferred inorganic zinc compounds, and zinc organic salts though the specific toxicity of each (or in combination with other included zinc substances) with respect to the animal should be tested for the particular animal species first. Many naturally occuring zinc minerals may also be suitable.
• a preparation may be administered in a variety of ways. For instance, while oral administration is possible, not all the zinc may be absorbed and the preparation will normally pass through the animal's digestive tract in a relatively short period of time, thus providing no lasting results. The acidity of the stomach may also convert alkaline or amphoteric zinc compounds to other more soluble zinc salts which may end up being flushed relatively quickly from the system. Oral, or suppository, administration may be useful as an initial, shock, or top-up application but according to the present invention this is not the preferred method of administration unless it can repeated on a regular basis (e.g. for dairy stock rather than high-country stock).
• An intravenous, intramuscular or subcutaneous injection or implant is more effective, introducing the preparation in a manner providing a theoretical 100% release into the body. This allows the preparation to be more accurately administered as the differences in different animal's metabolisms and digestive characteristics are not as significant. Further, it has been found that this method of administration ensures the components remain within the animal's system for a much greater period of time. Preliminary trials suggest effective treatment periods of 3 months (before a further dose is required) is not out of the question, and up to 6 months or longer may be realised.
• Fi ure 1 is a graph of the relationship between GGT levels and days on treatment for trials with mixed sex lambs - Sporidesmin dose rate of 0.2mg/kg body weight;
• Figure 2 is a graph of the relationship between GGT levels and days on treatment for trials with mixed sex lambs - Sporidesmin dose rate of 0.3mg kg body weight
• Figure 3 is a graph of weight gains during the same trials.
• zinc oxide is a representative of preferred zinc substances.
• This compound has many desirable attributes, such as being cheap and plentiful, available in a finely divided form, being insoluble in water and for the purposes of tests, free from any other components which could influence the trial results.
• oxide is useful for testing
• other zinc substances may be used in various embodiments of the present invention.
• Compounds such as zinc sulphide and zinc selenide, which also have low solubilities in water, can help supply other elements which are commonly deficient. Proportions of these compounds (or others which can be a source of another element) may be combined with other zinc compounds to prevent toxicity by the additional element.
• Other members of the group of preferred inorganic compounds also exhibit low solubility rates, as do many zinc organic salts. Consequently most embodiments of the present invention will rely on a member of one of these groups, or a combination thereof, as the main zinc substance.
• Preferred embodiments of the present invention will comprise one or more members of the groups of preferred inorganic zinc compounds and zinc organic salts.
• members having a solubility of O.Olg/ml H2O at 35°C, or less will be chosen. Even more preferably, a solubility of O.OOlg/ml H2O at 35°C will often be chosen as the main zinc substance.
• the one or more zinc substances will usually be dispersed in a pharmacologically acceptable carrier which will comprise at least one of: i) a plant derived oil; ii) a fatty acid or a solution or dispersion thereof; iii) a non-aqueous fluid.
• Typical plant derived oils are vegetable oils such as sunflower, linseed etc though soya oil appears to impair the efficiency of the invention.
• a fatty acid may be present in the plant derived oil, or added to a carrier. Trials indicate that the use of oils high in fatty acid appear to enhance the efficiency of the invention.
• Other non-aqueous fluids typically oily may be used as carriers or bulking agents.
• the zinc substance will be insoluble in the carrier and the composition will comprise a dispersion of a finely divided form of the insoluble components.
• the present invention may take the form of a bolus, which shall be defined as including within its scope any substantially solid form, lump or capsule of a composition. Capsules having small pores to control release of components may also be adopted. Most bolus embodiments of the present invention will include at least one zinc substance, such as would be used for a fluid or paste-like embodiment, but often include a higher amount of solid material. This may also include substances such as gums to bind the other ingredients together. A proportion of fatty acids or oils may also be included.
• fillers or binders may also be used, including at least one of: i) a calcium containing compound or mineral; ii) a magnesium containing compound or mineral; iii) a selenium containing compound or mineral; iv) a fatty acid; v) sulphur or a sulphide or sulphur containing compound.
• Acceptable fillers and binders need not be restricted to this group, though the aforementioned group includes substances which appear from trials to enhance the effectiveness of the present invention.
• the tests were based on a dose of 20 ml of the preparation (100 mg ml) per 200 kg of beast weight. These tests have exhibited remedial effects in disorders such as Facial Eczema and Fading Elks Disease (FED). Possible resistance to further attacks was also indicated.
• FED Facial Eczema and Fading Elks Disease
• An off-shoot of an eczema or FED treatment according to the present invention is the addressing of some other zinc responsive disorders, some examples of which that trials have indicated will be responsive to the present invention including (apart from facial eczema and fading elks disease): mycotoxin poisoning, poisoning from alkaloid toxins, and disorders relating to phyto-oestrogen levels. Each of these are disorders which occur predominantly from matter which livestock have ingested. In the same manner that zinc is able to provide resistance to an animal against poisoning by the mycotoxin sporidesmin, so too does the availability of zinc appear to increase the resistance of an animal to these other disorders. The provision of an available zinc depot within an animal will provide the exhibited enhanced resistance to these disorders typical of animals receiving regular zinc dosing, for substantially the life of the zinc depot.
• Caution should be exercised when including alkaline or acidic components. Inclusion of large quantities of components such as alkaline magnesium oxide or hydroxide has the potential to alter the pH and other chemistry of tissue surrounding the injection site. A large or single intravenous dose could affect blood chemistry. Consequently it may be preferable, for some applications of the invention, to predominantly use substantially neutral components or to administer a preparation in smaller, tolerable, doses.
• oxide of zinc and/or comparable zinc compound(s) 0-25% sulphate, oxide and/or hydroxide of magnesium and/or calcium
• a preparation according to preparation #4 may take many forms. For instance it may comprise a paste or substantially dry form which, while could be used for less preferred routes af oral or suppository type application, is generally intended to be used as a concentrate for dilution and injection.
• a suitable carrier such as a vegetable oil is typically used for subsequent dilution.
• the proportion of diluent in the injectable composition should be sufficient for the composition to pass through the needle and be taken up by the animal. Typically, total carrier or diluent proportions of 60% or greater would be used for many applications.
• oils are not particularly suitable. For instance, while soya bean oil could be used, it not found to be particularly suitable. From this early research, no apparent problems arose from the use of sunflower oil. This is thought due to its high levels of fatty acids and Vitamin E (and its antioxidant effects). However it is envisaged that many other oils, both vegetable and mineral may be suitable. Other pharmacologically acceptable carriers and diluents (providing they do not react with the components) could, undoubtedly, also be incorporated or substituted.
• a magnesium containing compound or mineral 0-20% a magnesium containing compound or mineral; 0-80% a fatty acid;
• Preparations #5 and #6 are based on those used in trials and are directed to facial eczema risk livestock. Preparation #5, and especially preparation #6, may include a higher proporition of zinc than normally used for other zinc-responsive disorders. Preparation #2 and its dosage was in respect of a medium/high risk exzema site/season. Compositions for lower or higher risk areas may have correspondingly lower or higher zinc proportions or their dosages altered accordingly.
• Preparations #5 and #6 are directed towards livestock under New Zealand conditions, the inclusion of selenium addressing a deficiency readily recurring amongst livestock in this country.
• Typical forms of selenium include zinc selenide, zinc selenate or other selenium compounds used for veterinary use. The proportion will depend on the calculated rate of release within an animal so as to avoid selenium poisoning.
• the sulphur component may commonly comprise elemental sulphur, magnesium sulphate or zinc sulphide but need not be restricted to these compounds.
• Preparations #5 and #6, as well as other preparations, are also suitable for the preparation of a bolus though the percentage of fluid components may be reduced.
• the formation of a bolus may be by pressing or other pill manufacturing methods.
• a gum or resinous material may also be used to bind components together. Many natural and synthetic gums (and equivalent materials) are known which may be used. The rate of dissolution of the binder
• the 13 may also influence release of the zinc constituent, enabling zinc compounds of greater solubility (and often mobility) to be used. This may be useful for non-intravenous sites.
• the predominant zinc component will have a low aqueous solubility (e.g. less than or equal to 0.01 g/ml of H 2 O at 35°C, or typically less than or equal to 0.001 g ml of H 2 O at 35°C), whilst the additional zinc component(s) will have a solubility exceeding 0.01 g/ml of H 2 O at 35°C.
• these additional components will not be excessively soluble (e.g. solubility in the range 0.01-0.1 g/ml of H 2 O at 35°C) and many zinc organic compounds are suitable.
• Yet additional higher solubility zinc components may be included, typically as an additional shock treatment.
• An example of a preparation is as follows: 1-40% zinc substance(s) having solubilities of less than or equal to
• Preparation #2 was given by subcutaneous injection to 60 Romney-cross, mixed-sex lambs (20-30 kg live weight).
• Treatment groups (5 animals per group) received various amounts of preparation #2, as well as sporidesmin toxin. In comparison with an untreated control, results show that preparation #2 has protected sheep against damage caused by sporidesmin, and that the best treatment provided protection for 100 days.
• Groups 6, 7 and 8 contained animals that were given individual rates of 10, 20, 30, 50 and 100 ml/animal respectively of preparation #2.
• Figure 1 illustrated the movements of the GGT levels from day to to day 90.
• Figure 3 shows the toxic effects of sporidesmin dosing by a dramatic reduction in growth rates of lambs.
• the protective effect of preparation #2 at various dose rates to reach adequate levels is also illustrated.
• the growth enhanced effect of preparation #2 is apparent in group 6.
• Figure 2 also shows a similar result with the straight line effect of protection in group 12 at a 9 ml treatment with preparation #2.
• Figure 3 illustrates a distinctive weight gain over the controls, along with the dramatic toxin effect on weight gain, and the close relationship to the levels of protection offered by the various dose rates.
• Toxicity of preparation #2 There appears to be no visible change of gross pathology or histopathology at approximately 4-5 times the recommended dose rates of 10 ml preparation #2/24 kg lamb. At 100 ml/24 kg body weight, or between 4 and 5 times the recommended dose rate.
• sheep In dosages that are effective for protection against the toxin, sheep have shown a weight gain in excess of 1.5 kg above the control group, whether they have been exposed to the toxin or not.
• Results for preparation #2 and variations indicates protection to 130 days which would cover any normal eczema season.
• the Fading Elks Disease affects both male and female. It is not as pronounced in fallow deer as in the elks and wapiti which are substantially larger and faster growing. It is considered that any adversity in their performance is exasperated by their higher metabolic and growth rates.
• administration is by injection which avoids the stomach system - an inefficient and least preferred pathway for administration of the preparation.
• Swabs of the granulomatous skin reactions of the slaughtered trial preparation sheep were taken for bacteriology.
• the trial preparation test material was also tested for sterility.
• Tissue levels of copper, zinc and selenium were measured on liver and kidney samples taken from the six sheep euthanased on each of Days 21 and 56 and are displayed in Table 3. These analyses show no significant differences between the treated and control animals for copper and selenium on Day 21, but on Day 56 the three trial preparation-treated animals had a significantly higher level of kidney copper (P ⁇ 0.04) than the untreated controls.
• the liver and kidney levels of zinc in the three treated sheep are significantly higher (P ⁇ 0.01) compared with the three control animals at both sampling intervals. These elevated levels are at the low end of the toxic range as specified by New Zealand's Ruakura Animal Health Laboratory and illustrated in Table 3.

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• 1993
  • 1993-02-17 HU HU9402308A patent/HUT69388A/hu unknown
  • 1993-02-17 CA CA 2130443 patent/CA2130443A1/en not_active Abandoned
  • 1993-02-17 EP EP93905657A patent/EP0626856A1/de not_active Ceased
  • 1993-02-17 BR BR9305932A patent/BR9305932A/pt not_active Application Discontinuation
  • 1993-02-17 AU AU36498/93A patent/AU677179B2/en not_active Ceased
  • 1993-02-17 WO PCT/NZ1993/000005 patent/WO1993016708A1/en not_active Application Discontinuation

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