ORALLY ADMINISTERABLE CALCIUM SUPPLEMENT FOR CATTLE

Abstract: The orally administerable composition for prevention or treatment of calcium deficiency, in particular milk fever, in cattle contains a readily absorbable calcium compound, preferably calcium chloride, suspended or emulsified in an oil phase, preferably soybean oil. The emulsion contains a water soluble, preferably non-ionic emulsifier, in particular a polyglycerol ester of polymerized oils. The composition consists of 0-80 % by weight of water phase and 100-20 % by weight of oil phase, preferably 40-70 % by weight of water phase and 60-30 % by weight of oil phase. The calcium content calculated as free Ca<++> in the finished mixture is 1-25 % by weight, preferably 10-20 % by weight, and the emulsifier content is 0.5-10 % by weight, preferably 1-4 % by weight, in particular 1.5-2.5 % by weight, calculated on the total mixture. The composition is taken willingly by cows without any risk of aspiration.

Description: Orally administerable calcium supplement for cattle The present invention concerns an orally administerable composition for prevention and treatment of calcium de¬ ficiency in cattle, e.g. milk fever, said composition con¬ taining as active component a readily absorbable calcium compound. Milk fever is a disease which is particularly caused by a strong decline in the Ca content of the blood in the period immediately up to calving and at the beginning of lactation. The predominant part (about 75%) of the inci¬ dences occur during the first 24 hours after calving (M. Dantzer, Dansk Vet. Tidsskr. 1987, 70, 4 15/2, p. 148- 154). The disease is normally treated by intravenous in¬ jection of calcium, in particular in the form of calcium borongluconate. In Denmark 4-6% of first-time parturitions are complicated by milk fever, but in Sweden the figure is even higher, about 8%, cf. G. Jonsson, The Veterinary Record, (1978), 102, 165-169. However, there are considerably variations between the herds, depending upon race, yield, average age and feed composition. Cows which have once suffered from milk fever are parti¬ cularly predisposed to acquire the disease again at the time of subsequent parturitions, and the disease occurs frequently in older cows (Dantzer, op. cit.). A preferred method, cf. G. Jonsson op. cit., to prevent milk fever is short term oral administration of readily absorbed calcium salts. The rapid absorption of calcium from a calcium chloride solution has been demonstrated by i.a. Hallgren, Wien. Tierartztl. Mschr. 5_2 (1965), p. 359- 369, whose preliminary experiments showed a good preven¬ tive effect. However, the bitter taste and locally irri¬ tating effect of calcium chloride entail that the cows are extremely unwilling to take the solutions, which involves a risk of aspiration and consequent aspiration pneumonia, etching of lung and dead. A stomach probe was therefore used in Hallgren's experiments so that the solution was administered directly in the stomach. I goes without saying that this method is not feasible as a general prevention without veterinary assistance. To remedy these drawbacks, CaCl 2 in the form of viscous liquids have been used for several years. Since cows can- not spit, they generally have no alternative but to swal¬ low liquids which are so viscous that they do not run out of the mouth. A commercially available product contains CaCl~ and MgO in a viscous solution. This product is not taken willingly by the cows and therefore involves a risk of aspiration. The aspiration problem can be reduced additionally by mix¬ ing calcium chloride in gels on the basis of water and in- ert cellulose derivatives, such as hydroxyethylcellulose or ethylcellulose. The US Patent Specification 3 461 203 reports experiments where water-free CaCl 2 in amounts of 232, 115 and 100 were mixed with 9-10 g of hydroxyethyl¬ cellulose and water up to 450-400 ml. These gels were ad- ministered daily for 5-10 days, of which two days were post partum. The milk fever incidence was reduced by from about 50% in the control groups to about 10% in the treated groups. According to G. Jonsson, op. cit., the drawbacks of this method are the difficulty in predicting calving with sufficient accuracy, just as the farmers re¬ gard the method as very laborious, in particular because of the resistance of the cows. In view of this Jonsson and associates shortened the gel treatment, but still administered 150 g or 100 g of water- free CaCl 2 dispersed in hydroxy ethyl cellulose and water up to 450 ml leading to a reduction of the milk fever in¬ cidence from 46 to 23%. However, Jonsson concluded that even though gel intake is relatively convenient, voluntary intake of CaCl 2 would be better. Jonsson therefore disguised the bitter taste of CaCl 2 in a feed supplement, but obtained no preventive ef¬ fect on milk fever, which he attributes to the fact that almost all cows cease eating on the day of calving or the day before. Dantzer, op. cit., moreover states that CaCl 2 gels are acid and taken only unwillingly by the cows. As mentioned more fully below, Jess Jørgensen et al., Dansk Vet. Tidsskr. 1990, 73, 3 1/2, p. 140 reports exa¬ minations which show that CaCl 2 gels on the basis of hy- droxyethylcellulose can have an etching effect on the stomach wall in cows. Dantzer also examined the effect of the so-called calving lime which consists of 95% CaHPO^ and 5% MgO as well as 96000 vitamin D 3 per dose. Dantzer reports that the product is willingly taken per- orally by the cows. MgO is added because many cows suffer from hypomagnesemaemia, which makes them predisposed to milk fever. Dantzer's conclusion to the admittedly limited test material is that calving lime is less effective than CaCl 2 gel. The reason is presumably the limited solubility of CaHPO. and the consequent limited calcium absorption. Thus, there is still a need for a calcium based composi¬ tion which effectively prevents milk fever, which is taken willingly by the cows, and which is not vitiated by any risk of aspiration upon oral intake. The invention is based on the surprising finding that the troubles can be remedied by the use of calcium compounds, in particular calcium chloride, if the calcium compound is suspended or emulsified in an oil phase. In view of this the invention concerns an orally admini¬ sterable composition for prevention or treatment of milk fever in cattle, said composition containing as active ingredient a readily absorbable calcim compound, the com- position being characterized in that the calcium compound is suspended or emulsified in an oil phase. As explained by Hallgren and Dantzer, op. cit., the total calcium content in serum consists of a diffusable portion (about 55%) in equilibrium with a protein bonded portion (about 45%). The diffusable portion, which is the readily useful portion, consists of about 45% free calcium ions and about 10% complex bonded calcium. This equilibrium is pH dependent and is shifted towards free calcium ions with a declining pH. Since only the ionized calcium (Ca ) is absorbed from the intestine of the cow, the constituent calcium compound must therefore be water soluble, and to make the pH of the serum go in an acidic direction salts having an acidosing effect, such as calcium chloride, are preferred. Also other soluble calcium salts are useful, such as cal¬ cium formate, calcium acetate, calcium propionate, calcium gluconate, calcium borongluconate, calcium lactate, cal¬ cium laevulate, and calcium ascorbate. The oil phase is formed by an edible oil. Preferred oils are vegetable oils, such as soybean oil, rapeseed oil, olive oil, groundnut oil, apricot kernel oil, grapeseed oil, almond oil, linseed oil, peach kernel oil, palm oil, coconut oil, castor oil, sunflower oil and corn oil. Also animal oils, such as fish oils, can be used. As mentioned, the composition of the invention is charac¬ terized in that the calcium compound is suspended or emul- sified in an oil phase. Based on weight, the composition may thus comprise 0-80%, in particular 0-70% water phase, and 100-20%, in particu¬ lar 100-30% oil phase. The preferred mixing ratio is 40- 70% water phase and 60-30% oil phase. The content of calcium calculated as free Ca in the fi¬ nished mixture is 1-25% by weight, preferably 10-20%. It could not be expected in advance that it would be possible to formulate emulsions with such a high content of dissolved calcium compound in such a large amount of water phase, i.a. because of the increased density and increased ion strength of the water phase. In the preferred embodiment, the calcium compound is thus dissolved in the aqueous phase in a water-in-oil emulsion. To ensure suitable emulsion stability, the emulsion con¬ tains one or more emulsifiers. Suitable emulsifiers are e.g. oil soluble non-ionic emulsifiers, in particular es¬ ters of polyvalent alcohols, preferably glycerol, with fatty acids or polymerized oils. It has been found that a particularly good emulsion stabi- lity may be obtained with polyglycerol esters of polyme¬ rized soybean oil. The concrete emulsifier selection and emulsifier amount depend i.a. upon the ratio of water phase to oil phase, the type of the oil phase and the amount of dissolved cal¬ cium compound. The most expedient emulsifier and emulsifier amount can thus be found by experiments. The emulsifier is used in an amount of 0.5-10%, calculated on the finished mixture, in particular 1-4%, preferably 1.5-2.5%. The composition of the invention may moreover contain additives such as mineral supplements, e.g. magnesium or selenium, vitamin D and flavouring substances, sweetening agents, antioxidants and preservatives. If desired, thickeners may moreover be added to one or both phases. To produce the present composition in the form of an emul- sion, the calcium compound is dissolved in water together with optional preservatives and thickeners and is heated to about 50°C. This solution is mixed with an about 50°C hot solution of emulsifier and optional antioxidants, sweetening agents and flavouring substances in the oil used with vigorous stirring. The resulting emulsion may be homogenized if desired. The suspension may be produced analogously, however with¬ out addition of water. The desirable peroral dose is 50 g of free Ca which is administered in prophylactic treatment 24 hours before ex¬ pected calving, immediately after calving as well as 12 and 24 hours later. Peroral treatment is also used as a supplement to intra- veneous calcium treatment and is then dosed with 50 g of Ca 4, 12 and optionally 24 hours after the intraveneous treatment. A composition according to the invention may e.g. be com¬ posed as follows: CaCl 2 , Ph. Nord. 25% Soybean oil 47% Emulsifier 3% Water 25% Flavouring substances (coconut and vanilla) 0.04% Saccharine sodium 0.01% Antioxidant Preservative A typical composition may consist of: CaCl 2 , 6H 2 0 300 g (corresponding to 50 g of Ca ++ Water 100 g Emulsifier 16 g Soybean oil 380 g Additives 4 g 800 g The commercially available products "Calol®" and "KOVEL®" respectively contain - 8 - CaCl 2 2H2 0 200 g 200 g Soybean oil 280 g 380 g Water 200 g 200 g Auxiliary substances and flavour 20 g 20 g 700 g 800 g The composition of the invention is being tested in a large number of herds. Initial experiments have shown that the cows willingly take the composition. The composition has till now been tested as a supplement for intravenous administration of calcium borongluconate in confirmed milk fever incidences, where CaCl 2 gel as well as placebo control were used for comparison. 8 g of Ca were administered intraveneously, as well as 8 g of Ca subcutaneously for precipitation in three groups of ten cows, where two groups were subse¬ quently treated with 50 g of Ca either as Calol®/ KOVEL® or as CaCl 2 gel. The third group served as control. Both oral treatments showed significant effects on the clinical symptoms. In terms of effect, there was no dif¬ ference between Calol®/KOVEL® and the gel, but Calol®/ KOVEL® was accepted much better by the cows and were much easier to administer. The test will be reported at the XVI World Buiatrics Congress, Bahia, Brazil, Wermuth et al. "New Treatment of Milkfever". Jess Jørgensen et al., Dansk Vet. Tidsskrift, 1990, 73, 3 1/2, p. 140 refers to comparitive examinations between CaCl 2 gels with hydroxyethylcellulose as gel former and a composition according to the invention in the form of an emulsion in 380 g of soybean oil. Both compositions con- tained 400 ml, 49% aqueous CaCl 2 , H 2 0. It was conluded that the gel composition in the dose used can cause pronounced clinical and pathological side ef¬ fects, in particular by way of lesions of the stomach wall while the composition of the invention only involved rela- tively mild clinical symptoms and superficial or no patho¬ logical lesions. In a further examination by the National Institut of Ani¬ mal Science, Ole Aaes "Report on the influence of various culture calcium compositions on feed intake when feeding according to appetite" it was demonstrated that, in addi¬ tion to the above-mentioned lesions on the stomach wall, the CaCl 2 gels also reduced the appetite. Thus, feed in¬ take measured as kg dry matter was reduced by 2.8 feed units (FU), while Calol®/KOVEL® only reduced the feed in¬ take by 2.1 FU. However, to this should be added that about 3.2 FU were added with the soybean oil, which will give an unchanged or positive energy balance even with a digestibility of about 75%.

Claims: P a t e n t C l a i m s : 1. An orally administerable composition for prevention or treatment of calcium deficiency, e.g. milk fever in cattle, said composition containing as active ingredient a readily absorbable calcium compound, c h a r a c t e r ¬ i z e d in that the calcium compound is suspended or emulsified in an oil phase. 2. A composition according to claim 1, c h a r a c ¬ t e r i z e d in that the calcium compound is a water soluble calcium salt, preferably calcium chloride. 3. A composition according to claims 1-2, c h a r a c ¬ t e r i z e d in that the calcium compound is wholly or partially dissolved in the aqueous phase in a water-in-oil emulsion. 4. A composition according to claims 1-3, c h a r a c ¬ t e r i z e d in that the emulsion contains a water soluble, preferably non-ionic emulsifier in an amount of 0.5-10% by weight, preferably 1-4% by weight, in particu¬ lar 1.5-2.5% by weight, calculated on the total mixture. 5. A composition according to claim 4, c h a r a c ¬ t e r i z e d in that the emulsifier is an ester of a polyvalent alcohol, preferably glycerol, with fatty acids or with a polymerized oil. 6. A composition according to claim 5, c h a r a c ¬ t e r i z e d in that the emulsifier is a polyglycerol ester of polymerized soybean oil. 7. A composition according to any of the preceding claims, c h a r a c t e r i z e d in that the oil phase consists of one or more edible oils, preferably selected among soybean oil, rapeseed oil, groundnut oil and grape- seed oil. 8. A composition according to any of the preceding claims, c h a r a c t e r i z e d in that it consists of 0-80% by weight of water phase and 100-20% by weight of oil phase, preferably 40-70% by weight of water phase and 60-30% by weight of oil phase. 9. A composition according to any of the preceding claims, c h a r a c t e r i z e d in that the calcium content calculated as free Ca in the finished mixture 1-25% by weight, preferably 10-20% by weight. 10. A composition according to any of the preceding claims, c h a r a c t e r i z e d in that it further con¬ tains additivies selected among minerals, vitamin D, fla¬ vouring substances, sweetening agents, antioxidants and preservatives.

Inventors: KJEMS GUNNAR, KJEMS, GUNNAR
Applicants: KJEMS GUNNAR, KJEMS, GUNNAR
Application year: 1990
Main classification: A61K33
IPC codes: A61K9, A61K31, A61K33, A61K47, A61P3