WO2002089763A1

WO2002089763A1 - Pulse-release bolus

Info

Publication number: WO2002089763A1
Application number: PCT/GB2002/002023
Authority: WO
Inventors: William Leslie Porter
Original assignee: William Leslie Porter
Priority date: 2001-05-10
Filing date: 2002-05-02
Publication date: 2002-11-14
Also published as: GB0111391D0; GB2376630A; GB2376630B; GB0210067D0

Abstract

An intraruminal bolus for pulsed release of an active material comprising inert wax discs stacked upon one another, at lease some containing an on-axis pocket in which lies a pellet of the active material, whereby as the bolus wears away from one end, the active material is released in pulses at regular intervals.

Description

Title: Pulse-release bolus

Field of the invention

This invention relates to an intraruminal bolus giving periodic pulsed release of one or more active ingredients, with or without controlled prolonged release of additional substances.

Background to the invention

Ruminant animals, particularly when grazed, may require administration of certain substances, beneficial nutritionally or medicinally, for instance micronutrients or anthelmintics. Due to the difficulty and inconvenience of feeding supplements and administering beneficial substances to grazing animals, particularly under extensive hill or range conditions, the practice is commonly employed of administering beneficial substances in a physical form, such as boluses, rods or the like, generally referred to herein as boluses, which are retained in the ruminant fore-stomachs for prolonged periods to release beneficial substances from this site.

For some beneficial substances such as micro-nutrients, continuous release is generally most preferable, since the animal's requirements are relatively constant, although for some such substances, e.g. copper, periodic release would be sufficient, because of the animal's capacity to store copper in the liver.

For administration of certain other substances, however, continuous release is not ideal. In the case of anthelmintics, ectoparasiticides or antibiotics, continuous exposure of target organisms to the drug or substance employed for its control encourages the development of strains of that organism which are resistant to that substance. In the particular case of antibiotics, cross-resistance may also develop against other potential controlling agents. For this reason, it is desirable that release of substances intended to control parasites or micro-organisms should be intermittent, to discourage the emergence of resistant strains. It is also desirable that administration of antiparasitic drugs should be at intervals coinciding with the pre-patent period of the parasite, so that the larval stage of the parasites are killed before the emergence of new populations of egg-laying adults, thus minimising on-going reinfestation of pastures. Timing of release of endoparasitic drugs is therefore important, as well as their release being intermittent.

A further situation in which timed intermittent release of drugs is of value is in control of breeding, where it may be desired to administer drugs such as hormones at particular stages of the oestrus cycle.

In the case of anthelmintics, means are already known whereby this may be achieved. Such a method employs a bolus containing a central core of alloy, which corrodes at an even rate, releasing annular tablets containing anthelmintic, the tablets being interspersed with inert spacers.

Such boluses have the disadvantage that, in animals slaughtered during the life of the bolus, a metal rod remains in the rumen contents, which can damage slaughterhouse equipment. Also, it is expensive to manufacture, and delivers only a single beneficial substance.

Also known are layered boluses in which only alternating layers contain an active drug released as the bolus progressively erodes or wears away starting from one end. These boluses have the disadvantage that if, as is fairly common, the bolus erodes or wears away unevenly, so that the exposed face becomes oblique to the bolus axis, the pulses of active drug may not be released at required uniform intervals and/or may overlap one another. The present bolus aims to provide an economical means of pulsed ruminal delivery, with the capacity reliably to deliver additional substances by constant or pulsed release, and containing no parts sufficiently hard to damage slaughterhouse machinery.

Summary of the invention

According to one aspect of the invention a pulsed-release intraruminal bolus consists of a plurality of discs, also referred to herein as segments, which may contain one or more active materials, layered one upon the other to form a cylindrical body, and in the body of at least some of the discs, preferably of each disc, is a circumscribed depression in which lies a pellet containing an active material or materials to be released in serial pulses. The pellets most preferably are positioned substantially on the bolus axis, i.e. in the centre of the respective discs. Preferably the discs and pellets, possibly together with an end weight to aid rumen retention, are stacked in a casing, preferably by encasing in a coating of an insoluble non-toxic material, leaving only one end face uncoated and accessible to rumen fluid.

The discs are most preferably wax discs.

According to another aspect of the invention, there is provided a method of manufacturing a pulsed-release intraruminal bolus according to which wax, especially wax of melting characteristics to be solid at ambient temperatures but surface sticky at rumen temperature (39 degrees C), is mixed with densifier, such as powdered zinc, manganese, copper, copper oxide or iron, to which one or more beneficial substances may be added, and are formed into discs, at least some having a depression in one face, preferably in the centre thereof, pellets containing one or more active material to be released in serial pulses are located in the depressions, and the discs are stacked as aforesaid. The discs may be produced by heating the mixture, filling into moulds and cooling. Alternatively, the mixed components may be formed into discs by compression or, after heating, by injection moulding. The bolus according to the invention has the advantage that even if the bolus erodes or wears away obliquely from one end, the pulses of the substance or substances to be released will nevertheless be released regularly as required and the pulses will not overlap.

In a preferred bolus in accordance with the invention having pellets located on the bolus axis, the discs or segments have, especially for cattle, a diameter in the range 10 to 30mm and preferably 14 to 25mm, and have, especially for sheep, a diameter in the range 4 to 20mm, preferably 6 to 17mm and ideally 8 to 14mm. The thickness (axial length) of the segments is, especially for cattle, preferably in the range 4 to 30mm, more preferably 8 to 20mm, and especially for sheep, preferably in the range 3 to 20mm, more preferably 5 to 15mm.

The pellet dimensions, as a percentage of the corresponding dimensions, i.e. diameter and thickness, of the segments, most preferably lie in the range 5 to 50%, preferably 20 to 30%.

It is apparent that, by variation of the diameter and thickness of the segments and pellets, most desirably within the aforesaid ranges, and also by alteration of the composition of the segments, the intervals between the successive releases of the serial pulses can be controlled, in practice to any period from a few days up to a few months.

It is to be noted that, in general, the segments, preferably wax segments, may not all incorporate a beneficial substance, or in fact, none may do so, the sole purpose of the bolus being to release the active material or materials contained in the pellets. Yet again one segment, typically the segment at the exposed end of the bolus, may incorporate a nutritionally of medicinally beneficial substance but possibly no pellet, so that a pulse of the substance or substances may not be released until a short interval after administration of the bolus has passed.

Whilst the invention is not limited thereto, beneficial substances which may be included in the discs, preferably wax discs, are trace elements, such as salts of iodine, cobalt, selenium or copper, water soluble vitamins such as vitamin B12, oily substances such as vitamins A, D3 or E, or oils for bloat control in ruminants, such as peanut or Soya oil.

Waxes, meaning fats or oils which are solid at ambient temperatures, are waxes which are non-toxic. Where oily beneficial substances are to be incorporated, the waxes should be miscible with them. Such waxes preferably have a melting point of from 40-100 degrees C, more especially 45-90 degrees C, preferably 50-80 degrees C, even more preferably 50-70 degrees C and ideally from 55-65 degrees C.

The pellets, which alternatively may be referred to as tablets, and incorporate the active material or materials to be released in pulses, may or may not contain densifier, as previously described. They may be formed of water-soluble readily dispersible non-toxic materials as employed in tablet manufacture, such as, but by no means confined to, sugars, e.g. sucrose, fructose, lactose or maltose: cellulose may also may be employed, as may starch, sodium chloride or sodium bicarbonate. Inert carriers, such as calcium carbonate, may also be incorporated. Such substances serve as binder, carrier and release agents for the active material to be released in pulses.

The pellets or tablets, when produced using water dispersible components, may be manufactured by conventional tabletting methods, as in a tablet press.

The functions of binder, carrier and release agents in the pellets may also be served by non-toxic wax preferably but not necessarily of lower melting point than that employed in the wax discs. For instance, cocoa butter may be employed. This may be combined by mixing (before or after melting by heat) with densifier, if employed, and with the active material or materials to be released by pulsing. The pellets may be formed by melting, pouring into moulds and removal when cool, or they may be formed from mixed unmelted components by compression, or else, following melting of the mixed components, by injection moulding. The active material or materials to be incorporated in the pellets for pulsed release may include, but are not confined to, anthelmintics such as avermectins or ivermectins, moxidectin or doramectin, benzimidazoles, levamisole, ftukicides such as closantel, coccidiostats such as amprolium, antibiotics such as enrofloxacin and hormones such as oestradiol or progesterone.

Substances such as selenium (in the form of soluble salts such as sodium selenate or sodium selenite) or vitamin B12, which alternatively may be given continuously from the discs, are also capable of incorporation in the tablets or pellets.

It is also possible as hitherto suggested for a further section or sections of the bolus to incorporate one or more discs comprising copper oxide rods together with binding and release agents such as starch and salt. Where this is incorporated, the sections or discs containing the copper oxide rods would preferably extend over the whole diameter of the bolus, and would preferably be the first part of the bolus exposed to the rumen fluid in use.

The casing, preferably a coating, which encases all but the releasing surface at one end of the bolus, may consist of a non- toxic insoluble material which breaks off or erodes as the releasing surface is abraded or eroded. The coating may consist of wax, such as carnauba wax or candelilla wax, which remains solid at room temperature. The wax coating may also incorporate powdered inert metal such as zinc or manganese, to increase density of the bolus and to reduce loss of coating from abrasion.

The coating may alternatively be formed from non-toxic material such as acrylates, polyester or epoxy, and should be of a character and thickness to permit the coating, when left extended beyond the release surface through loss by erosion or abrasion from that surface, to break off, thus avoiding any shrouding of the release surface, which might otherwise reduce the rate of release. Experimental work

The invention has been tested in stages, summarised as follows :-

Stage 1

First an assessment was made of the rate of erosion from the uncoated end of otherwise coated boluses, formed of a mixture of wax and metallic zinc powder, and anchored by nylon cord in the rumen of a rumen-fistulated sheep. This bolus is referred to as the Control Bolus.

Stage 2

A test apparatus was employed to give rapid in-vitro erosion, and the erosion rate measured for the same bolus (Control Bolus) as employed in Stage 1. An approximate relationship between the rates of erosion of identical boluses in the rumen and in the test apparatus was thus established.

Stage 3

Alternative matrix formulations (bolus compositions) and bolus diameters were then examined in the test apparatus. The rates of surface loss observed, compared to the Control Bolus, were used to calculated the expected rate of surface loss from these boluses if located in the rumen.

Stage 4

Segmented boluses were fabricated, employing matrix formulations and bolus diameters found to be suitable from Stages 1 to 3. Each segment incorporated, in an axial location, a water-dispersible tablet containing test active materials to be released, plus a colour indicator. Stage 5

The segmented boluses, with the active materials in embedded tablets, were examined in the test apparatus to establish:

(a) their rate of surface loss;

(b) that the tablets containing active material were broken down in a segmented manner to give pulsed release of the active material;

(c) the frequency of the pulsed release in the test apparatus was established and thus, by extrapolation from Stages 1 to 3, the likely rate of sequential release of the active material in the rumen was calculated.

Stage 6

A further example was tested of a segmented bolus, as described in Stage 5. This example incorporated a rapidly released segment, to be exposed and broken down before all other segments. The rapidly releases segment incorporated rods of oxidised copper, in a matrix of sodium chloride and maize starch. Release into the rumen of rods of oxidised copper provides a well-recognised means of prolonged copper supplementation for ruminants.

Detailed Methods and Results

The methods employed in Stages 1 to 6 and the results obtained were as follows :-

Stage 1

Preparation of Control Boluses

Wax derived from fish processing (Afamasol 351) of melting point 41°C was heated to 80°C and mixed with metallic zinc powder of particle size 45 to 125 microns. By weight, 13% wax was mixed with 87% zinc. The mixture was poured into latex cylindrical moulds, whereby to envelop a knotted end (2cm) of a 20cm length of braided Terylene^® cord, to be sued to anchor the bolus. The boluses, with cords embedded, were allowed to solidify by cooling to ambient temperature. They were then coated by dipping in polymethylmethacrylate at 35°C, leaving one end, opposite to the cord attachment, uncoated.

The completed boluses were dimensioned as follows :-

Length: 43mm

Diameter: 18mm

Weight: 40g

Density: 2.7g/ml

Test procedure:

Single control boluses were suspended by their anchoring cords in the rumens of 3 rumen- fistulated sheep, for a period of 10 weeks.

At 2-week intervals the boluses were removed, measured and replaced in the rumen. As the boluses progressively lost substance from the single, uncoated end, this surface loss was measured.

Results:

Mean surface loss from the uncoated surfaces was 1.5mm per 14 days.

Stage 2

The test apparatus consisted of 500ml dimpled conical shake flasks, with the internal surface of the bottom of each flask completely covered by a mat of nylon industrial carpet, with looped fibres, 5mm thick. Test boluses, one per flask, were suspended by their anchoring cords from the necks of the flasks, with the uncoated surfaces of the boluses resting on the carpet, and with 5mm of slack, i.e. surplus length, in the anchoring cords. The flasks were charged with 400ml of buffered saline, pH 7, and placed in an incubator at 39°C. They were then orbitally agitated at 180 rpm, with a radius of movement of 30mm.

Stage 3

The results permit the following comparisons :-

Surface loss in rumen versus test apparatus

Identical boluses, both 40mm x 18nn, with attached Terylene^® cords, coated with polymer as above, leaving the anchored end uncoated, were examined: a) in the rumen of 3 rumen fistulated sheep, and b) b) in the test apparatus as described in Stage 2 above.

Mean measured loss from the uncoated surface was as follows :-

Rumen Test apparatus

15 mm in 2 weeks 1 mm in 9 minutes

(i.e. 1 mm in 22.4 hours)

Surface loss from boluses of different diameter, in the test apparatus.

Boluses of Afamasol 351, of diameter 18mm and 22mm but otherwise identical, coated with polymer and with cord anchors as above, were observed in the test apparatus.

Measured loss from the uncoated surfaces were as follows :-

18mm diameter 22mm diameter lmm in 9 minutes 1mm in 16 minutes A 22mm diameter bolus therefore erodes nearly twice as slowly as an 18mm diameter bolus.

Surface loss from boluses fabricated from different materials, in the test apparatus

Boluses of 18mm diameter, coated and with cord anchors as previously described, were fabricated employing two different waxes. Formulations were:-

a) Afamasol 351 13% by weight; zinc particles, 45 to 125 microns, 87% by weight b) Tallow substitute (veg) 6240, 13 % by weight; zinc particles, 45 to 125 microns, 87% by weight

In the test apparatus, measured loss from the uncoated surfaces were as follows :-

Afamasol 351 Tallow substitute 6240 lmm in 9 minutes 1mm in 23 minutes

Trial pulsing discs

Discs of wax and metal powder, of formulations given above, were formed in latex moulds, to give cross-sectional shapes as shown in either Fig 1 or Fig 2 of the accompanying drawings.

The disc of Fig 1, 22mm diameter and 12mm thickness, simply has a pocket of 4mm diameter and 2mm depth to hold a pellet.

The disc of Fig 2 has an additional recess and head so that the discs can be axially interlocked. Pellets containing active materials)

Disc-shaped pellets of 4mm diameter and 2mm depth were formed from the following constituents :-

Ivermectin: 16% w/w

Microcrystalline cellulose: 83 % w/w

Water soluble dye (Ponceau 4R): 1 % w/w

Approximately 0.05g of this material was filled into a steel mould and compressed at 1000kg/cm², whereby to form pellets of an appropriate size.

Fabrication of complete boluses

Pellets were inserted into the pockets of each wax/ballast segment, and the segments (up to 5) assembled to form a cylindrical bolus. A farther segment of wax or ballast, of 12mm depth and with no contained pellet, but incorporating an anchoring cord as described above, was placed at one end. The segments were fused together by light pressure, and in the case of segments having no recesses and corresponding heads, with moderate heat applied.

The boluses were then coated with polymer as before, leaving the surface distal to the chord attachment uncoated.

Testing

1. Segmented bolus as above, employing Afamasol 351. Observation in the test apparatus revealed the following :- a) The first pellet, lying at the exposed surface, released entirely within 5 minute. b) Subsequent pellets released at mean intervals of 382.5 minutes. Previous observations (Stage 3) indicated that surface loss per minute in the test apparatus is comparable to 2.5 hours surface loss in the rumen. By calculation, 382.5 minutes per mm in the test apparatus is equivalent to 40 days per pulse in the rumen.

2. Segmented bolus as above, employing Tallow substitute 6240 Observation in the test apparatus revealed the following :- a) The first pellet, lying at the exposed surface, released entirely within 5 minutes b) Subsequent pellets released at intervals of 900 minutes.

This equates to a rumen release interval of approximately 100 days.

3. Segmented bolus as above, employing Afamasol 351, and with an additional segment incorporating rod-form copper oxide.

This bolus was tested in order to confirm the practicality of delivering simultaneously a slow release particulate form of copper oxide, as a medicine or supplement.

The copper-containing segment measured 18mm diameter and 40mm thickness, and was composed of:-

Rod-form copper oxide: 25g

Sodium chloride : 10g

Maize starch : 5g

This segment was attached to the bolus, at the end opposite to the cord, by molten wax. Subsequent coating, as described above, which included the lower 15mm of the copper bolus, further secured this segment to the main bolus body.

Observation in the test apparatus revealed the following :-

a) copper oxide needles were released within 12.5 minutes. b) The first pellet released within 18 minutes of commencement c) Subsequent pulsing followed the pattern described above. The trials have shown pulsing approximately equivalent to 40 days intervals or more.

For particular purposes, e.g. control of endoparasites, different time intervals of pulsing may be desired, e.g. 21 days. The experiments show that the release intervals can be altered by varying the segment diameter, and composition. It is obvious that the segment depth can also be readily varied to achieve desired pulse intervals.

Advantage over alternating layers

It is known that pulse release of drugs or other active materials from a bolus may be achieved by alternating layers of active and non-active formulations or materials.

Such boluses have the disadvantage that, in the rumen, surface loss from an exposed surface is frequently uneven, resulting in an oblique, angled surface. This means that two active layers can be exposed at the same time, so that one pulse merges with the next.

The present invention circumvents this problem, because of the relatively small size and axial location of the active material-containing pellets.

Even a steeply angled (e.g. 45°) exposed or eroding surface does not cause two pellets to release at the same time.

Claims

1. An intraruminal bolus giving pulsed release of one or more active materials, comprising a plurality of disc-like segments, layered upon one another to form a cylindrical body, at least some of the segments containing a circumscribed depression in which lies a pellet containing an active material to be released in serial pulses.

2. A bolus according to claim 1, wherein the segments are made of wax.

3. A bolus according to claim 1 or claim 2, wherein the segments are stacked in an inert casing.

4. A bolus accordmg to claim 3, wherein the casing is an applied coating of an insoluble non-toxic material, one end-face of the bolus being uncoated in use to be exposed to rumen fluid.

5. A bolus according to claim 4, wherein the coating is a polymer.

6. A bolus according to any of claims 1 to 5, wherein the pellets have an axial thickness and diameter lying in the range between 5 to 50%, preferably 10 to 30%, of the axial thickness and diameter of the segments.

7. A bolus according to any of claims 1 to 6, wherem the wax segments also incorporate a densifier.

8. A bolus according to any of claims 1 to 7, wherein the wax segments also incorporate one or more beneficial substances to be continuously released.

. A bolus according to any of claims 1 to 8, having a non-pellet-containing segment additional to the said wax segments, said segment containing a beneficial substance or substances different from the active material(s) in the pellets.

10. A bolus according to claim 9, wherein the non-pellet-containing segment incorporates copper oxide.

11. A bolus according to claim 2 or any claim appendent to claim 2, wherein the wax of which the discs are constituted is a wax solid at room temperatures but surface sticky at 39 degrees C.

12. A bolus according to any of claims 1 to 11, wherein the pellets lie substantially centrally on the axis of the bolus.

13. A bolus according to any of claims 1 to 12, wherein the wax discs are fused together under heat and/or pressure.

14. A bolus according to any of claims 1 to 13, in which the pellets are formed of a binder comprising a water-soluble non-toxic material incorporating the active material or materials.

15. A bolus according to any of claims 1 to 13, in which the pellets are formed by moulding a non-toxic wax.

16. A bolus according to any of claims 1 to 15, wherein the active material or materials in the pellets comprise anthelmintics.

17. A bolus according to any of claims 1 to 16, wherem the active material in the pellets includes selenium.

18. A method of manufacturing an intraruminal bolus for periodic release of an active material according to which a series of disc-like segments are formed at least some with pockets for holding a pellet, the pellets incorporating the active material are formed and inserted in the pockets, and the segments are stacked to form a cylindrical bolus.

19. A method accordmg to claim 19, wherein the stack of segments is coated except at one end, to form an open-ended casing.

20. A method according to claim 19 or claim 20, wherein the segments are formed by moulding of a mixture of wax and a densifier.

21. A method accordmg to any of claims 19 to 21, wherein the pellets are formed by moulding a mixture of at least wax and the active material.