Method and device for administering two components into the teat canal of a non-human animal

The invention relates to a method and device for treating or preventing or suppressing a disease or condition in a non-human animal. The method comprises the steps of providing a single delivery device containing two components for sequential delivery from the delivery device. A first component is delivered from the single delivery device into a teat canal of a non-human animal and subsequently the second component is delivered from the single delivery device into the teat canal. The components are delivered without substantial mixing of the components.

INTRODUCTION

The invention relates to a method and device for administering two components into the teat canal of a non-human animal.

Bovine mastitisis a severe, potentially fatal, inflammatory disease of the udder, caused by a broad range of infectious organisms, but most notably by various Gram positive bacteria of the generaStaphylococcusandStreptococcusand the Gram negative species,Escherichia coli. The infection usually enters the udder via the teat or streak canal. Mastitis is treated by a variety of antibiotic cerates, infused into the udder via the teat or streak canal. In severe cases, high doses of antibiotic are also given by injection. A high proportion of mastitic infections are contracted during the “dry” period, which precedes calving. The infection may later become clinically significant either during the dry period, or after calving when lactation has resumed.

It is known to treat mastitis using a twin injector pack, one injector containing an anti-bacterial formulation and a second injector containing a seal or barrier formulation. The anti-bacterial formulation is delivered first to the teat canal followed by delivery of the seal formulation forming a physical barrier in the teat canal against the entry of bacteria into the udder. These twin injector packs are sold under the name Teat Seal™. WO94/13261 and WO95/31180 describe the twin injectors in detail and are hereby incorporated by reference.

While the twin injector system provides an effective method to reduce the incidence of clinical mastitis administration of the injectors can be time consuming, doubles the risk of introducing extraneous environmental bacteria and doubles the risk of causing damage to the epithelium of the streak canal. The use of two injectors also increases the cost of treatment and creates additional non-degradable waste.

There is a need for an improved method and device for preventing intrammary disorders which will overcome at least some of these problems.

STATEMENTS OF THE INVENTION

According to the invention there is provided a method for treating or preventing or suppressing a disease or condition in a non-human animal comprising the steps of:—providing a single delivery device containing two components for sequential delivery from the delivery device;delivering a first component from the single delivery device into a teat canal of a non-human animal; andsubsequently delivering the second component from the single delivery device into the teat canal without substantial mixing of the components.

In one embodiment the delivery device comprises an injector device containing the two components, the components being separated by a barrier and the method comprises the steps of:—delivering the first component from the injector device;at least partially releasing the barrier; andsubsequently delivering the second component from the injector device.

In another embodiment the disease or condition is mastitis and the method of the invention is for treating or preventing a mastitis-causing micro-organism.

In a further embodiment the second component comprises a seal.

According to a further aspect the invention provides a method for treating, preventing or suppressing mastitis or a mastitis causing micro-organism comprising the steps of sequentially delivering from a single delivery device an antimicrobial formulation and a seal formulation into the teat canal of a non-human animal wherein the antimicrobial formulation and the seal formulation are delivered into the teat canal without substantial mixing of the formulations prior to delivery into the teat canal.

In one embodiment the seal formulation comprises a non-toxic heavy metal salt.

In another embodiment the seal formulation comprises greater than 40% by weight of the heavy metal salt.

In a further embodiment the seal formulation comprises between 50% and 75% by weight of the heavy metal salt.

In one embodiment the seal formulation comprises approximately 65% by weight of the heavy metal salt.

In another embodiment the heavy metal is bismuth.

In a further embodiment the salt is a sub-nitrate salt.

In one embodiment the seal formulation comprises a gel base.

In another embodiment the gel base is a gel based on aluminium stearate.

In a further embodiment the gel base includes liquid paraffin as a vehicle.

In one embodiment the first component comprises an antimicrobial.

In another embodiment the antimicrobial is selected from any one or more of betalactam antibiotics, polymyxins, glycopeptides, aminoglycosides, lincosamides, macrolides, pleuromutilins, “fenicols” such as chloramphenicol and florfenicol, tetracyclines, sulphonamides and potentiated sulphonamides such as mixtures of trimethoprim and one or more sulphonamide, quinolones and fluoroquinolones, ionophores, courmarins such as novobiocin, natural or synthetic peptides, aminoglycosides, antimicrobial peptides or antimicrobials, lantibiotics, or other products of bacteria and other micro-organisms.

In a further embodiment the betalactam is selected from any one or more of penicillin, modified penicillin such as cloxacillin, amoxycillin, ampicillin, cephalosporins or beta lactam antibiotics potentiated by beta lactamase inhibitors such as clavulanic acid.

In one embodiment the aminoglycoside is selected from any one or more of streptomycin, dihydrostreptomycin, neomycin, gentamycin, framycetin, aparamycin or kanamycin.

In another embodiment the antimicrobial is selected from any one or more of macrolide, lincosamide or pleuromutilin, erythromycin, spiramycin, tylosin, spiramycin, tilmicosin, lincomycin, spectinomysin, pirlimycin or tiamulin.

In a further embodiment the antimicrobial is selected from any one or more of potentiated sulphonamide mixtures, trimethoprim plus sulphadiazine, sulphadimidine, sulphadoxine, sulphadimethoxine or other sulphonamide, oxytetracycline, minocycline or doxycycline, fluoroquinolones, enrofloxacin, ciprofloxacin, norfloxacin, danofloxacin, difloxacin or marbofloxacin.

In one embodiment the first component comprises an anti-inflammatory.

In another embodiment the anti-inflammatory is selected from any one or more of steroids such as prednisolone, betamethazone, dexamethazone, phenylbutazone, or non-steroids such as flunixin, ketoprofen, carprofen, vedaprofen, meloxicam, tepoxalin, eltenac, nimesulide or tolfenamic acid.

According to further aspect of the invention there is provided an injector device for delivery of components into the teat canal of a non-human animal comprising:a barrel for containing a first component,an outlet nozzle at one end of the barrel,an internal receptacle for containing a second component,a barrier for separating a first component and a second component, anda delivery means for delivery of a first component from the barrel and sequential delivery of a second component from the internal receptacle through the outlet nozzle.

In one embodiment the barrier is normally closed.

In another embodiment the barrier is releasable for delivery of the second component.

In a further embodiment the barrier is defined by at least a portion of the internal receptacle.

In one embodiment the barrier comprises one or more passageways.

In another embodiment the one or more passageways are opened when the barrier is released for delivery of the second component through said one or more passageways.

In a further embodiment the device comprises an activator for releasing the barrier.

In one embodiment the activator comprises a mechanical activator means.

In another embodiment the activator comprises at least one projecting member.

In a further embodiment the activator is located in the barrel.

In one embodiment the activator is located adjacent to the outlet nozzle.

In another embodiment the activator comprises one or more passageways.

In a further embodiment the activator is configured for engagement with the internal receptacle to provide a direct passageway for delivery of the second component from the internal receptacle into the outlet nozzle.

In one embodiment the delivery means comprises a plunger for the barrel.

In another embodiment the barrier is released by the delivery means.

In a further embodiment the internal receptacle comprises an inner barrel located within an outer barrel defined by the barrel of the injector.

In one embodiment the inner barrel is a close fit within the outer barrel.

In another embodiment the delivery means comprises the inner barrel.

In a further embodiment the inner barrel defines a plunger for the outer barrel.

In one embodiment the delivery means comprises a plunger for the inner barrel.

In another embodiment the inner barrel comprises engagement means for engagement with the outer barrel on assembly.

In a further embodiment the engagement means comprises an external seal.

In one embodiment the outer barrel comprises engagement means for engagement with the inner barrel.

In another embodiment the outer barrel comprises a locking ring for engagement with the inner barrel.

In a further embodiment the inner barrel comprises engagement means for engagement with the plunger.

In one embodiment the inner barrel comprises a locking ring for engagement with the plunger.

In another embodiment the receptacle comprises a bag.

In a further embodiment the receptacle comprises a capsule.

In one embodiment the receptacle is attached to or forms an integral part of the delivery means.

In another embodiment the activator comprises a rupturing means for at least partially releasing the barrier.

In a further embodiment the rupturing means comprises a mechanical rupture member.

In one embodiment the rupture member comprises at least one blade.

In another embodiment the rupture member comprises at least one tooth.

In a further embodiment the rupture member is located in the barrel.

In one embodiment the rupture member is located adjacent to the outlet nozzle.

In another embodiment the barrel contains a first component.

In a further embodiment the first component comprises an antimicrobial formulation.

In one embodiment the internal receptacle contains a second component.

In another embodiment the second component comprises a seal formulation.

In a further embodiment a first component is delivered from the barrel and a second component is subsequently delivered from the internal receptacle without substantial mixing of the components.

In one embodiment the seal formulation may comprise the seal formulation as described above.

In another embodiment the antimicrobial formulation may comprise the antimicrobial formulation as described above.

DETAILED DESCRIPTION

The invention provides an injector device that allows for the sequential delivery of two incompatible components such as an antimicrobial formulation and a seal formulation into the teat canal of a non-human animal. The seal formulation and antimicrobial formulation are contained separately within a single injector device. This enables the product to be stored without affecting the stability of either component. The device also provides for the delivery of the antimicrobial formulation ahead of the seal formulation which effectively forms a physical barrier in the teat canal preventing any further entry into the teat canal. The seal formulation also prevents the possibility of the antimicrobial phase leaking or being expressed from the teat by gravitational or hydrostatic forces.

The seal formulation may comprise a viscous oil-based cerate containing a high proportion of a heavy metal salt, bismuth subnitrate. The product Teat Seal (trade mark of Cross Vetpharm Group) is described in detail in WO98/26759 and comprises a non-toxic heavy metal salt in a gel base. The base is a gel based on aluminium stearate. The gel preferably includes a vehicle such as liquid paraffin. The gel may also comprise a polyethylene gel. The gel may be based on low density polyethylene or on high density polyethylene. Preferably, the heavy metal salt is present in an amount of greater than 40%, preferably between 50% and 75% by weight, most preferably approximately 65% by weight.

The seal formulation prevents infection entering the udder via the teat or streak canal through a combination of its viscosity, density and adhesiveness.

The antimicrobial or anti-inflammatory formulation may be selected from any one or more of a wide variety of compounds that are known to be effective for the treatment, prevention and elimination of mastitis and mastitis-causing organisms, including inter alia gram positive and gram negative bacteria, yeasts, fungi and rickettsias. The antimicrobial or anti-inflammatory materials may include inter alia beta lactam antibiotics such as penicillins and cephalosporins, beta lactam antibiotics potentiated by beta lactamase inhibitors such as clavulanic acid, polymyxins, glycopeptides, aminoglycosides, lincosamides, macrolides, pleuromutilins, “fenicols” such as chloramphenicol and florfenicol, tetracyclines, sulphonamides and potentiated sulphonamides such as mixtures of trimethoprim and one or more sulphonamide, quinolones and fluoroquinolones, ionophores, coumarins such as novobiocin, natural or synthetic peptides, lantibiotics, and other antimicrobial products of bacteria and other micro-organisms.

The second component may be selected from any one or more of anti-inflammatory compounds, steroids such as prednisolone, betamethazone, dexamethasone, phenylbutazone, or non-steroids such as flunixin, ketoprofen, carprofen, vedaprofen, meloxicam, tepoxalin, eltenac, nimesulide or tolfenamic acid.

Other antimicrobial or anti-inflammatory compounds used in the treatment of intramammary infections in non-human animals may also be used.

These antimicrobial or anti-inflammatory materials may be formulated either singly or in combinations of two or more compounds as liquids, cerates, solutions, suspensions emulsions or flowable powders in water, oil (of animal, vegetable, mineral or other origin) or other organic vehicles. Other excipients such as solubilising, suspending or emulsifying agents, viscosity modifiers, surfactants, encapsulating agents and other means to adjust the rate at which the compound(s) is released from the formulation, buffers and such agents to maintain the pH of the formulation, anti-inflammatory agents such as various steroidal and non-steroidal compounds commonly used for this purpose, and various preservative agents commonly used in pharmaceutical preparations.

Referring to the drawings an initially toFIGS. 1 to 8there is illustrated an injector device1according to the invention. The injector device1in this case comprises an inner barrel2and an outer barrel3. The outer barrel3has a nozzle4. The inner barrel2contains a first component comprising a seal9. The barrel2has a barrier or membrane5at its distal end. A plunger6is inserted into proximal end of the inner barrel2above the seal component9. An antimicrobial or anti-inflammatory component10is contained within the outer barrel3below the inner barrel2. In use, the nozzle4is inserted into a teat canal20of a non-human animal such as a cow. The inner barrel2is pushed through the outer barrel3by the plunger6to expel the antimicrobial or anti-inflammatory component10(FIG. 8(a)). When the antimicrobial or anti-inflammatory component10has been expelled (FIG. 8(b)) the plunger6on the inner barrel2is further depressed to expel the seal9from the inner barrel2. The pressure of the plunger6may be sufficient to release or rupture the barrier/membrane5on the inner barrel2allowing the seal9to be expelled from the injector device through the nozzle4and into the teat canal (FIG. 8(c)). Rupturing means such as teeth30situated within the outer barrel3adjacent to the outlet nozzle4, may be used to release or rupture or open the barrier/membrane5.

Referring toFIGS. 9 and 9(a) there is illustrated another injector which is similar to the injector ofFIGS. 1 to 8and like parts are assigned the same reference numerals. The injector device1comprises an inner barrel2and an outer barrel3. The outer barrel3has a nozzle4. In this case the barrier is released by an activator defined by a number of spikes50projecting upwardly to different lengths. The membrane/barrier has a portion51which is knocked-out by the spikes50to allow ejection of the seal component. The distal end of the inner barrel2has a seal or frill53which seals with the inner wall of the outer barrel3.

Referring toFIGS. 10 to 13there is illustrated a further injector which is again similar to that ofFIGS. 1 to 8and like parts are assigned the same reference numerals. The injector device1comprises an inner barrel2and an outer barrel3. The outer barrel3has a nozzle4. In this case the barrier comprises a valve60at the distal end of the inner barrel2. An activator61projects upwardly from the lower wall of the outer barrel. In use, when the inner barrel2is in the configuration ofFIG. 11the valve60is lifted by engagement with the activator61and allows the seal component9in the inner barrel2to pass through the injector nozzle4.

When the plunger6is pushed down, the inner barrel2also travels down through the outer barrel3. The outside of the inner barrel2is a close fit in the outer barrel3so that the inner barrel2itself acts as a delivery device or plunger for delivery of the first component from the outer barrel3through the nozzle4.

Referring toFIGS. 14 to 16there is illustrated another injector which is again similar to the injector ofFIGS. 1 to 13and like parts are assigned the same reference numerals. The injector device comprises an inner barrel2and an outer barrel3. The outer barrel3has a nozzle4. The inner barrel2contains a seal component9. A plunger6is inserted into proximal end of the inner barrel2above the seal component9. Antimicrobial10is contained within the outer barrel3. In use, the nozzle4is inserted into a teat canal20. The inner barrel2comprises a distal end74having an outlet75and the barrier comprises a valve70which is received in the outlet75. The valve70is normally closed (FIGS. 14(a), (b)) during delivery of the first component from the outer barrel3. An activator71projects upwardly from the lower wall of the outer barrel3. In use, when all of the first component has been delivered and the inner barrel2is in the configuration ofFIG. 14(c) the valve70is released by engagement with the activator71and the seal component9in the inner barrel2is allowed to pass through side passageways76in valve through the outlet75and into the injector nozzle4.

The inner wall of the inner barrel2is formed for engagement with the plunger6and comprises a locking ring173between the proximal and distal ends thereof. The inner barrel2comprises a distal portion178and a proximal portion179, the distal portion178having an internal diameter less than the internal diameter of the proximal portion179. The plunger6comprises a seal77which passes over the locking ring173of the inner barrel on assembly and the plunger6is thus sealingly engaged with the inner barrel2.

The inner barrel2further comprises an external seal72for engagement with the internal wall of outer barrel3. The external seal72may for example comprise an integrally formed seal or an o-ring housed in a recess172in the external side wall of the inner barrel2. The external seal72is located near the distal end74of the inner barrel.

The internal wall of the outer barrel3is formed for engagement with the inner barrel2and comprises a locking ring73between the proximal and distal ends thereof for engagement with the external seal72of the inner barrel2. The outer barrel3comprises a distal portion78and a proximal portion79. The distal portion78having an internal diameter less than the internal diameter of the proximal portion79. The external seal72passes over locking ring73of the outer barrel3on assembly and sealingly engages the outer barrel. The antimicrobial or anti-inflammatory formulation10is thus prevented from passing between the barrels as the plunger6is depressed.

The valve70comprises a plurality of channels76which are exposed when the valve70is released to allow the seal component to pass out through the valve. Thus upon releasing of the valve the channels76which define a passageway for the seal component are opened.

The activator71defines a substantially cylindrical form defining a passageway and corresponds in form to the outlet75enabling it to be received in a portion of the outlet. The activator71is a close fit with the outlet75.

In use the inner barrel2is pushed through the outer barrel3by the plunger6to expel the antimicrobial10(FIG. 14(a)). The outside of the inner barrel2has the geometry of the plunger6so that the inner barrel2itself acts as a plunger. When the antimicrobial10has been expelled (FIG. 14(b)) the plunger6on the inner barrel2is further depressed to expel the seal9from the inner barrel2. The valve70is released by engagement of the inner barrel with the activator71and the seal component9in the inner barrel2is allowed to pass through the valve passageways into the injector nozzle4and is expelled into the teat canal (FIG. 14(c)).

Referring toFIGS. 14 to 16, and in particularFIGS. 16(b) and (c) the operation of the valve is described in more details.

When closed the valve70which is a close fit with the outlet75rests in the outlet and prevents any mixing of the components in the outer and inner barrels (FIGS. 14(b) and16(b)).

When the activator71is received in the outlet75(FIGS. 14(c) and16(c)) the valve is released and the passageways76in the valve are opened to enable the seal component to pass into the valve passageways76through the passageway defined by the activator71and into the injector nozzle4.

The engagement of the activator71with the outlet of the inner barrel2provides for alignment of the respective passageways76of the valve and the activator before the valve is released and the seal component is allowed to pass from the inner barrel. The respective passageways76of the valve and activator provide a closed and isolated pathway for the seal component to pass from the inner barrel2directly into the injector nozzle4.

One advantage of a valve type barrier of this embodiment is that there is not risk of any part of the barrier becoming mobile. The barrier is retained with the injector.

Referring toFIGS. 17 to 18there is illustrated an injector device81of an alternative embodiment of the invention (which is similar to the injector ofFIGS. 1 to 16and like parts are assigned the same reference numerals). The injector device81comprises a barrel3, an outlet nozzle4and a plunger6. Two incompatible components9and10are placed within the barrel3of the injector device81. The two components such as an antimicrobial10and a seal9are separated from one another by a barrier/membrane. The antimicrobial10is placed in the barrel3and a seal9is placed in a receptacle86such as a bag which is defined by an outer membrane87which provides the barrier.

The receptacle86may comprise a capsule into which the seal is filled on manufacture. The capsule may then be readily dropped into the barrel3of the injector before a plunger6is inserted.

When the nozzle4of the device81is inserted into a teat canal16a user depresses the plunger6to effect delivery of the antimicrobial10from the injector device into the teat canal (FIG. 17(a)). After the antimicrobial10is expelled from the injector device further pressure applied to the plunger results in puncturing or bursting of the receptacle86allowing egress of the seal9which is delivered into the teat canal (FIG. 17(b)).FIG. 17(d) shows the position of a seal formulation9and antimicrobial formulation8on delivery into the teat of a non-human animal.

The injector device may comprise rupturing means such as sharp teeth88at the distal end of the barrel3to assist in puncturing or bursting the receptacle86.

It will be appreciated that for ease of manufacture and use, the receptacle86may be attached to the plunger6. In this case the receptacle is unable to come into contact with the rupturing device until substantially all of the first component has been expelled from the device.

When delivering a seal9and antimicrobial or anti-inflammatory formulation10into the teat canal of a non-human animal the injector device is typically positioned vertically below the teat with the delivery nozzle uppermost. The seal formulation9has a much higher specific gravity than the antimicrobial or anti-inflammatory formulation10and therefore the receptacle containing the seal formulation remains at the lower end of the barrel3containing the antimicrobial or anti-inflammatory formulation during the delivery of the antimicrobial or anti-inflammatory formulation into the teat. In this case the receptacle comes into contact with the rupturing device only when substantially all of the antimicrobial or anti-inflammatory formulation has been delivered into the teat.

Referring toFIGS. 19 and 20there is illustrated another injector device90of the invention. The injector device90comprises an inner barrel92and an outer barrel93. The outer barrel93has a nozzle94. The inner barrel92comprises a breakable/burstable barrier or membrane at its distal end and a plunger98at its proximal end. Antimicrobial10is contained within the outer barrel93. In use, the nozzle94is inserted into a teat canal16. The inner barrel92is pushed through the outer barrel93to expel the antimicrobial (FIG. 20(b)). This procedure may be facilitated by a flange97around the proximal end of the inner barrel92and a flange99around the proximal end of the outer barrel93. When the antimicrobial10has been expelled (FIG. 20(c)) the plunger98on the inner barrel92is depressed to expel the seal9from the inner barrel91. The pressure of the plunger98is sufficient to burst or rupture the barrier/membrane96on the inner barrel92allowing the seal9to be expelled from the injector device through the nozzle94and into the teat canal (FIG. 20(c)). Alternatively rupturing means such as sharp teeth situated within the outer barrel93at its aperture into the nozzle, ruptures the barrier/membrane96.

A seal96may be provided at the front end of the inner injector barrel92to provide a positive seal. The inner injector may be moulded with a weak burstable barrier/membrane95across the outlet aperture.

It will be appreciated that the seal portion of the formulation may be manufactured in one facility and subsequently combined with the anti-bacterial portion of the formulation at a later stage, in the same or another facility.

The invention is not limited to the embodiments hereinbefore described which may be varied in detail.