EP1303309A1 - Rapidly-disintegrating tablets for animals - Google Patents
Rapidly-disintegrating tablets for animalsInfo
- Publication number
- EP1303309A1 EP1303309A1 EP01931233A EP01931233A EP1303309A1 EP 1303309 A1 EP1303309 A1 EP 1303309A1 EP 01931233 A EP01931233 A EP 01931233A EP 01931233 A EP01931233 A EP 01931233A EP 1303309 A1 EP1303309 A1 EP 1303309A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tablet
- animal
- tablet according
- agent
- dyestuff
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to orally-administered preparations for veterinary and/or human therapeutic purposes. More particularly, the invention provides a tablet formulation which rapidly disintegrates in the mouth/oesophagus of an animal/human into a pallatable and readily swallowed mass.
- veterinary preparations such as tablets, pastes and solubilised/suspended "drenching" formulations to livestock and other animals (e.g. companion animals)
- livestock and other animals e.g. companion animals
- sub-therapeutic dosing which can, in the case of agents such as antibiotics and anthelmintics, lead to the development of resistance in the target organism.
- sub-therapeutic dosing which can, in the case of agents such as antibiotics and anthelmintics, lead to the development of resistance in the target organism.
- tableted formulations which animals must be forced to swallow, losses of the active ingredient are frequently caused through animals "spitting out" all or part of the tablet placed in their mouth/oesophagus.
- the present invention provides a novel tablet formulation which appears to be less objectionable to animals than previous tablet formulations and thereby offers a much increased likelihood that all or, at least, the vast majority of the tablet composition will be swallowed and retained by an animal.
- the tablet therefore offers advantages in terms of more successful and accurate dosing of animals while avoiding the abovementioned stability and compliance problems of solubilised/suspended formulations.
- the present invention provides a tablet for orally administering at least one agent to an animal or human subject, said tablet comprising said at least one agent dispersed within a matrix comprising particles of a natural, fibrous cellulose material, and characterised in that the tablet disintegrates in about 15 seconds or less when placed in still water at room temperature.
- the present invention provides a method for orally administering an animal or human subject with at least one agent, said method comprising delivering a tablet according to the first aspect into the mouth or oesophagus of said animal or human subject.
- tablets according to the present invention are characterised in that they disintegrate, when placed in still water at room temperature (i.e. about 22°C), in about 15 seconds or less, more preferably about 10 seconds or less, and most preferably about 5 seconds or less.
- room temperature i.e. about 22°C
- Such disintegration times may be readily measured with the unaided eye by placing a tablet into a container with, preferably, sufficient water to cover the tablet.
- Commencement of disintegration is observed as a rapid swelling of the tablet.
- the tablet is to be regarded as completely disintegrated. In some cases, the disintegrated tablet will appear as a "pile" of material at the bottom of the container.
- the disintegrated tablet will retain some shape related to the original tablet shape (e.g. a disc-shaped tablet may swell and disintegrate into a bar or "sausage" shape - the tablet may swell up to 5 - 10 times or more in the longitudinal axis), however slight agitation of the water (e.g. by gentle swirling) will reveal that the disintegrated tablet is very unstable and, accordingly, a tablet which has swelled into a shape related to its original shape is also to be regarded as completely disintegrated.
- Preferred tablets according to the present invention rapidly disintegrate after being placed in the mouths/oesophaguses of animals (e.g.
- the particulate nature of the fibrous cellulose material of the disintegrated mass has a "feel" in the mouth/oesophagus which is more akin to that of normal foods or digesta rather than the somewhat “foreign" feel provided by a solid tablet, and is therefore more conducive to being swallowed.
- the disintegrated mass is formed so quickly after the tablet is placed in the mouth/oesophagus, "spitting out" of the tablet or its components by animals such as sheep may be largely avoided.
- the tablet of the present invention is primarily intended for veterinary use (particularly for livestock and companion animal usage), but is also expected to be suitable for human use.
- suitable flavourings and/or colours, and/or agents which alter the "feel" of the tablet in the mouth tablets according to the present invention may be readily prepared for use with children and elderly adults who frequently have difficulty in swallowing medicines in traditional tablet, caplet or capsule forms.
- the at least one agent may be selected from biologically active agent(s) or essentially inert agents such as dyestuffs (e.g. rhodamine B).
- Biologically active agent(s) may be selected from agents of veterinary or human therapeutic significance, such as antibiotics, anthelmintics, antiviral agents, antigens (i.e. for vaccination purposes), vitamins and hormones (e.g. steroids and growth hormone).
- agents of veterinary or human therapeutic significance such as antibiotics, anthelmintics, antiviral agents, antigens (i.e. for vaccination purposes), vitamins and hormones (e.g. steroids and growth hormone).
- anthelmintic agents e.g. macrocylic lactone anthelmintic agents
- Suitable rumen-protected anthelmintics for use in tablets of the present invention have been described in International patent publication No. WO 94/27598, the entire disclosure of which is to be regarded as incorporated herein by reference.
- the present invention makes the use of such rumen-protected anthelmintics (and other rumen-protected biologically active agents) commercially feasible, since drench formulations including such rumen-protected anthelmintics have previously proved to be unstable.
- the at least one agent may comprise 0.01-50 wt% of the tablet.
- the at least one agent comprises 5-45 wt%, more preferably 35-45 wt%, of the tablet.
- the natural, fibrous cellulose material may be any natural, non-toxic cellulose plant material or mixtures containing such plant material.
- Such plant material is generally in the form of fibres of crystalline cellulose embedded in a matrix of amorphous hemicellulose and lignin, although other compounds may also be present.
- the cellulose and hemicellulose typically comprises 40 - 70 wt% of the matrix and lignin 5 - 25 wt% of the matrix.
- the fibrous nature of the plant material facilitates the rapid disintegration of tablets according to the invention by providing pores and capillarity for ingress of water/saliva.
- Suitable natural, fibrous cellulose materials include wood, cane (especially sugar cane), seeds (especially cereal seeds such as wheat, oats and barley), legumes, grasses (especially lucerne) and mixtures thereof.
- the natural, fibrous cellulose materials are required to be in a particle form (but, preferably, not a fine powder form), more preferably, a relatively coarse particle form wherein the particles have an average dimension of 0.5 to 2 mm (i.e. they will be retained by a 10-14 mesh screen but will readily pass through larger screens).
- the most preferred natural, fibrous cellulose material is a mixture of two types of wood particles (e.g.
- particulated pine needles and ground sheep feed nuts are also suitable.
- 1 mm particles of oats, dried lucerne or a mixture thereof are also suitable and may offer some advantages in terms of increased quality control in supply and tablet production.
- tablets according to the invention may be produced by methods involving low compression forces.
- the tablets are produced using standard tableting machines and compression forces applied to achieve a "soft" tablet form having sufficient physical robustness to retain shape and integrity for packaging, storage and transport.
- the ability to produce tablets according to the invention with low compression forces provides an advantage in that it allows production of tableted formulations with certain biologically active agents which show compromised absorption and bioavailability (e.g. microorganisms and coated or micro-encapsulated materials) when subjected to pressure or shear forces typical of production methods for highly compressed tablets.
- Tablets according to the invention may be produced in any of the common tablet shapes, for example, disc-like or pellet shapes, spheroids, ovoids, and caplet shapes.
- the present applicants have found that disc-like or pellet shaped tablets with a diameter ranging from about 7 - 15 mm and thickness of about 2.5 - 7 mm (weight range approx. 10 - 800 mg) are particularly suitable for rapid disintegration. However, most preferred are disc-like tablets with a diameter of about 8 mm and thickness of about 3 mm (weight approx. 150 mg).
- Tablets according to the present invention may be readily delivered into the mouth/oesophagus of an animal or human subject by hand. They may, however, be delivered by more automated procedures.
- tablets according to the present invention may be conveniently provided in long strips of bubble or blister-pack type packaging (i.e. with one or more tablets per blister), so that a strip containing large numbers of tablets (e.g. 50 to 250 or more) can be rolled into a cartridge or magazine which might be fitted into a dosing gun.
- a gun preferably includes a ratchet or similar mechanism to continuously feed the strip to a dispensing mechanism which punches tablets from their respective blisters to a dispensing tube adapted for easy placement in an animal's mouth/oesophagus.
- tablets according to the present invention may be conveniently provided in a substantially tubular container, wherein the tablets are arranged in a "stack" formation and dispensed through a dosing gun or, alternatively, by providing the container with a plunger.
- the present invention provides a package containing a plurality of tablets according to the present invention, wherein said package is in the form of a strip and comprises, along the length of the strip, a plurality of receptacles each containing one or more of said tablets.
- the strip package is adapted such that pressure applied to a receptacle by, for example, a human finger/thumb or a simple punch mechanism, results in the contained tablet(s) being discharged from that receptacle.
- the tablet(s), when discharged from the package are substantially intact.
- the package is formed from a laminate of a foil strip and a strip of durable but deformable plastic (e.g. cellophane, polycarbonate or polypropionate) defining receptacles or "blisters".
- the receptacles may be substantially equally spaced along the length of the package strip.
- the receptacles are water impermeable.
- the present invention provides a package containing a plurality of tablets according to the present invention, wherein said package is in the form of a substantially tubular container defining a lumen containing said tablets.
- the substantially tubular container package may include a plunger at a distal end of said container and, at the proximal end, said container may be adapted such that movement of the plunger towards the proximal end permits controlled dispensing of one or more tablets from said container.
- the substantially tubular container package may otherwise be adapted for attachment to a dosing gun such that one or more tablets may be controllably fed into the breech of the dosing gun for dispensing.
- the tablets may be fed into the breech of the dosing gun through gravity or by providing the substantially tubular container package with a spring mechanism such as those typical of gun magazines.
- the present invention provides a kit comprising a dosing gun and a package of tablets according to the present ivention, wherein said dosing gun and package cooperate to permit dispensing of said tablets.
- a tablet according to the invention which comprises;
- the tablet comprises 30 - 45 wt% of at least one biologically active agent, 45 - 65 wt% of a natural, fibrous cellulose material in particle form, and 5 - 10 wt% of at least one binding material.
- biologically active agents such as hormones and antigens may be used at amounts as little as 0.01 - 1 wt%.
- the binding material(s) may be selected from any of the binders commonly used in the production of tablets for veterinary and/or human therapeutic purposes (e.g. lactose, icing sugar, synthetic celluloses, polyethylene oxides and others). Especially preferred by the applicants are lactose and F160 (a synthetic sucrose ester; Croda).
- Tablets according to the invention may further comprise other excipients such as disintegrant materials (e.g. gelling materials such as Aquasorb (ICI) and Separan AP30 (Dow Chemicals)), wetting agents (e.g. sodium lauryl sulphate at about 2 - 5 wt%) and builders/fillers. They may also comprise flavourings and/or colours, and/or agents which alter the viscosity, grannlarity, or "feel" of the tablets.
- disintegrant materials e.g. gelling materials such as Aquasorb (ICI) and Separan AP30 (Dow Chemicals)
- wetting agents e.g. sodium lauryl sulphate at about 2 - 5 wt%
- builders/fillers e.g. sodium lauryl sulphate at about 2 - 5 wt%
- They may also comprise flavourings and/or colours, and/or agents which alter the viscosity, grannlarity, or "feel" of the tablets.
- a tablet according to the invention which comprises:
- Tablets according to the present invention may be produced by standard methods well known in the art. For high speed production methods such as those wherein large dry volumes of tablet components are shaken into die cavities for compression, in order to avoid non-uniform distribution of the at least one agent in a tablet batch (i.e. as may result from settling of "heavy" agent particles from the natural, fibrous cellulose material), it may be preferred to spray the at least one agent onto all or a portion of the particles of the natural, fibrous cellulose material prior to compression. This may be achieved, for example, by forming a solution or suspension of the at least one agent and spraying the solution or suspension onto all or a portion (e.g. 10%) of the particles of the natural, fibrous cellulose material with a suitable spraying apparatus (e.g. a fluid-bed spray dryer).
- a suitable spraying apparatus e.g. a fluid-bed spray dryer
- tablets according to the invention may comprise a dystuff such as rhodamine B.
- a dystuff such as rhodamine B.
- Such tablets may be useful in methods of assessing wool growth in wool-growing animals and, additionally, in methods for monitoring feeding of livestock.
- a method of measuring wool growth in a wool growing animal comprising; (i) administering said animal with a first tablet according to the present invention comprising a wool fibre-staining dyestuff as the at least one agent, such that a first band of dyestuff may be subsequently detected in the wool fibres of said animal,
- a second tablet according to the present invention comprising a wool fibre- staining dyestuff as the at least one agent, such that a second band of dyestuff may be subsequently detected in the wool fibres of said animal, and wherein the dyestuff of said second tablet may be the same or different to said dyestuff of the first tablet, and (iii) thereafter obtaining a wool fibre sample from said animal and measuring the distance between said first and second bands of dyestuff in said wool fibre sample.
- the distance between the first and second bands of dyestuff in said wool fibre sample indicates the wool growth during the administration of the first and second tablets.
- the said predetermined period will be 7 - 42 days, but any period which results in distinct bands of dyestuff in the wool fibres may be suitable.
- the said predetermined period will be about 28 days.
- the wool fibre sample may be obtained from the animal within about 7 - 21 days after administration of the second tablet, although shorter and longer periods may also be suitable.
- the one or both of the bands may need to be visualised using a UV light source.
- the wool growing animal may only be administered with a first tablet according to the present invention comprising a wool fibre- staining dyestuff as the at least one agent, and wool growth may be assessed by measuring the width of the band produced in the wool fibres of that animal. That is, the width of the band will correspond to the time that it takes the animal to clear the dyestuff from its circulation after administration, and will therefore indicate the wool growth during that time.
- the present invention provides a method of monitoring feeding of a livestock animal, said method comprising providing feed to said animal which includes at least one tablet according to the present invention comprising a dyestuff as the at least one agent, and after a period whereby it would be normally expected that said animal would have fed on the provided feed, determining the presence or absence of said dyestuff in a suitable sample from said animal.
- Such a method allows monitoring of feeding of livestock animals from feed provided in feed bins or the like.
- the feed may be readily blended with a dyestuff-comprising tablets according to the present invention in an amount whereby a feeding animal is likely to consume one or more of said tablets.
- the suitable sample is preferably selected from urine and/or droppings.
- Figure 1 provides a graph showing the systemic concentration of ivermectin in sheep over 100 hours following administration of 0.2 mg/kg ivermectin formulated as either a tablet according to the present invention or as an oral drench (i.e. IVOMEC).
- Example 1 Tablets comprising rumen-protected abamectin
- Rumen protection of an orally administered biologically active agent is designed to prevent association with particulate digesta material in the rumen but to provide for degradation and bioavailability as it passes through the abomasum and small intestine of the sheep.
- Such a “carrier” technology has been developed by the present applicants and is described in International patent publication No. WO 94/27598.
- ABA for preparation of rumen-protected ABA for tableting, pure ABA was evenly dispersed in vegetable oil (sunflower or soybean oil) at a w/w ratio of 1 part ABA to 1 part oil.
- the ABA-oil mixture was then emulsified with a solution of 16.5% w/v casein adjusted to pHlO in distilled water.
- the w/w ratio of ABA: oil: casein was 1:1:1, and the microparticle product therefore had a 33% loading of ABA.
- the emulsions were then dried using standard freeze drying or fluid bed drying procedures after which the dry matrix was comminuted in a small grinder to particles of 0.5 - 1.0 mm diameter.
- Three levels of lipid and protein "protection" for ABA formulations (low: 10 - 15%), medium (40 - 45%) and high (75 - 80%) were prepared by cross-linking or denaturing the protein surface of the microparticle by exposure to formaldehyde.
- the fine particles were placed in a sealed chamber and exposed to formaldehyde (36%) vapour for 10 days, the degree of protection (medium or high) depending on the concentration of formaldehyde used.
- the degree of protection medium or high depending on the concentration of formaldehyde used.
- the high level protection matrix could be prepared by adding the appropriate quantity of formaldehyde at the oil-protein emulsifying stage to form a gelatinous matrix. This material was then dried and comminuted as described above.
- In vitro determination of the degree of rumen-protection A donor sheep was surgically fitted with a cannula in the reticulo- rumen and fed a daily ration of 75 Og equal parts lucerne :wheaten chaff. Water was provided ad libitum. Rumen digesta was freshly obtained and the fluid was separated from particulate material by centrifugation (12000xg for
- the level of protein protection (ammonia content) was determined by comparison with protein standards and "blank" rumen fluid, expressed as a percentage. The levels of lipid and protein protection was designated as low (10 -
- Tablets were produced using either of a single 7mm diameter cavity press (constructed in the CSIRO Armidale, NSW workshop) with a hand operated screw-thread pushing a compression plunger, and a motor-driven
- Manesty F3 tablet machine modified to permit slow hand filling of the cavity and single compression strokes when required. Cavities and punches are interchangeable to allow production of tablets with diameters up to approx.
- the required components for each formulation were weighed out separately and mixed by gentle shaking in an air-filled plastic bag.
- the cavity of the tabletting machine was then filled with the mixture either by hand (i.e. using a spatula to fill to the top of the die) or automatically with a filling shoe which clears the top of the die. Low compression force was then applied to achieve a tablet form.
- Tablet stability is usually described in terms of "hardness”. Due to the softness of tablets according to the invention, conventional measures for stability was unsuitable. Accordingly, a simple "drop test” was adopted involving dropping tablets from a height of 1.5m onto a hard surface such that the tablets landed edge-on. Tablets fracturing with loss of more than about 3% were considered to be failures. Because of the known propensity for compressed mixtures to undergo some change over time after the compression force is released, the drop test was repeated after storage for extended periods.
- Trial 1 (rumen-protected formulation v commercial formulation): Eight of the animals were divided randomly into 4 sub-groups of 2 animals with similar bodyweight distribution. The 4 sub-groups were orally administered with ABA at a dose rate of 0.2mg/kg either as the commercial formulation, Virbamec (Virbac Animal Health) or rumen-protected ABA matrix formulation with low, medium or high level of protection (see “Preparation of rumen-protected anthelmintic” below). Virbamec was administered by intraruminal injection whereas the rumen-protected doses were dispensed into a gelatin capsule and administered per os using a balling gun.
- Trial 2 f 'free" v tableted rumen-protected formulation The remaining nine sheep were divided into 3 groups of 3 animals with similar bodyweight distribution and were orally administered with ABA at a dose rate of 0.2mg/kg either as the commercial formulation, Virbamec or rumen-protected ABA matrix formulation with medium-high level of protection either as "free" matrix or as the rumen-protected matrix which had been compressed with cellulose (wood shavings) into a soft tablet according to the present invention.
- Virbamec was administered by intraruminal injection whereas the protected doses were dispensed into a gelatin capsule and administered per os using a balling gun.
- Plasma and abomasal fluid were separated from blood and abomasal digesta by centrifugation at 200 rpm and 20000 rpm for 20 minutes respectively. Both analytical matrices were stored at - 11°C for subsequent analysis. Determination of ABA concentration
- ABA and the internal standard, IVM were determined in plasma and abomasal fluid after pre-extraction and derivatisation following a method modified from that described by Nowakowski, M. A., Lynch, M. J., Smith, D. G., Logan, N..B., Mouzin, D. E., Liukaszewitz, J., Ryan, N. I., Hunter, R. P. & Jones, R. M. (1995), Pharmacokinetics and bioequivalence of parenterally administered doramectin in cattle. Journal of Veterinary Pharmacology and Therapeutics, 18, 290-298.
- the derivatised samples were analysed by reverse phase HPLC using a Waters (Waters Associates, USA) 4 ⁇ m Nova-Pak 3.9 x 150mm analytical steel column, eluted isocratically with a mobile phase of 50: 30: 20 (volume/volume) acetonitrile: tetrahydrofuran: water at a flow rate of 1.2ml/min using a Waters Model 510 solvent pump.
- the fluorescent derivatives of ABA and IVM were detected after excitation at a wavelength of 360nm and emission wavelength 470nm using a Waters Model 470 scanning fluorescence detector. Waters "Millennium-32" data handling software was used for all instrument control, data logging, peak integration and sample quantitation.
- the mean accuracy of estimation of ABA or IVM over the range of concentrations examined was 103.9 (7.8%, the %CV was highest at the lowest standard (19.9(5.0% at the 3.125 ng/ml standard) but was ⁇ 5.0%, with the precision of analysis ⁇ 4% over the remaining standard range to 50ng/ml.
- the limit of quantitation was 0.25ng/ml.
- Tablet stability and disintegration tests are provided in Table 1.
- P indicates a pass
- F indicates failure
- Density refers to mass per unit volume (gm cc). All tablets passed the drop test immediately after production in accord with the manufacturing set-up of the machine for each formulation. Tablets including binding materials such as lactose and F160 also generally passed the drop test after 20 hours and 3 weeks (F160 only) post production. It is considered that the diminishing hardness of some tablet formulations after production would not necessarily preclude their commercial use, particularly if they were to be packaged into blister-type packs as described above.
- the disintegration test was a simple model for the disintegration behaviour of the tablets upon placement in an animal's mouth/oesophagus. It is, however, considered that in in vivo application, abrasion and movement by the tongue and mouth of an animal and the effect of higher temperature will result in significantly more rapid disintegration times then those recorded using this test. Thus, it is considered that tablet formulations which achieve a disintegration time with the water test of 15 seconds or less will disintegrate in an animal's mouth sufficiently rapidly so as to reduce the likelihood of the animal spitting out the delivered tablet.
- tablet formulations which achieve a disintegration time with the water test of 5 seconds or less are likely to disintegrate in an animal's mouth within about 2 to 3 seconds or less thereby providing the animal with substantially no opportunity to spit out the tablet before it disintegrates into a pallatable and readily swallowed mass.
- Visual tests conducted with sheep using tablet formulations prepared from wood chip or shavings have indicated this to be the case.
- tablet formulations comprising the biologically active agent ("drug") and wood chips/shavings or 1 mm oat alone (i.e. without the inclusion of a binding material or gelling agent) showed suitable disintegration times of 15 seconds or less.
- drug biologically active agent
- wood chips/shavings or 1 mm oat alone i.e. without the inclusion of a binding material or gelling agent
- suitable disintegration times 15 seconds or less.
- Further studies of these wood chips/shavings formulations has shown that, when stored under normal atmospheric conditions (i.e. humidity and temperature), they retained their physical characteristics passing the "drop test" for at least 6 months after manufacture. These tablets also retained their required disintegration rate of 15 seconds or less and it was clearly observed that the application of any additional force (i.e. agitation) significantly speeded up the disintegration.
- Trial 1 The disposition of ABA in plasma and abomasal fluid is shown in Tables 2 and 3 respectively. Compared to administration of conventional ABA, the protected formulations displayed higher C max and AUC of ABA in both plasma and abomasal fluid. In plasma there were no differences between the three levels of protection whereas in abomasal fluid the "low” level appeared to show higher mean C max but this was largely attributed to one high value. From these results a "medium" level of protection was then used for subsequent tableting and efficacy studies.
- Trial 2 The disposition of ABA in plasma and abomasal fluid is also shown in Tables 2 and 3 respectively .
- the protected formulations either as the free matrix or in the form of "soft" cellulose tablets prepared from wood chip or shavings displayed higher C max and AUC of ABA in both plasma and abomasal fluid.
- the tablet preparation provided higher C max and AUC of ABA compared to the free matrix.
- Table 2 Kinetic behaviour of Abamectin in PLASMA following administration as conventional (Intra ruminal) administration of a commercial formulation and as oral administration as protected (targetted) matrix in a free form or as tabletted as described above. Abamectin administered at 0.2mg/kg.
- Table 3 Kinetic behaviour of Abamectin in ABOMASAL FLUID following administration as conventional (Intra ruminal) administration of a commercial formulation and as oral administration as protected (targetted) matrix in a free form or as tabletted as described above. Abamectin administered at 0.2mg/kg.
- Example 2 Tablets comprising ivermectiii
- Group 2 were given ivermectin as the commercial oral drench “IVOMEC” (Merial, Australia).
- Table 4 shows the mean ⁇ standard deviation concentration for ivermectin (ng/ml) at each of the 4 time points for the two treatments. From this, the concentration of ivermectin appears greater in the tablet group compared to the IVOMEC drench, but this is not statistically significant. Nevertheless, the tablet performed as well, if not better, than the commercial drench. Table 4:
- Figure 1 shows the profile of ivermectin concentration after administration with the tablet and drench formulation. While there is not statistically significant difference (only 3 animals per group were analysed) the tablet formulation appeared to have a better response than rvOMEC. From previous studies, it has been found that ivermectin from a soluble drench strongly associates with particulate digesta in the rumen which reduces its availability for absorption. Bioavailability is only about 30%.
- the ivermectin is present as a solid form which is likely to reduce to the extent of association with particulate digesta and allow more of the drug to be available for absorption. Hence, there appears a more rapid, and to a greater extent, appearance of ivermectin in the bloodstream, after administration of ivermectin in the tablet formulation compared with IVOMEC drench. Thereafter, from the higher maximum concentration, the ivermectin is eliminated following the conventional "first order" process. Also, it would appear that at any given concentration (say, at 6 ng/ml), the duration that ivermectin is present in the bloodstream is longer than with the drench. Because these drugs largely rely on duration of contact for efficacy, the tablet formulation may provide better efficacy.
- Example 3 Tablets comprising rhodamine
- Gross wool growth can be measured by the mass harvested at shearing each year, but there is frequently a need to measure growth over shorter periods of time and without the need for a complete harvest. Dye-banding has long been recognised as a way to achieve this.
- a liquid-based, (but water insoluble), dye placed on the skin surface will mark the adjacent fibres, and will "grow out” as the fibre lengthens. Provided that the dye is placed carefully and not allowed to spread, any subsequent application at a later time will produce another discrete band further along the fibre. Measurement of the distance between the bands allows an estimate to be made of the growth rate. While the process of dye- banding appears to be simple it is not well suited to on-farm use, since it actually requires considerable expertise to avoid unwanted spreading of the band, is time-consuming, and can result in (colour) contamination of the wool. UV fluorescent dyes have been suggested as alternatives. Furthermore, a dye which can be absorbed quickly from the GI tract and then be incorporated into the fibre would provide a relatively simple and reliable process.
- Rhodamine B has been demonstrated as a suitable candidate for oral drenching, but in solution is a highly intense red colour which stains everything including the operator, the sheep's mouth, and anything else it inadvertently contacts. The process by which it is absorbed from the gut and transferred to the skin results only in the UV fluorescent band, and no red colouration of the skin or fibres.
- Rhodamine B provided in the form of a tablet according to the present invention provides a convenient alternative to oral drenching.
- a matrix mix of 85 wt% meranti/15 wt% pine was used to produce tablets containing 40 wt% rhodamine B (Manesty).
- Ten sheep were each treated 3 times at intervals of about 28 days, with either an aqueous mixture or tablets containing rhodamine B. Some animals received only the oral drench, others a different treatment at the individual time intervals (see Table 5). A staple was harvested from each animal 14 days after the last treatment, and about 30 fibres from each staple were examined for the presence of bands using a fluorescent microscope. The available magnification provided for clear measurement of the length of each band, but it did not allow for measurement of the between band intervals within a single field of view of the microscope.
- Treatment allocations and results are presented in Table 5.
- the measured band widths listed below refer to the start and end of each band of fluorescence.
- the meanwidth and staple S.D. standard deviation represent the mean of about 30 fibres from the same staple.
- the mean and S.D. in the right hand columns refer to the mean for each animal over the duration of the trial (3 dosings).
- bandwidths are between about 550 and 800 ⁇ m. There were clearly individual animal differences, but the widths coincide with expected growth rates of 300 to 600 ⁇ m per day, and an effective residence time in the body of between 1 and 2 days. A consistent increase in band width from period 1 to period 3 is undoubtedly associated with increased growth rates over time (i.e. a normal seasonal trend in Western Australia, where the trial was conducted, as pastures improve from winter to spring).
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPQ7702A AUPQ770200A0 (en) | 2000-05-23 | 2000-05-23 | Tablets for animals |
AUPP770200 | 2000-05-23 | ||
PCT/AU2001/000596 WO2001089575A1 (en) | 2000-05-23 | 2001-05-23 | Rapidly-disintegrating tablets for animals |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1303309A1 true EP1303309A1 (en) | 2003-04-23 |
EP1303309A4 EP1303309A4 (en) | 2004-01-28 |
Family
ID=3821779
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01931233A Withdrawn EP1303309A4 (en) | 2000-05-23 | 2001-05-23 | Rapidly-disintegrating tablets for animals |
Country Status (6)
Country | Link |
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EP (1) | EP1303309A4 (en) |
CN (1) | CN1444485A (en) |
AU (1) | AUPQ770200A0 (en) |
NZ (1) | NZ522681A (en) |
WO (1) | WO2001089575A1 (en) |
ZA (1) | ZA200209526B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9511062B2 (en) | 2011-03-31 | 2016-12-06 | Qualitech, Inc. | Compacted rumen protected nutrient pellets and method of manufacture |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1178982A (en) * | 1966-04-29 | 1970-01-28 | Merck & Co Inc | Anthelmintic Compositions |
US4869908A (en) * | 1987-01-09 | 1989-09-26 | K.V. Pharmaceutical Co. | Fibre formulations |
GB2263065A (en) * | 1992-01-13 | 1993-07-14 | Rhone Poulenc Nutrition Animal | Coated amino acids for increasing wool production and quality and liveweight of lambs |
DE19608563A1 (en) * | 1996-03-06 | 1997-10-02 | Hittich Katharina | Preparation for oral delivery of pharmaceutical or nourishing materials |
WO1997041741A1 (en) * | 1996-05-02 | 1997-11-13 | Josef Palicka | Tablet made of vegetable substance |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MA19678A1 (en) * | 1982-01-13 | 1983-10-01 | Ciba Geigy Ag | ANTI-HELMINTIC AGENTS. |
NZ207655A (en) * | 1983-04-07 | 1986-09-10 | Merck & Co Inc | Synergistic veterinary compositions containing an avermectin compound and clorsulon |
ATE152879T1 (en) * | 1989-12-19 | 1997-05-15 | Smithkline Beecham Corp | ANTIPARASITIC COMPOSITION FOR USE IN ANIMALS |
-
2000
- 2000-05-23 AU AUPQ7702A patent/AUPQ770200A0/en not_active Abandoned
-
2001
- 2001-05-23 EP EP01931233A patent/EP1303309A4/en not_active Withdrawn
- 2001-05-23 CN CN01813265A patent/CN1444485A/en active Pending
- 2001-05-23 WO PCT/AU2001/000596 patent/WO2001089575A1/en not_active Application Discontinuation
- 2001-05-23 NZ NZ522681A patent/NZ522681A/en unknown
-
2002
- 2002-11-22 ZA ZA200209526A patent/ZA200209526B/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1178982A (en) * | 1966-04-29 | 1970-01-28 | Merck & Co Inc | Anthelmintic Compositions |
US4869908A (en) * | 1987-01-09 | 1989-09-26 | K.V. Pharmaceutical Co. | Fibre formulations |
GB2263065A (en) * | 1992-01-13 | 1993-07-14 | Rhone Poulenc Nutrition Animal | Coated amino acids for increasing wool production and quality and liveweight of lambs |
DE19608563A1 (en) * | 1996-03-06 | 1997-10-02 | Hittich Katharina | Preparation for oral delivery of pharmaceutical or nourishing materials |
WO1997041741A1 (en) * | 1996-05-02 | 1997-11-13 | Josef Palicka | Tablet made of vegetable substance |
Non-Patent Citations (1)
Title |
---|
See also references of WO0189575A1 * |
Also Published As
Publication number | Publication date |
---|---|
AUPQ770200A0 (en) | 2000-06-15 |
EP1303309A4 (en) | 2004-01-28 |
NZ522681A (en) | 2004-09-24 |
CN1444485A (en) | 2003-09-24 |
ZA200209526B (en) | 2003-11-24 |
WO2001089575A1 (en) | 2001-11-29 |
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