WO2013091882A1

WO2013091882A1 - A pharmaceutical package

Info

Publication number: WO2013091882A1
Application number: PCT/EP2012/005322
Authority: WO
Inventors: Vincent Naughton
Original assignee: Athlone Laboratories Limited
Priority date: 2011-12-23
Filing date: 2012-12-21
Publication date: 2013-06-27
Also published as: GB2499567A; GB201122245D0

Abstract

The invention provides a pharmaceutical package comprising first (2) and second (4) sealed containers connected together along a common axis by means of a hollow connector (6); one of the first and second containers containing a pharmaceutical composition in a dispersible solid form and the other of the first and second containers containing a liquid diluent; wherein the package can be activated to mix the pharmaceutical composition and the diluent to form a suspension or solution; and wherein: the first container (2) has a mouth (3) which is sealed by a removable closure (12); an end wall (22) opposite the mouth; and a side wall or walls constructed such that the first container is at least partially collapsible along the common axis; a cutting element (16) is attached to the first container and extends into the container from the mouth thereof towards the said end wall; the second container (4) has a mouth (34) which is sealed by a sealing element (36) and which faces the end wall of the first container; the package is activated by relative movement between the first container and the hollow connector such that the first container is at least partially collapsed along the common axis thereby bringing the cutting element (16) into contact with the said end wall so that it cuts through and displaces at least part of the end wall (22) and at least part of the sealing element of the second container to create a flow path between the interiors of the first and second containers to allow dispersion and mixing of the pharmaceutical composition and the liquid diluent; and the removable closure is removable from the mouth of the first container to allow a suspension or solution formed by the mixing of the pharmaceutical composition and the liquid diluent to be dispensed from the package.

Description

A PHARMACEUTICAL PACKAGE

This invention relates to a pharmaceutical package for use in preparing a liquid pharmaceutical composition and in particular pharmaceutical solution and suspension compositions. Background of the Invention

There are many circumstances where it is desirable or preferable to administer a drug substance or other pharmaceutical substance in a liquid form. Such circumstances include the administration of drugs to children or to patients who, for various reasons, are unable or unwilling to swallow capsules or tablets. Whereas many pharmaceutical substances can be formulated as solutions or suspensions and have acceptable shelf lives when in solution or suspension, there are many other substances that are relatively unstable in solution over even short periods. For drugs that are insoluble in water, it is often possible to prepare suspensions. However, excipients such as suspending agents, formulation stabilizers and thickeners are typically required in order to prepare stable solutions and suspensions and, even with the inclusion of such excipients, solutions and suspensions may still suffer from poor long term stability.

For the above reasons, many drugs are manufactured and sold in a dispersible solid form and are then mixed with a liquid diluent such as sterile water shortly before use. For example, penicillin antibiotics such as amoxicillin and flucloxacillin are often supplied to pharmacists in powder form and are then made up into suspensions for immediate use over a short term by patients, typically five to seven days.

Whereas making up a suspension formulation in a pharmacy does not usually pose any problems for a trained pharmacist, there is nevertheless potential for errors to be made, particularly if part-trained or untrained staff members are used to perform the task and are inadequately supervised. Making up suspensions can also be somewhat time consuming meaning that customers may have to wait longer for a prescription to be fulfilled. It would therefore be advantageous if compositions intended to be made up into suspensions could be provided to the pharmacist in a form which requires shorter preparation times and which avoids the possibility of weighing and measuring errors within the pharmacy.

The extemporaneous preparation of liquid pharmaceutical formulations can also be highly problematic in circumstances where sterile water is in short supply or simply not available at all, for example in field hospitals and disaster relief operations. In such circumstances, rather than refuse to dispense potentially lifesaving drugs because there is no sterile water available, there will be a strong temptation or indeed a need for medical personnel to use water from a supply of potable water or other source of water that appears to be clean. In such circumstances, the presumed clean water may not in fact be clean and hence there exists ample opportunity for medicines to become contaminated by dirty or non-sterile water. In the case of antibiotics, there is also the possibility that some of the antimicrobial activity of the antibiotic will be used up by killing the bacteria present in the contaminated water, thus leaving the patient with a sub-potent medicine. The foregoing problems are exacerbated when there are not even adequate supplies of potable water available, as is frequently the case when supplying medical aid in natural disaster situations.

Summary of the Invention

The present invention sets out to provide a pharmaceutical package that overcomes many of the aforementioned problems.

Accordingly, in a first aspect, the invention provides a pharmaceutical package comprising first and second sealed containers connected together along a common axis by means of a hollow connector;

one of the first and second containers containing a pharmaceutical composition in a dispersible solid form and the other of the first and second containers containing a liquid diluent;

wherein the package can be activated to mix the pharmaceutical composition and the diluent to form a suspension or solution; and wherein:

the first container has a mouth which is sealed by a removable closure; an end wall opposite the mouth; and a side wall or walls constructed such that the first container is at least partially collapsible along the common axis;

a cutting element is attached to the first container and extends into the container from the mouth thereof towards the said end wall; the second container has a mouth which is sealed by a sealing element and which faces the end wall of the first container;

the package is activated by relative movement between the first container and the hollow connector such that the first container is at least partially collapsed along the common axis, thereby bringing the cutting element into contact with the said end wall so that it cuts through and displaces at least part of the end wall and at least part of the sealing element of the second container to create a flow path between the interiors of the first and second containers to allow dispersion and mixing of the pharmaceutical composition and the liquid diluent; and

the removable closure is removable from the mouth of the first container to allow a suspension or solution formed by the mixing of the pharmaceutical composition and the liquid diluent to be dispensed from the package.

Particular and preferred embodiments of the invention are as set out in the claims appended hereto and as described below. The first container and hollow connector are typically provided with mutually engaging threaded regions for securing the container and connector together. Preferably, the first container is provided with an externally threaded region which screws into an internally threaded region of the hollow connector. In this embodiment, during assembly of the package, the first container will typically be screwed into the hollow connector sufficiently far to ensure that the two items are firmly connected together but not so far that the first container begins to collapse. In order to activate the package to mix the dispersible solid and liquid diluent, the first container is screwed further into the hollow connector so that it is compressed against an abutment surface inside the connector and/or against a surface of the second container. As the first container is subjected to axial compression, it undergoes partial collapse with the result that the interior of the container is shortened and the cutting element moves into contact with the end wall of the container.

Typically, the first container has a side wall with a threaded region adjacent or towards the mouth of the container and a collapsible region adjacent or towards the end wall of the container. The wall of the container in the collapsible region may be provided with one or more folds (e.g. concertina folds) to aid collapse. Thus, in one embodiment, the collapsible region may take the form of a concertina tube.

The cutting element is attached to the first container and extends into the container from the mouth of the container towards the end wall. Therefore, as the first container moves further into the hollow connector (e.g. as a result of being screwed further into the connector), the cutting element will move with it. In a preferred embodiment, the cutting element is secured in the mouth of the first container. In this embodiment, in order that the cutting element does not block the mouth of the container and prevent the dispensing of the suspension or solution, the cutting element is typically provided with a passage or channel through which the suspension or solution can be dispensed. For example, the cutting element may have an open-ended cylindrical or tubular outline, preferably wherein the walls of the cylinder or tube have been partially cut away to minimise inhibition of flow of materials around the interior of the container. The cutting element is provided with a cutting edge that is sufficiently sharp to penetrate the end wall of the first container and the sealing element of the second container. The cutting element may have a circular cutting edge so that it cuts a circular or part circular opening in the end wall and sealing element. The cutting edge may be angled so that it presents a cutting tip which makes initial contact with the end wall and sealing element. For example, the cutting edge may lie in a plane which is angled (e.g. at an angle of 55-75° with respect to the common axis).

The cutting element may conveniently be connected to a plug which sits in the mouth of the first container, the plug having a passageway (e.g. a central passageway) through which the suspension or solution can be dispensed. The plug is typically formed so that its outer surface forms a seal against the mouth of the container. The plug may be provided with gripping ridges around its

circumference that enable it to grip and seal against a neck of the first container.

The first container is preferably provided with a neck, in which case the removable closure of the first container may comprise a cap which is secured to the neck. The neck may be threaded (in which case the removable closure may be a screw cap). Alternatively, the cap and neck may be provided with inter-engaging formations which cooperate to form a bayonet fitting or a snap fit. In a further alternative, a cap may be provided with a frangible link or a tear strip which can be broken or removed to allow removal of the cap.

The second container and hollow connector are typically provided with mutually engaging threaded regions for securing the container and connector together. The second container typically has an external thread which engages an internal thread on the hollow connector to secure the second container to the hollow connector. The external thread may be carried on a neck region of the second container.

Thus, the hollow connector may be provided with two separate internal threaded regions, one for connection to the first container and the other for connection to the second container. The two separate internal threaded regions may be of the same or different radius. In one embodiment, the internal threaded region for connection to the first container is of greater radius than the internal threaded region for connection to the second container. The threaded region which engages the second container may be an integrally moulded part of the hollow connector or it may be constituted by an internally or externally threaded tube or cylinder that is formed separately and then secured (e.g. by means of a snap fit) inside the hollow connector.

Preferably, the pharmaceutical package comprises means for preventing unintended activation, for example by preventing the collapsing of the first container. The means for preventing unintended collapsing of the first container may comprise an abutment on or in the hollow connector which engages an abutment on the first container to prevent relative movement (e.g. rotational movement) between the first container and the hollow connector. The abutments therefore prevent the first container from being screwed further into the connector. The abutment on the hollow connector may take the form of a removable tab and the abutment on the first container may take the form of a shallow recess in the wall of the container in which the removable tab is accommodated prior to activation, the tab and recess serving to prevent rotation of the first container in the hollow connector. In order to enable the package to be activated, the tab is removed, for example by breaking it off (where it is frangibly linked to the connector) or lifting out of the recess (where it is hingedly linked to the connector or is deformable by bending), so that the first container can be rotated and screwed further into the hollow connector. Premature activation of the package can also be prevented or hindered by the application of a label (preferably a tamper-evident label) to the package which overlies at least part of the first container and at least part of the hollow connector. Preferably, the label (e.g. tamper evident label) extends around the greater part (e.g. at least 75%) of the perimeter (e.g. circumference) of the package so that the join between the first container and the hollow connector is substantially concealed. The tamper evident label can be formed from a paper material or a synthetic polymeric material and is typically affixed to the package by means of a peelable adhesive so that at least part if not all of the label can be removed prior to activation of the package.

When the package has been activated and a flow channel has been created between the interiors of the first and second containers, it is important to ensure that leakage of the contents of the two chambers does not occur. Therefore, it is most preferred that a seal is provided between the first and second containers, or between the first container and the connector and the second container and the connector. In one embodiment, an annular gasket is disposed between the end wall of the first container and the mouth of the second container. When the package is assembled, the first and second containers are inserted (e.g. screwed) into the hollow connector sufficiently tightly that the annular gasket is clamped firmly between the two containers. As an alternative to a single gasket between the two containers, two or more gaskets may be employed. For example, one gasket may be clamped between the first container and a surface of the hollow connector and another gasket may be clamped between the second container and a surface of the hollow connector. The second container has a mouth which is sealed by a sealing element so that the contents of the second container (e.g. sterile water) do not escape prior to activation of the package. The sealing element may comprise a membrane, for example a membrane formed from a single layer or multilayer polymeric material. The sealing element (e.g. membrane) is designed to be punctured or ruptured by the cutting element when the package is activated. The sealing element may be provided with a line of weakness (e.g. a region of reduced membrane thickness) to assist puncturing or rupturing. The second member and/or the hollow connector may be provided with means for preventing removal of the second container from the package after assembly. For example, the second container and hollow connector may have formations (e.g. asymmetric sawtooth projections or recesses) that cooperate to form a ratchet arrangement.

The pharmaceutical package may be configured so that when the package is placed in an upright position on a surface, the second container serves as a base and the first container is uppermost.

After activation, the package is typically shaken to mix the contents of the two containers to form the suspension or solution. The resulting suspension or solution may be dispensed from the package by removing the removable closure (e.g. cap) and pouring out a dose into a suitable receptacle such as a spoon (e.g. a measuring spoon). Alternatively, a dispensing device such as a syringe (e.g. an oral syringe) may be used to remove the suspension or solution from the package. In a preferred embodiment, the pharmaceutical package may further comprise an oral syringe which, after removal of the removable closure from the mouth of the first container, can be inserted through the mouth of the first container and through into the interior of the second container to enable extraction of the suspension or solution. The first and second containers and hollow connector are typically formed from moulded plastics materials such as polyethylene.

In one embodiment, the first container contains the pharmaceutical composition in a dispersible solid form and the second container contains the liquid diluent.

The dispersible solid form may be, for example, selected from a powder, granules, pellets or a tablet (i.e. a rapidly disintegrating tablet).

In one preferred embodiment, the dispersible solid form is a powder or granules, and most preferably a powder.

The pharmaceutical composition may contain a drug substance and optionally one or more pharmaceutical excipients. The drug substance may be, for example, an antibiotic such as a penicillin. Examples of penicillins include benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V or penicillin VK), nafcillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, ampicillin, amoxicillin, bacampacillin, carbenicillin indanyl, ticarcillin, mezlocillin and piperacillin. Preferred penicillins are flucloxacillin, phenoxymethylpenicillin and amoxicillin. The liquid diluent is typically aqueous. It may for example contain water and another liquid diluent such as ethanol but typically it contains water as the only liquid component.

In one embodiment, the liquid diluent is substantially pure water.

Preferably the liquid diluent is sterile water. In one embodiment, the pharmaceutical composition and liquid diluent are selected such that when mixed and shaken, they form a pharmaceutical suspension.

In another embodiment, the pharmaceutical composition and liquid diluent are selected such that when mixed and shaken, they form a pharmaceutical solution.

Further embodiments and aspects of the invention will be apparent from the following description of a specific embodiment and the claims appended hereto.

Brief Description of the Drawings

Figure 1 is a side elevation of a pharmaceutical package according to a first embodiment of the invention.

Figure 2 is a side sectional elevation of the pharmaceutical package of Figure 1. Figure 3 is an exploded view showing the components of the pharmaceutical package of Figures 1 and 2.

Figure 4 is a side view of the first container forming part of the pharmaceutical package of Figures 1 to 3.

Figure 5 is a view from above of the first container shown in Figure 4. Figure 6 is a view from above of the hollow connector linking the first and second containers of the pharmaceutical package of Figures 1 to 3. Figure 7 is a side sectional view of the hollow connector of the pharmaceutical package of Figures 1 to 3.

Figure 8 is a perspective view of the hollow connector.

Figure 9 is a perspective view of the second container forming part of the pharmaceutical package of Figures 1 to 3.

Figure 10 is a side view of the second container.

Detailed Description of the Invention

The invention will now be illustrated, but not limited, by reference to the specific embodiment shown in the accompanying drawings Figures 1 to 10. As shown in the Figures, the package comprises a first container 2 and a second container 4, the two containers being connected together by two separate threaded regions of a hollow connector 6. An adhesive tamper-evident label 8 is affixed around the greater part of the circumference of the package and conceals the join between the first container and the hollow connector. In the embodiment illustrated in the drawings, the first container 2 contains a pharmaceutical composition in dispersible solid form. It may, for example, be in a finely divided form such as a powder or granules. The second container 4 contains a liquid diluent, and in particular an aqueous liquid diluent. The liquid diluent may be, for example, sterile water. The two containers 2 and 4 and the hollow connector 6 are typically formed from a pharmaceutical grade of polyethylene.

The first container 2 has a mouth 3 at the end of a neck 10 which is externally threaded to enable it to be connected to a screw cap 12. Set into the mouth 3 and neck 10 and held in place by means of annular gripping ribs is a plug 14 from which a cutting element 16 extends into the interior of the first container. The plug 14 has a central passage 18 through which the contents of the package can be dispensed once the package has been activated.

The cutting element 16 is of generally tubular form but with windows cut into the side walls of the tube so that it does not represent a significant obstruct to the flow of materials inside the package. The cutting element 16 has an angled cutting edge 20 that lies in a plane at an angle Θ with respect to the central axis (common axis) A (see Figure 3) of the package.

The end wall 22 opposite the neck 8 (i.e. the lower wall when the package is in an upright position) has an annular line of weakness (not shown) extending around its lower surface, the wall thickness being reduced along the line of weakness.

The upper part of the first container, beneath the neck, is provided with an external thread 24 which engages an internally threaded region 26 on the inner surface of the hollow connector 6. Beneath the threaded region 24 of the side wall, the first container has a collapsible region 28 in which the side wall has a number of concertina folds to facilitate collapsing of the side wall.

The second container has an externally threaded neck 30, which engages a correspondingly threaded region 32 of the hollow connector 6. The correspondingly threaded region 32 of the hollow connector may be integrally formed with the hollow connector 6 or it may be a component which is formed separately (e.g. as an internally threaded tubular element) and then secured using adhesive, solvent welding or by means of a snap fit connection, into the main body of the hollow connector.

The mouth 34 at the end of the neck 30 is sealed by a sealing element in the form of a membrane 36 which prevents premature escape of the contents of the container. Below the neck 30, the second container 4 has a shoulder region on which are moulded saw tooth formations 38. During assembly of the package, the filled sealed second container 4 is screwed into the hollow connector so that the saw tooth formations click over the internal saw tooth profiles 40 on the inner surface of the hollow connector. The saw tooth formations 38 and saw tooth profiles 40 together form a ratchet arrangement so that the second container 4 cannot be unscrewed from the hollow connector after assembly.

In order to provide a liquid-tight seal between the first and second containers, an annular gasket 42 is clamped between the neck 30 of the second container and the end wall 22 of the first container. The hollow connector 6 has an axially extending security tab 44 which, after assembly but prior to use, sits in a shallow recess 46 in the wall of the first container 2. The edge of the recess 46 acts as a stop which engages the security tab and prevents the first container 2 from being accidentally rotated in the hollow connector 6. The peelable tamper-evident label 8 attached to the first container 2 and the hollow connector 6 provides a further barrier to premature rotation of the first container in the hollow connector. The label 8 extends around the greater part of the circumference of the first container but does not cover the security tab 44.

The hollow connector 6 is provided with a side arm or clip 48 which holds an oral syringe comprising a syringe barrel 50 and a syringe plunger 52 disposed inside the barrel 50. When assembled, the syringe covers the security tab 44 and helps prevent inadvertent removal of the tab.

In this embodiment, the first container 2 typically contains a powdered

pharmaceutical composition. The second or lower container 4 typically contains sterile water. In order to form a pharmaceutical solution or suspension, the oral syringe 50/52 is removed from the clip 48 to reveal the security tab 44 which is then broken off. The label 8 is peeled away and the package is then ready for activation. In order to activate the package, the first container 2 is rotated in the hollow connector 6 so that it screws further into the connector thereby subjecting the first container 2 to axial compression. The axial compression results in the progressive collapsing of the concertina tube region 28. As the concertina tube region of the first container collapses, the tip 16a of the cutting element 16 moves into engagement with the end wall 22 of the container and cuts along the circular line of weakness to form a flap which is then pushed aside by further movement of the cutting element.

Once the cutting element 16 has cut through the end wall 22 of the first container, the tip 16a of the cutting element then moves into contact with the sealing membrane 36 covering the mouth of the second container 4. Further rotation of the first container 2 causes the cutting element 16 to cut into the membrane 36 to form a second flap which is also displaced by further movement of the cutting element. As the two flaps formed by the cutting of the end wall 22 and the membrane 36 are pushed aside, a flow path is opened up between the first and second containers that allows the contents of the first container to fall into the second container. The package may then be shaken vigorously to provide thorough mixing of the powder and liquid contents of the two containers to form either a solution or a suspension. The screw cap 12 can then be removed and the syringe 50/52 inserted through the central passage 18 in the plug 14 and through the centre of the tubular cutting element 16 to extract a dose of suspension or solution from the package for administration to a patient. The pharmaceutical composition typically contains one or more drug substances. Alternatively, it may contain non-drug materials such as an oral rehydration composition. Examples of pharmaceutical compositions are those containing drug substances that form suspensions in aqueous media. Particular examples of pharmaceutical compositions are those containing antibiotics and in particular penicillin antibiotics such as phenoxymethylpenicillin, amoxicillin and flucloxacillin.

Equivalents

It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.

Claims

A pharmaceutical package comprising first and second sealed containers connected together along a common axis by means of a hollow connector; one of the first and second containers containing a pharmaceutical composition in a dispersible solid form and the other of the first and second containers containing a liquid diluent;

wherein the package can be activated to mix the pharmaceutical composition and the diluent to form a suspension or solution; and wherein: the first container has a mouth which is sealed by a removable closure; an end wall opposite the mouth; and a side wall or walls constructed such that the first container is at least partially collapsible along the common axis;

a cutting element is attached to the first container and extends into the container from the mouth thereof towards the said end wall;

the second container has a mouth which is sealed by a sealing element and which faces the end wall of the first container;

the package is activated by relative movement between the first container and the hollow connector such that the first container is at least partially collapsed along the common axis thereby bringing the cutting element into contact with the said end wall so that it cuts through and displaces at least part of the end wall and at least part of the sealing element of the second container to create a flow path between the interiors of the first and second containers to allow dispersion and mixing of the pharmaceutical composition and the liquid diluent; and

A pharmaceutical package according to claim 1 wherein the first container and hollow connector are provided with mutually engaging threaded regions for securing the first container and hollow connector together.

3. A pharmaceutical package according to claim 2 which is activated by rotating the first container inside the hollow connector so that it screws further into the hollow connnector.

4. A pharmaceutical package according to claim 3 wherein the first container has a side wall with a threaded region adjacent or near the mouth of the container and a collapsible region adjacent or near the end wall of the container.

5. A pharmaceutical package according to claim 4 wherein the collapsible region takes the form of a concertina tube. 6. A pharmaceutical package according to any one of claims 1 to 5 wherein the cutting element is secured in the mouth of the first container and has a passageway therethrough through which the suspension or solution can be dispensed.

7. A pharmaceutical package according to claim 6 wherein the cutting element is connected to a plug which sits in the mouth of the first container, wherein the plug has a passageway therethrough through which the suspension or solution can be dispensed.

8. A pharmaceutical package according to any one of claims 1 to 7 wherein the removable closure of the first container comprises a screw cap. 9. A pharmaceutical package according to any one of claims 1 to 8 wherein the second container has an external thread which engages an internal thread on the hollow connector to secure the second container to the hollow connector.

10. A pharmaceutical package according to claim 9 wherein the external thread is carried on a neck region of the second container.

11. A pharmaceutical package according to any one of claims 1 to 10 which comprises means for preventing unintended collapsing of the first container. A pharmaceutical package according to claim 11 wherein the means for preventing unintended collapsing of the first container comprises a removable tab on the hollow connector which engages an abutment surface on the first container to prevent relative movement between the first container and the hollow connector.

A pharmaceutical package according to claim 12 wherein the tab and abutment surface prevent rotation of the first container in the hollow connector.

A pharmaceutical package according to any one of the preceding claims which further comprises an oral syringe which, after removal of the removable closure from the mouth of the first container, is insertable through the first container and into the interior of the second container to enable extraction of the suspension or solution.

A pharmaceutical package according to any one of the preceding claims which is configured so that when the package is placed in an upright position on a surface, the first container is uppermost.

A pharmaceutical package according to any one of the preceding claims wherein the first container contains the pharmaceutical composition in a dispersible solid form and the second container contains the liquid diluent.

A pharmaceutical package according to any one of the preceding claims wherein the pharmaceutical composition in a dispersible solid form is a powder.

A pharmaceutical package according to any one of the preceding claims wherein the pharmaceutical composition contains a drug substance and optionally one or more pharmaceutical excipients.

A pharmaceutical package according to claim 18 wherein the drug substance is an antibiotic.

A pharmaceutical package according to claim 19 wherein the antibiotic is a penicillin.

21. A pharmaceutical package according to any one of the preceding claims wherein the liquid diluent is aqueous.

22. A pharmaceutical package according to any one of the preceding claims wherein the liquid diluent is sterile water.

23. A pharmaceutical package according to any one of the preceding claims wherein the pharmaceutical composition and liquid diluent are selected such that when mixed and shaken, they form a pharmaceutical suspension.

24. A pharmaceutical package according to any one of claims 1 to 23 wherein the pharmaceutical composition and liquid diluent are selected such that when mixed and shaken, they form a pharmaceutical solution.