MXPA96002829A - Device for administering rumian beneficial materials - Google Patents
Device for administering rumian beneficial materialsInfo
- Publication number
- MXPA96002829A MXPA96002829A MXPA/A/1996/002829A MX9602829A MXPA96002829A MX PA96002829 A MXPA96002829 A MX PA96002829A MX 9602829 A MX9602829 A MX 9602829A MX PA96002829 A MXPA96002829 A MX PA96002829A
- Authority
- MX
- Mexico
- Prior art keywords
- bolus
- core
- beneficial agent
- physiologically acceptable
- fatty acid
- Prior art date
Links
- 239000000463 material Substances 0.000 title claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 47
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 239000011248 coating agent Substances 0.000 claims abstract description 24
- 238000000576 coating method Methods 0.000 claims abstract description 24
- 239000011230 binding agent Substances 0.000 claims abstract description 19
- 210000004767 Rumen Anatomy 0.000 claims abstract description 17
- 210000004940 Nucleus Anatomy 0.000 claims abstract description 6
- 241000282849 Ruminantia Species 0.000 claims abstract description 6
- 239000001993 wax Substances 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 21
- XLOMVQKBTHCTTD-UHFFFAOYSA-N zinc monoxide Chemical group [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 20
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 19
- 239000000194 fatty acid Substances 0.000 claims description 19
- YQEMORVAKMFKLG-UHFFFAOYSA-N 2-stearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 claims description 12
- 150000004665 fatty acids Chemical class 0.000 claims description 11
- 239000008240 homogeneous mixture Substances 0.000 claims description 10
- 239000004615 ingredient Substances 0.000 claims description 10
- 239000011787 zinc oxide Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- -1 fatty acid ester Chemical class 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000003921 oil Substances 0.000 claims description 5
- 230000001225 therapeutic Effects 0.000 claims description 5
- TZCXTZWJZNENPQ-UHFFFAOYSA-L Barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000003925 fat Substances 0.000 claims description 4
- 235000019197 fats Nutrition 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 235000015097 nutrients Nutrition 0.000 claims description 4
- 235000019198 oils Nutrition 0.000 claims description 4
- 150000002894 organic compounds Chemical class 0.000 claims description 4
- RFVNOJDQRGSOEL-UHFFFAOYSA-N Glycol stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229940100242 Glycol Stearate Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000007952 growth promoter Substances 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 150000004668 long chain fatty acids Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- AJCDFVKYMIUXCR-UHFFFAOYSA-N oxobarium;oxo(oxoferriooxy)iron Chemical compound [Ba]=O.O=[Fe]O[Fe]=O.O=[Fe]O[Fe]=O.O=[Fe]O[Fe]=O.O=[Fe]O[Fe]=O.O=[Fe]O[Fe]=O.O=[Fe]O[Fe]=O AJCDFVKYMIUXCR-UHFFFAOYSA-N 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 159000000000 sodium salts Chemical group 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 2
- 230000000050 nutritive Effects 0.000 claims 1
- 239000003232 water-soluble binding agent Substances 0.000 claims 1
- 208000005679 Eczema Diseases 0.000 description 26
- 201000004624 dermatitis Diseases 0.000 description 25
- 231100001003 eczema Toxicity 0.000 description 25
- 241001465754 Metazoa Species 0.000 description 15
- 241000283898 Ovis Species 0.000 description 13
- 206010067125 Liver injury Diseases 0.000 description 7
- 231100000234 hepatic damage Toxicity 0.000 description 7
- 230000001815 facial Effects 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
- 229910052725 zinc Inorganic materials 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 3
- 235000013869 carnauba wax Nutrition 0.000 description 3
- 239000004203 carnauba wax Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 210000004369 Blood Anatomy 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 244000144980 herd Species 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 210000004051 Gastric Juice Anatomy 0.000 description 1
- 229940060367 Inert Ingredients Drugs 0.000 description 1
- 210000000088 Lip Anatomy 0.000 description 1
- 210000004185 Liver Anatomy 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 244000045947 parasites Species 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
The invention describes a bolus for the controlled release of a beneficial agent in the rumen of a ruminant animal. The bolus consists of a core that contains a binder, a solubilizing agent, the beneficial agent to be released and, when required, a densifier. The core is coated with a wax coating, preferably with an opening that exposes a small part of the core to the rumen juices. The nucleus dissolves gradually releasing the beneficial agent. As the core dissolves the wax coating wears out until the bolus disappears completely
Description
DEVICE TO ADMINISTER BENEFICIAL MATERIALS TO RUMINANTS
D E S C R I P C I O N
Caropp Technical
This invention relates to a controlled release device. More particularly it refers to a bolus to release beneficial substances in the rumen of ruminants.
Background
Slow release or bolus devices are well known in the art. In patent GB-2 '122, 086 a bolus having a compressed core containing an active ingredient and a cover layer of brittle material has been described. The nucleus is exposed to the fluids of the rumen and gradually disintegrates. The fragile cover layer that is supported by the core breaks when the support disappears. The core is made of dry mixed materials that are compressed together. It is difficult to compress a core of uniform density. If the core is not homogeneous in its density there is an uneven distribution of material during disintegration which can be a disadvantage if the beneficial material has to be dispersed at particular regimes. The patent of the U.S.A. number 3 '535, 419 discloses a bolus having three separate components: a) One or more highly insoluble materials in water such as solid wax, grease, oil, fatty acid amide, ester, alcohol or polymer; b) a high density non-toxic metal derivative; and c) a therapeutic agent.
The method of operation is by disintegration of the composition and separation by leaching of the active ingredient. The rate of dissolution is determined by the degree of compression. It is an object of the present invention to overcome in a certain way the disadvantages of the prior art or at least to offer the public a useful selection.
The invention
According to the foregoing, the invention may be broadly construed as consisting of a bolus which comprises: i) a core comprising a substantially homogeneous mixture of: a) a water-insoluble physiologically acceptable binder comprising wax, fat, oil , fatty acid, fatty acid ester, fatty acid amide, fatty acid alcohol or the like organic compound having a melting point above 50 ° C; b) a physiologically acceptable solubilizing agent; c) a beneficial agent; and d) when required, a physiologically acceptable inert densifier of sufficient density and in sufficient quantity to give the bolus a minimum density of 1.5 g / cm; and ii) a coating of a physiologically acceptable wax on practically the entire surface of the core but leaving exposed a core portion whereby, in use the rumen liquid will dissolve the core allowing the release of the beneficial agent in the rumen. Preferably, the binder comprises a fatty acid ester. Preferably the fatty acid ester is glycerol monostearate. Preferably the solubilizing agent is polyethylene glycol stearate. Alternatively, the solubilizing agent is a sodium salt of a long chain fatty acid. Preferably the mentioned beneficial agent is a nutrient. Alternatively, the aforementioned beneficial agent is a growth promoter. Alternatively, the aforementioned beneficial agent is a therapeutic substance. Alternatively, the aforementioned beneficial agent is a mixture of a nutrient and a therapeutic substance. Preferably, the aforementioned beneficial agent is zinc oxide. Preferably, the densifier is iron powder, barium sulfate or iron oxide.
Preferably, the bolus is in the form of a cylinder that is closed at one end and open at the other. Preferably, the closed end has a hemispherical shape. In an alternative construction the core is cylindrical and consists of alternating cylindrical layers, each alternating layer contains all the core ingredients except the beneficial agent, whereby the beneficial agent is released in separate doses. Preferably, the bolus is as described herein with reference to the drawings. In another embodiment the invention may broadly consist of a method for making a bolus, comprising: a) melting a mixture of a water-insoluble physiologically acceptable binder comprising wax, fat, oil, fatty acid, fatty acid ester, amide fatty acid, fatty acid alcohol or the similar organic compound having a melting point above 50 ° C; a physiologically acceptable solubilizing agent; a beneficial agent; and when required, sufficient inert, physiologically acceptable filler material of sufficient density to give the bolus a minimum density of 1.5 g / cm; b) mixing that mixture until it is substantially homogeneous; c) dividing the substantially homogeneous mixture into predetermined doses; and d) coating the dosages with a physiologically acceptable wax. Preferably, in step c) above, the virtually homogeneous mixture is extruded and cut into predetermined dose sections. Alternatively in step c) above the substantially homogeneous mixture in its predetermined dose volume form is melted in a mold and allowed to solidify. In another alternative process, the binder and the solubilizing agent are dissolved in a physiologically acceptable solvent and the solvent is allowed to evaporate from the doses within which the mixture has been divided before the coating step. Preferably, the coating step comprises coating all but a small area of each dose section. Preferably, each dose is in the form of a cylinder and the coating step comprises covering everything except one end. This invention may also consist broadly of the parts, elements, and features referenced or indicated in the specification of the application, individually or collectively and any or all combinations of two or more of the parts, elements or features and where specific integers are mentioned. having equivalents known in the art to which this invention relates, such known equivalents are intended to be incorporated herein as if individually indicated. The invention consists of the foregoing and also contemplates constructions of which examples are given below.
Brief Description of the Drawings
The invention may also be understood with reference to the accompanying drawings, in which: Figures IA, IB and 1C are sectional elevations of a first embodiment of a bolus made in accordance with the invention showing the mode of release of the beneficial agent . Figure 2 is a sectional elevation of a second embodiment of a bolus according to the invention showing alternating active and inert core layers. Figure 3 is a sectional elevation of another embodiment of a bolus according to the invention in which the beneficial agent is stored in transverse cavities or grooves of the core. Figure 4 is an elevation of another embodiment of a bolus according to the invention in which the beneficial agent is present in longitudinal holes in the surface of the core just below the outer coating. Figure 5 is a sectional elevation of another embodiment of a bolus according to the invention in which the beneficial agent is present in a longitudinal hole within the bolus core.
Figure 6 is a graph of the percentage of controls that show facial eczema against protection percentage achieved by a four-week bolus. Figure 7 shows a graph of percentage of controls showing facial eczema against protection percentage achieved by a bolus of 6 weeks.
Ways of Carrying Out the Invention
The bolus illustrated in Figure 1 comprises a core 12 coated by a wax coating 10. The covering 10 is closed at one end 13 and opened at the other 14. The closed end 13 may be of hemispherical shape or have a substantially flat bottom as illustrated. The open end 14 of the wax coating allows the core 12 to be exposed to the juices in the rumen. As illustrated in FIG. IB as the juices in the rumen gradually dissolve the core 12 releasing the particles 16 of active agent. As the wax coating 10 erodes, the open end 14 of the core 12 is dissolved so that the bolus as illustrated in Figure 1C becomes progressively shorter until it completely disintegrates. In Figure 2 the bolus is identical to that illustrated in Figure IA except that instead of being provided with a homogeneous core it is provided with a core consisting of altered layers 18 and 20. The layer 18 consists of all the filling materials and includes the benefit agent as described below. The layer 20 contains only the filling materials and without beneficial agent. The bolus illustrated in Figure 2 is gradually dissolved and eroded in the same manner as that illustrated in Figures IA to 1C, but the beneficial ingredient is separated by leaching at spaced intervals. That bolus will be used when beneficial agents, such as medications, have to be administered in pulsed doses. the length of time between dose administration can be controlled by the thickness of the inert layers 20. The bolus in Figure 3 is intended to deliver beneficial agents in pulsed doses as well. The core 12 contains all the inert ingredients, that is the binder, the solubilizing agent and the densifier if necessary. The core 12 is provided with holes 22 extending transversely through the circumferential core or rings or grooves 24. The holes 22 or the grooves 24 contain the beneficial agents 23 or 25, respectively, in a concentrated form. The core and orifice or grooves are coated with wax in the same manner as for the other embodiments. As the coating wax erodes, the beneficial ingredient 23 or 25 is released in pulsed doses, when exposed to the rumen juices. As shown in Figure 4, the beneficial agent can also be placed in longitudinal grooves 23 cut into the surface of the core 12. The filled grooves are then covered with the wax coating 10 together with the remainder of the core 12. As shown in FIG. Figure 5, a beneficial agent can also be placed in the longitudinal orifice 27.
Method of production
The cores according to the invention can be produced either by extrusion or casting and allowing either the molten binder agent to solidify or allowing the solvent to evaporate as the case may be. All ingredients except the outer wax coating are mixed together. When no solvent is used, the mixture is heated to melt the binder and then agitated in a virtually homogeneous mixture. If a molding method is used, the mixture is emptied into molds having the shape of the cores of the drawings and allowed to cool. Then the cores are separated from the mold and covered with wax either by submerging or emptying wax on the core. If a solvent is used, the binding agent dissolves in the solvent instead of melting and the solvent is allowed to evaporate. When an extruder is used the mixture of ingredients is allowed to cool or the solvent is allowed to evaporate in the form of a semi-solid paste. The extruded material is cut into sections of appropriate doses. When a core of the construction shown in figure 2 is the one to be made, a pair of extruders are put to work one after the other. An extruded mixture does not contain beneficial agent. The other contains the beneficial agent in the desired dosage form. The extrusions are then cut into relatively short lengths as illustrated in Figure 2 and placed together in alternating active and inert layers and coated as described above. When the core illustrated in Figure 3 is produced, an extrusion that contains all the ingredients except the beneficial ingredient and is cut, the sections are then perforated by a series of drilling operations in parallel grooves or otherwise using a milling cutter and device. rotary to produce already the holes 22 through the core or the grooves 24 around the core. The beneficial agent 23 in a virtually molten form is then emptied into the holes 22 and then the core is covered with waxes described above. In order to keep the active ingredient within the core, the holes that produce the holes 22 are positioned so that they do not pass completely through the bottom of the core until behind it. When the grooves 24 are used, the beneficial ingredient in the form of a paste is extruded into the grooves and the core is coated in the usual manner. The longitudinal grooves 23 and the longitudinal holes 27 (see Figures 4 and 5) are formed and filled with beneficial agent in a similar manner.
Alternative formulations
The binder for the core can be any physiologically acceptable water-insoluble component which can be formed in a substantially homogeneous mixture with the solubilizing agent, the beneficial agent and the densifying agent. More preferably the binder will be one that will melt at temperatures not detrimental to the other components or one that is soluble in solvents that can evaporate to allow the core to solidify. The bonding molding point could be sufficiently over the internal body temperature of the digestion of the animal that is that it is not combined in situ. For more applications on animals the appropriate molding point is at least 50 ° C. Any solvent used could be psychologically acceptable for the animal being taken bolus. Suitable binding agents are those exemplified in the U.S. Pat. No. 3 '535, 419. We have found that a particularly suitable binding agent is glycerol monostearate. The solubilizing agent works in conjunction with the binder in the rumen environment in a manner not fully understood. However, it is believed that the solubilizing agent together with the gastric juices gradually dissolves the binding agent in the core. In the embodiment described in the following example, the beneficial agent is zinc oxide. Zinc oxide has a sufficient density that it is not necessary to include a high density inert material to remove weight from the bolus so that it is not vomited from the rumen. Persons skilled in the art will contemplate other beneficial ingredients that can be administered through the use of this bolus. This may include additional nutrients where they are needed and other therapeutic agents for the treatment of parasites, diseases or other conditions of ruminants. In order to prevent the bolus from being regurgitated from the rumen, it preferably has a minimum density of 1.5 g / cm. More preferably the density is 2.5 g / cm. With many therapeutic agents it will be necessary to include densifying substances other than zinc oxide. These will be inert and physiologically acceptable to the animal destined to ingest the bolus. The density of the densifier will be sufficient to give the minimum density desired to the complete bolus. A wide variety of waxes can be used. A mixture of paraffin wax and carnauba wax, a mixture of beeswax and carnauba wax has been found to be successful. The wax used must be physiologically acceptable to the animal intended for ingestion and will be of a composition that erodes the open end under the conditions within the rumen.
EXAMPLE 1: Preparation of a bolus containing zinc oxide. A mixture containing 83.5% zinc oxide and 16.5% glycerol monostearate was melted and mixed. The glycerol monostearate contained 75 to 90% EMULDAN HS40 (a trade name of self-emulsifying glycerol ramonostearate, which is a mixture of glycerol monostearate and polyethylene glycol monostearate). The mixture was then extruded and core sections were cut at predetermined dose lengths and coated with wax. The wax consisted of 25% carnauba wax and 75% paraffin wax. The EMULDAN HS40 was obtained from Grindsted
Products A / S by Brabrand, Denmark and LIPOMULSE 165 by Lip Chemicals Inc., of Paterson, New Jersey, E.U.A. all percentages are by weight of the mixture of the core or the wax coating.
EXAMPLE 2: Bolus with different release times a) Release time of four weeks. A bolus was prepared as in Example 1. The glycerol monostearate consisted of 80% non-self-emulsifying glycerol monostearate (EMULDAN HS40) and 20% self-emulsifying glycerol monostearate (LIPOMULSE 165). It was found that a Bolus containing 43 g of zinc oxide was completely dissolved and eroded in sheep with a weight scale of 20 to 40 kg on average in about 4 weeks. b) Release time of six weeks. A bolus was prepared as in Example 1. Glycerol monostearate consisted of 85% non-self-emulsifying glycerol monostearate (EMULDAN HS40) and 15% self-emulsifying glycerol monostearate (LIPOMULSE 165). It was found that the nucleus of a bolus containing 43 g of zinc oxide was completely dissolved and corroded in sheep weighing 20 to 40 kg on average in approximately six weeks.
EXAMPLE 3: Field Tests
Bolus for administration of zinc to sheep containing the same amount of zinc, was prepared according to the method of examples 1 and 2. One released zinc for a period of 4 weeks and the ortho for 6 weeks. These devices were approved for their ability to prevent facial eczema (FE) in sheep on farms in Northland, Auckland, Waikato and Wanganui in New Zealand during the 1994 FE season. (February to March 1994). Groups of approximately 50 sheep in 26 farms in these regions received one or other of the devices, which were renewed every 4 to 6 weeks until the end of the FE season. On farms, FE precautions were usually taken, a control group was left untreated so that the effect of the devices could be tested. No precautions were taken on properties, a group of sheep selected at random was used as control. Blood samples were regularly taken from the control group to test Y-glutamyl transferase (GGT) activity, a measure of liver damage caused by FE. When significant liver damage was detected in the control group, all the sheep were bled and the severity of liver damage categorized according to the GGT activity (measured in international units) as follows: < no eczema 55-150 mild eczema 151-330 moderate eczema > 330 severe eczema
Facial eczema occurred in 15 of the farms under study. Some farms were severely affected by FE during 1994, with more than 80% of unprotected control sheep showing liver damage. In two farms, the outbreak was very prolonged and a second blood sample was taken in May showing a continuous severe challenge in the control sheep. Excellent protection was obtained with both devices, with less than 10% of the animals showing some sign of liver damage throughout the observation period. Good protection was also seen in the other two most affected farms, with incidence and severity of liver damage being greatly reduced. A less severe challenge was seen in 7 farms with between 40 and 65% of the control animals being affected. Again, excellent protection was given with intraruminal devices, with the incidence of eczema being generally less than 20% and then only in the "soft" category. Comparatively, little eczema was recorded in the remaining 4 farms with an incidence of liver damage of 18-38%. In these farms, the devices gave almost complete protection. In one of the severely affected farms, the non-control sheep were given zinc oxide by soaking at biweekly intervals through the FE station. A sample of these animals was bled on May 11 for comparison with the control sheep and those to which the intraruminal devices were given. These data show that biweekly doses decrease the incidence of facial eczema (90% in the control compared to 64% in animals dosed with zinc) although this was not as effective with the intraruminal zinc devices, both of which reduced the incidence of eczema to less than 10%.
Statistic analysis.
In the first analyzes, the animals were divided into two groups, those that did not show eczema and those that showed some signs of the disease, regardless of its severity. The full average percentage of animals that did not show eczema is shown in Table L
Table i: Total Average Percentage of Animals that did not show Eczema - Total Tests
• Significantly different from the control value, P < 0.001.
In order to establish the total efficiency of the devices, the data of each farm were analyzed by plotting the percentages of controls that show eczema against the percentage of protection achieved, defined as the percentage of animals in the group touched without eczema minus the percentage of animals in the control group without eczema. These graphs are shown in figures 6 and 7 for the 4 and 6 week devices, respectively. As expected, the lines pass through the origin in both cases; If there is no eczema there can be no protection. The points are in a straight line; From the slopes of these lines we could predict that 86 ± 3% of animals in the herd were protected by the device for 4 weeks and 81 ± 4% by the device for 6 weeks. In simple terms, this indicates that if 100 of the control sheep were put to pasture on toxic pasture and 80 were affected, to a greater or lesser degree, with eczema, on average, only 11 of the animals treated with the 4-year-old device weeks and 15 of those treated with the 6-week device showed some sign of eczema. However, these analyzes did not take into account the severity of the disease. A smaller amount of damage to the liver is of little consequence in practical terms and protection against moderate or severe eczema is of primary importance. Therefore, the data was reanalyzed, eliminating animals that suffered mild eczema only. From this analysis it is predictable that 95 ± 1% of animals in a herd were protected from moderate or severe eczema by the device of 4 weeks and 89% of animals by the 6-week device. The results of these experiments showed that the intraruminal devices consistently decreased the incidence and severity of facial eczema in sheep that grazed under normal farm conditions, even after a severe and prolonged challenge. Although this invention has been described in relation to the controlled release of zinc to control facial eczema, it will be appreciated by those skilled in the art that many other beneficial agents can be released through the use of the bolus of this invention. It will also be appreciated that the rate and time of release is controlled by both, the configuration of beneficial char within the nucleus and the solubility of the nucleus.
The solubility can be altered by the use of a greater or lesser proportion of solubilizing agent.
Claims (21)
1. A bolus which comprises: a core comprising a substantially homogeneous mixture of: a) a physiologically acceptable water-soluble binder comprising wax, fat, oil, fatty acid, fatty acid ester, fatty acid amide, acid alcohol fatty or similar organic compound having a melting point above 50 ° C; b) a physiologically acceptable solubilizing agent; c) a beneficial agent; and d) when required, a physiologically acceptable inert densifier of sufficient density and in sufficient quantity to give the bolus a minimum density of 1.5 g / cm; and a coating of a physiologically acceptable wax on practically the entire surface of the core but leaving exposed a core portion whereby, in use, the rumen liquid will dissolve the core allowing the release of the beneficial agent in the rumen.
2. Bolus according to clause 1, wherein the binder comprises an ester and fatty acid.
3. Bolus according to clause 1 or 2 wherein the fatty acid ester is < glycerol monostearate.
4. Bolus according to clause 1 62, wherein the solubilizing agent is polyethylene glycol stearate.
5.- Bolus according to any of the clauses 1 to 4 wherein the solubilizing agent is a sodium salt of a long chain fatty acid.
6. Bolus according to any of the preceding clauses, where the beneficial agent is a nutrient.
7.- Bolus according to any of the clauses 1 to 5, wherein the beneficial agent is a therapeutic substance.
8. Bolus according to clause 7, wherein the therapeutic substance is zinc oxide.
9.- Bolus according to any of the clauses 1 to 5, wherein the beneficial agent is a growth promoter.
10. Bolus according to any of clauses 1 to 5, wherein the beneficial agent contains both a nutritive substance and a therapeutic substance.
11. - Bolus according to any of the preceding clauses, where the densifier is iron powder, barium sulfate or iron oxide.
12. Bolus according to any of the preceding clauses, which is in the form of a cylinder that is closed at one end and open at the other.
13. Bolus according to clause 12, where the closed end has a hemispherical shape.
14. Bolus according to any of the preceding clauses, where the core is cylindrical and consists of alternating cylindrical layers, each alternating layer contains all the ingredients of the core, except the beneficial agent whereby the beneficial agent is released in separate doses.
15. A method for manufacturing a bolus, comprising: a) melting a mixture of a physiologically acceptable water-insoluble binder comprising wax, fat, oil, fatty acid, fatty acid ester, fatty acid amide, acid alcohol fatty or similar organic compound having a melting point above 50 ° C; a physiologically acceptable solubilizing agent; a beneficial agent; and when required, sufficient inert, physiologically acceptable filler material of sufficient density to give the bolus a minimum density of 1.5 g / cm 3; b) mixing that mixture until it is substantially homogeneous; c) dividing the substantially homogeneous mixture into predetermined doses; and d) coating the dosages with a physiologically acceptable wax.
16. Method according to clause 15, wherein in stage c) the virtually homogeneous mixture is extruded and cut into predetermined dose sections.
17. Method according to clause 15, wherein in step c) the virtually homogeneous mixture in the molten form of predetermined dose volume is emptied into a mold and allowed to solidify.
18. Method according to clause 15, wherein the binder and the solubilizing agent are dissolved in a physiologically acceptable solvent and the solvent is allowed to evaporate from those doses within which the mixture has been divided before the coating step.
19. Method according to any of clauses 15 to 18, wherein the coating step comprises coating all but a small area of each dose length. 20.- Method according to any of the clauses 1 to 19, wherein the dose is in the form of a cylinder and the coating step comprises covering everything except one end. 21. A method for administering a beneficial agent to a ruminant animal that comprises feeding an animal with a bolus according to any of clauses 1 to 14. SUMMARY The invention describes a bolus for the controlled release of a beneficial agent in the rumen of a ruminant animal. The bolus consists of a core that contains a binder, a solubilizing agent, the beneficial agent to be released and, when required, a densifier. The core is coated with a wax coating, preferably with an opening that exposes a small part of the core to the rumen juices. The nucleus dissolves gradually releasing the beneficial agent. As the core dissolves the wax coating wears out until the bolus disappears completely.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ250544 | 1994-01-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA96002829A true MXPA96002829A (en) | 2000-07-01 |
Family
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