AU2002334476B2

AU2002334476B2 - Intraruminal device

Info

Publication number: AU2002334476B2
Application number: AU2002334476A
Authority: AU
Inventors: Jason William Anderson; Murray Edward Fenton; Robert William Lachlan Holmes
Original assignee: Boehringer Ingelheim Animal Health USA Inc
Current assignee: Boehringer Ingelheim Animal Health USA Inc
Priority date: 2001-09-20
Filing date: 2002-09-20
Publication date: 2008-05-01
Anticipated expiration: 2022-09-20
Also published as: AU2002100728B9; WO2003024355A1; NZ514279A; AU2002100728B4

Description

00 0 FIELD OF THE INVENTION 0 This invention relates to an intraruminal device, more particularly an intraruminal t device adapted to deliver a medicament over a prolonged period.

00 BACKGROUND There are a large number of intraruminal devices and sustained release capsules o and formulations presently available. In general intraruminal devices currently available are in the form of a capsule, which comprises: a substantially hollow Cc tubular body, which is sealed at one end by a cap, and partially sealed at the C1 second end by an annular flange, which defines an opening. There is provision within the body for the inclusion of a solid therapeutic composition.

Many of the currently available intraruminal devices contain a spring and plunger mechanism for urging the solid therapeutic composition towards the opening. The cap end may also have attached to it a plurality of resilient arms.

Intraruminal devices are inserted through the oesophagus into the animal's rumen.

They are necessarily capable of existing in two states: a first state where arms run along the length of body for administration; and a second state where arms are extended to a maximum 900 to the body to permit retention of the intraruminal device within the rumen of the subject animal. The transition between the two states may be brought about by various means. However there are difficulties ensuring the transition of between states occurs very soon after administration of the intraruminal device.

Some instances of animals being accidentally killed during dosing using the above capsules have been reported. It is believed in such instances that mortality is caused by the arms opening up too early in the dosing process and perforating the oesophagus. Other instances have been reported where the arm or arms of a capsule has failed to open in the rumen and the capsule has been regurgitated by the animal, thus being ineffective.

Accordingly there is a need for an improved intraruminal device which reliably opens.

2103146 004/nk 2103146_004.DOC 00 OBJECT 0 It is an object of the present invention to provide an improved intraruminal device Sor one, which will at least provide the public with a useful choice.

STATEMENT OF INVENTION 00 In one aspect the invention can broadly be said to comprise of an intraruminal device suitable for administration to ruminants including a capsule and a holding means wherein the capsule includes Cc a body having a cavity therein, the body having an opening to the cavity, said cavity being adapted to receive one or more tablets; at least one arm attached to a first end of the body, the arm or arms being capable of being disposed in an open position where the arm or arms extend away from the body and in a closed position where the arm or arms rest or are held against the body, said arm or arms being biased to the open position; and wherein the holding means comprises a cap capable of being secured over the first end of the body said cap being configured to constrain the arm or arms in the closed position, and the cap being formed at least in part from a dissolvable material, so that in use when the intraruminal device is delivered to the rumen, contact with fluid dissolves at least part of the cap so that the arm or arms are free to return to the open position.

The present invention provides a device having a more efficient delivery of a capsule to the rumen and improved capsule retention following dosing compared to the prior art. In particular, the cap is configured such that in securing to the body, the cap both urges and maintains the arm or arms in a closed position for dosing. The cap is also at least partly dissolvable so that once in the rumen, the cap can be released from the secured condition and the arm or arms are free to move to the open position.

2103146_004/nk 2103146_004.DOC 4 00 Preferably the cap and the first end of the body are provided with co-operating 0 members adapted to interconnect to secure the cap to the first end of the body.

C Preferably the co-operating members are in the form of at least one aperture in the cap and at least one corresponding flange on the first end of the body.

00 Preferably the co-operating members interconnect in a snap-fit arrangement.

Preferably the cap is adapted to dissolve at least one a predetermined portion.

Cc More preferably the predetermined portion is a bridge located proximate the at least one aperture in the cap.

Preferably the capsule has at least two arms.

Preferably the cap contains a plasticized starch material.

Preferably the plasticized starch material is a plasticized corn or potato starch.

Preferably the shape of the cap enables easier administration and passage of said intraruminal device into the rumen.

Preferably the shape of the cap is semi-circular.

Preferably the cap begins to dissolve on contact with saliva or other liquid thereby becoming slippery to enable easier administration of the intraruminal device into the rumen.

Preferably the body is packed with one or more tablets including one or more medicaments, said tablets being soluble in the ruminal fluid, so that on administration the ruminal fluid contacts the tablet through the opening and the tablets gradually dissolve releasing said medicaments into the fluid.

In a further aspect the invention can broadly be said to comprise of a method of administering an intraruminal device to an animal comprising the steps of: a) ensuring the cap is secured to the first end of the body, and b) inserting the intraruminal device into the rumen of the animal.

2103146 004/nk 2103146_004.DOC 00 BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the invention will now be described, by way of example only, 3 with reference to the accompanying drawings in which: FIG. 1 is a plan view of the intraruminal device.

00 FIG. 2 is an exploded schematic view of the intraruminal device of the present invention.

INO

FIG. 3 is a top view showing line A-A.

FIG. 4 is a longitudinal section along line A-A of FIG 3.

Cc FIG. 5 is a bottom view showing line B-B.

FIG. 6 is a longitudinal section along line B-B from FIG FIG. 7 is a schematic view of the bolus structure.

FIG. 8 is a schematic of the bottom cap of the bolus.

FIG. 9 is a schematic of an alternate bolus structure.

FIG. 10 is a view of a holding means as a ring structure.

PREFERRED EMBODIMENT The following examples are given by way of illustration only and shall not be taken as being in any way limiting as the spirit or scope of the invention.

Referring to the drawings, where like numerals designate corresponding parts throughout the several figures.

In the preferred embodiment the invention comprises a multi-component intraruminal device with a cap, body and plug.

Figure 1 shows a view of the intraruminal device of the present invention. Figure 2 includes a detailed exploded view. Figure 1 is a plan view showing the intraruminal device and as can be seen the body is a tubular capsule.

Attached to a first end of the capsule 13 is a pair of arms 11 and a means for securing the cap 10 structure in place over the arms 11. The interior of the capsule is hollow so as to accommodate a spring and spring cap and also a medicament in a tabletted form. The bottom of the intraruminal device capsule is partially sealed with a plug.

2103146 004/nk 2103146_004.DOC 00 The cap 10 provides a bridge portion 19 underneath the aperture 21, which will 0 0gradually dissolve on contact with the ruminal fluid allowing the release of the cap

(N

from the capsule 13.

In the preferred embodiment the cap 10 structure is made entirely of a dissolvable 00 material so that on contact with moisture for example the ruminal fluid or saliva the cap 10 will begin to dissolve, allowing the release of the cap 10 from the capsule 13. The release of the cap 10 allows the movement of the arms 11 from the closed position close to the body to the open extended position ensuring Cc retention of the intraruminal device within the animals rumen.

l0 It has been found that plasticised cornstarch is particularly useful for the dissolvable cap 10. Plasticised cornstarch is sufficiently resilient and strong to hold the arms in a closed position while still displaying the preferred dissolving characteristics. Plasticised cornstarch has the further advantage of becoming slippery as it dissolves, accordingly when the capsule is inserted the saliva moistens the cap making it slippery and allowing an easier passage down the oesophagus to the rumen, and decreasing the likelihood of regurgitation.

The first end of the capsule 13 is sealed and has two resiliently flexible arms 11.

The use of the round cap structure eliminates the need to ensure smooth finish on the top of the capsule 13. However it is desirable to prevent the use of sharp edges and angles since once the cap structure dissolves the intraruminal device will be free floating within the rumen.

The top of the capsule includes means for securing the cap 10 onto the top of the capsule 13. This locking means comprises a flange 20 which in use interacts with the aperture 21.

The arms 11 are formed of a resiliently deformable plastic material, and are biased to an open position. For administration this bias is overcome by placement of the cap 10 to hold the arms in the closed position. When the cap 10 is released the arms 11 return to the open position.

2103146_004/nk 2103146_004.DOC 00 The capsule 10 is substantially hollow with its internal cavity being suitable for 0 accepting a spring 14, a spring cap 15 and medicament tablets 16.

t The first end of the cavity provides a base for the force of the spring 14 toward the capsule opening.

00 Within the cavity the spring 14 is positioned closest to the closed end with the IDspring cap 15 substantially sealing the area containing the spring 14.

Cc The tablets containing medicaments are included within the cavity.

The spring 14 and spring cap 15 are made with material which is resistant to Ni degradation by the ruminal fluid.

The cavity is partially sealed by a sealing cap 17. As can be seen from Figure 2 the bottom cap is substantially annular and defines an opening into the cavity area allowing the ruminal fluid to contact with the contents therewith.

The edges of the sealing cap 17 fit snugly with the edges of the capsule 13 to form a seal. This seal ensures that the tablets are only in contact with the ruminal fluid through the opening of the bottom of the capsule.

The spring 14 maintains a constant pressure via the spring cap 15 on the medicament 16 pushing it towards the aperture in the sealing cap 17. The tablets are formulated so they are dissolvable on contact with the ruminal fluid to give the desired dosage rate.

The tabletted medicament is inserted within the capsule cavity 13 between the spring cap 15 and the bottom cap 17. The medicament 16 is in the form of dissolvable, which are pressed tablets, of a size conforming with the dimensions of the capsule cavity.

The medicament is inserted as a single tablet running the length of the cavity or a number of discrete tablets. The tablets in the cavity may contain a selection of different medicaments for administration over an extended period of time in the rumen.

2103146 004/nk 2103146 004.DOC 00 As can be seen in Figure 2 the cap 10 has a semi-circular rounded top which is 0 formed in such a way as to ease passage of the device down the oesophagus of the ruminant animal.

The cap 10 is configured to fit over the sealed end of the capsule 13 and to secure 00oO the arms 11 in a closed position wherein the arms 11 are held close to the body of the capsule 13.

The capsule 13 and cap 10 together include mechanisms for securing the cap 10 in place. The cap 10 includes a means for securing it to the capsule 13. As seen in Figure 2 this means is in the form of flanges 20 protruding from the first end of the N 10 capsule and apertures 21 located on the cap 10. The flanges 20 are attached to the capsule 13 in such a way, as a small amount of flex is inherent in its position.

This flex allows the cap 10 to be "clicked" over the flange 20 and into place so that the flange 20 locates in the aperture 21 and secures the cap 10 on the capsule 13.

Those skilled in the art will appreciate that due to plastic creep the arms may not return completely to the original position.

Figure 3 is a top view of the intraruminal device and shows the relative placement of the arms 11 and the apertures 21. It can be seen from this top view that the cap structure 10 is substantially round and is able to seal completely around the top of the capsule 13 (not shown). The cap structure 10 has a number of faces, the area under which arms 11 will be held having a particularly faceted appearance. In addition the apertures 21 in the cap 10 are placed away from the area of the cap used to secure the arms 11 in the first closed position. This minimises the weakening in the cap structure around that mechanically constraining area. The longitudinal section indicated by the line A-A in this figure is displayed in Figure 4.

Figure 4 illustrates a longitudinal section with the section being between the two locking mechanisms on the cap and capsule. Figure 4 illustrates the relative positions of the spring 14, spring cap 15, and the medicaments 16 and bottom cap 17.

2103146_004/nk 2103146_004.DOC 00 It can be clearly seen from this illustration that the action of the spring 14 pushes the spring cap 15 toward the mass of medicament 16 which is in turn pressed toward the opening 18 in the sealing cap 17. The spring cap 15 is designed so it Sforms a seal between the spring 14 and the cavity of the capsule. This ensures 00 5 ruminal fluid is not able to pass through the cavity beyond the medicament 16 into the spring mechanism 14.

Figure 5 is a bottom view of the capsule structure that displays the arms 11 and the sealing cap structure 17. Figure 5 also indicates the position and relative size of the sealing cap hole 18. The size of this hole is increased or decreased to suit delivery requirements. Obviously the relative size of the hole can be varied to affect the rate of delivery of the medicament and therefore the total delivery time of the intraruminal device. Increasing the diameter of the hole leads to an increased rate of delivery and therefore a shortened delivery period. The sealing cap is more clearly illustrated in Figure 8. Figure 5 sets out the line B-B, which forms the basis of the longitudinal section of Figure 6.

Figure 6 displays the view along a section of line B-B as displayed in Figure The arms are displayed both in an open and closed position. The open position illustrated in Ila and the closed position in lib. It can be seen clearly from this picture that the shape of the arms 11 is such that it would fit under the cap structure 10 and lie along the length of the capsule 13. The aperture 21 and the flange 20 are also apparent in this view. In addition the structure of the top of the capsule 13 is illustrated in detail.

In this preferred embodiment the transition from the closed to open position is achieved by a resiliently biasing the arms to the open position. This means on release of the cap structure 10 the arms return to the open position.

It is essential the arms are in the closed position Figure lib for delivery of the device to the rumen via the oesophagus. The change to the open position of the arms once in the rumen enables the retention of the device within the rumen of the animal by preventing both regurgitation of the device and its passage further into the digestive system. The arms 11 are mounted to a central top portion of the 2103146 004/nk 2103146_004.DOC 00 capsule 13, this central portion has a diameter which is approximately half that of 0 the capsule. The surface of this extended protrusion is smooth and the uppermost surface is substantially flat. It is desirable that the profile obtained when the arms S11 are in a closed position is the same as or nearly so as the interior of the cap 00 5 structure 10. This is illustrated in Figure 6.

In Figure 6 the medicament 16 is illustrated as a series of tablets. This is considered the best form for the medicament as it allows the greatest flexibility with respect to a mix of medication and vitamin delivery. It is envisaged the Cc device be used to deliver a variety of medicaments in sequence. This could be achieved using the tablet form by varying the type of medicament in each tablet in the stack as desired, for example alternating anthelmintics with other medicaments such as dietary supplements, including vitamins, trace elements, growth promotants and minerals. Alternatively the tablets in the stack may not be independent and may in fact just be continuous along the length of the stack analogous to, for example a stick of chalk. The essential feature of the medicament is they fit snugly within the interior cavity of the capsule and are dissolvable by the ruminal fluid at a constant rate which allows delayed or prolonged dispersal of the medicament.

Figure 7 provides a scheme view of the intraruminal device displaying the arms in an open position.

The cap structure 10 is oriented as it would be for fitting over the arms The aperture 21 on the cap structure 10 is shown directly over the flange 20. In addition Figure 7 shows the strengthened portion of the cap designed to fit over the arms 11. The top of the capsule 13 is substantially to minimise damage to the rumen after release of the cap 2103146 004/nk 2103146004.DOC 00 Method of Use

O

0 In use the intraruminal device is sold as a prepacked unit including a series of

(N

Smedicament containing tablets. The arms are held in the closed position by the Scap structure.

00 The intraruminal device is administered to the animal using an intraruminal device gun which ensures the intraruminal device is delivered to the throat of the animal.

This ensures the intraruminal device is swallowed and passes through the n oesophagus to the rumen.

0 On contacting the animal's saliva the cap material begins to dissolve and becomes slippery. This aids the passage of the intraruminal device to the rumen.

Once in the rumen, the cap is exposed to the ruminal fluid and dissolves and is released from the capsule. Once dissolved the constrictive effect of the cap on the arms is removed and the arms are free to move to the open position.

The movement of the arms from a closed to an open position significantly decreases the chances the intraruminal device will either be regurgitated or will pass through the animal.

In addition the ruminal fluid passes through the aperture in the bottom cap and begins to dissolve the tabletted medicament. The tablet gradually dissolves releasing the medicament into the rumen for absorption through the animals stomach.

VARIATIONS

Figure 9 and 10 display an alternate embodiment. As can be seen from the illustration the configuration is similar to the embodiment included in Figures 1-8.

The securing means in this embodiment comprises an annular ring.

As with previous embodiments the capsule 13 is substantially hollow and tubular.

The intraruminal device has a cap 24 with a substantially circular base which attaches to the first end of the capsule 13. The top of the cap 24 is smooth and rounded. Elongate arms 25 formed integrally with the cap 24. The arms 25 lie 2103146 004/nk 2103146_004.DOC 00 substantially perpendicular to the top of the cap 24 so that their ends extend 0 0beyond the width of the cap. The arms 25 are made of a resiliently flexible

(N

material which is capable of moving from a first position shown in Figure 9 to a Gsecond position (not shown) where the arms 25 are held proximate along the 00 5 length of the capsule 13. The arms 25 are biased to the first position.

The arms 25 may be held in the second position alongside the capsule 13 by a ring 26 (illustrated in Figure 10). The ring 26 is of sufficient size to fit securely about the capsule 13 and arms 25 to hold the arms 25 in position proximate the capsule 13.

N 10 The ring 26 is made of a dissolvable material such as plasticised cornstarch so that in use the intraruminal device is presented to the animals oesophagus with the arms 26 held in the second position, that is proximate the capsule 13, by the ring 26. On exposure to the rumen fluid the ring 26 gradually dissolves. Once the ring 26 is sufficiently dissolved, the force exerted by the bias of the arms 25 to the first position breaks the ring 26.

On release of the ring 26 the arms 25 will move to the first position.

As with the preferred embodiment the second end of the capsule 13 is sealed with a sealing cap 17. The sealing cap forms a seal about the inner surface of the capsule 13 preventing passage of the rumen fluid to interior of the capsule 13 except through the aperture 18 in the centre of the sealing cap 17.

In use the rumen fluid will enter the interior of the capsule 13 through the aperture 18 and will contact the substantially solid medicament house in its interior.

Contact of the medicament with the ruminal fluid will allow the gradual dissolving of medicament and its consequent release into the rumen.

Various mechanisms are useable to ensure the medicament is held against the sealing cap 17. These have been described above and are equally applicable here.

The medicament 16 may in any formulation which is substantially solid, and dissolvable on contact with the ruminal fluid.

2103146 004/nk 2103146_004.DOC 00 It will be appreciated by those skilled in the art it is possible to use other means to 0 facilitate the change from closed to open positions. These may include spring (-i mechanisms incorporated in the top of the capsule 13 to physically push the arms S11 out into the open position.

00 The examples above describe the transition of the arms from the closed position to the open position as being triggered by the dissolving action of the ruminal fluid on the cap 10, and more specifically the portion of the cap 10 below the aperture 21. But this need not always be the case.

A system where the portion of the cap 10 over the arms 11, which is essentially C 10 responsible for holding the arms in a closed position, dissolves to trigger the release of arms to open position is equally acceptable. The dissolving of cap area over the arms 11 would allow the movement of arms 11 to position at 900 to body length.

One mechanism for securing the cap in place is described above. It will be appreciated that other mechanisms are equally useable.

In addition the rate at which the medicament can be dispersed can be varied by: Altering the composition to one, which dissolves either more quickly or more slowly in contact with ruminal fluid.

Changing the relative size of hole and thus the amount of medicament subjected/contacted with the ruminal fluid.

ADVANTAGES

The interaction of the cap and opening means is advantageous as it allows the movement of the arms from the closed state to the open state 90' to the body.

The use of the plasticised cornstarch results in a slippery surface on contact with saliva/mouth moisture, which will ease passage down the oesophagus. Thickening or thinning the wall section of the cap can also be used to alter the time taken to release the wings to their open state.

Finally it will be appreciated that various other alterations and modifications may be made to the foregoing without departing from the scope of the invention.

2103146 004/nk 2103146_004.DOC

Claims

2. An intraruminal device as claimed in claim 1, wherein the cap and the body are provided with co-operating members adapted to interconnect to secure the cap over the first end of the body.
3. An intraruminal device as claimed in 2, wherein the co-operating members are in the form of at least one aperture in the cap and at least one corresponding flange on the first end of the body.
4. An intraruminal device as claimed in either claims 2 or 3, wherein the co- operating members interconnect in a snap-fit arrangement.
5. An intraruminal device as claimed in any one of the preceding claims, wherein the cap is adapted to dissolve at least one a predetermined portion.
6. An intraruminal device as claimed in claim 5, wherein the predetermined portion is a bridge located proximate the at least one aperture in the cap. 2103146_004/nk 2103146_004.DOC 00 7. An intraruminal device as claimed in claim 1, wherein the capsule has at least 0 Stwo arms. c
8. An intraruminal device as claimed in any one of the preceding claims, wherein the cap contains a plasticized starch material.
9. An intraruminal device as claimed in any one of the preceding claims wherein IO said plasticized starch material is a plasticized corn or potato starch. F1- An intraruminal device as claimed in any one of the preceding claims, wherein the cap is shaped to allow easier administration and passage of the 0intraruminal device into the rumen.
11. An intraruminal device as claimed in claim 10, wherein the shape of the cap is semi-circular.
12. An intraruminal device as claimed in any one of the preceding claims, wherein the entire cap begins to dissolve on contact with saliva or other liquid thereby becoming slippery to enable easier administration of the intraruminal device into the rumen.
13. An intraruminal device as claimed in any one of the preceding claims, wherein the body is packed with one or more tablets including one or more medicaments, said tablets being soluble in the ruminal fluid, so that on administration the ruminal fluid contacts the tablet through the opening and the tablets gradually dissolve releasing said medicaments into the fluid.
14. An intraruminal device as claimed in any one of the preceding claims substantially as hereinbefore described with reference to the accompanying description and/or drawings. A method of administering an intraruminal device to a ruminant animal including: providing an intra-ruminal device including: 2103146 004/nk 2103146 004.DOC 00 a capsule, wherein the capsule includes a body having a cavity therein, the 0 0body having an opening to the cavity for receiving one or more tablets or 4 pharmaceutical formulations therein, at least one arm attached to a first end of the body, the arm or arms being 00 capable of being disposed in an open position where the arm or arms extend away from the body and in a closed position where the arm or arms rest or are rheld substantially against the body, said arm or arms being biased to the open position; and a holding means secured over the first end and upper part of said arm or arms N 10 for constraining the arm or arms in or towards the closed position, and wherein the holding means is formed at least in part from a material which becomes slippery when wet and dissolvable in contact with rumen fluid; the method including the step of delivering the device into the rumen of a ruminant animal, wherein the holding means becomes slippery upon contact with fluid thereby assisting passage of the device through to the rumen, and wherein at least part of the holding means is dissolved in the presence of rumen fluid to allow return of the arm or arms to the open position.
16. A method of administering an intraruminal device as claimed in claim substantially as hereinbefore described with reference to the accompanying description and/or drawings. 2103146_004/nk 2103148_004.DOC