Abstrict A container having a closure comprising a closure wall having a
puncturable region in communication with the interior of the vessel,
and having on an inwardly facing region of the closure wall a desiccant
material separated from the interior of the vessel by a semi-permeable
membrane which permits transmission of water vapor therethrough
but is substantially impermeable to liquid water.
Claims What is claimed is:
1. A closure capable of sealing engagement with the mouth opening
of a vessel, the closure comprising a closure wall having a puncturable
region therein in communication with the interior of the vessel
on which the closure is in place, and having on an inwardly facing
region of the closure wall a desiccant material covered with a semi-permeable
membrane which permits transmission of water vapor therethrough
but is substantially impermeable to liquid water.
2. The closure of claim 1 which comprises materials selected from
the group consisting of plastic materials, elastomeric materials
and composite materials.
3. The closure of claim 1 which comprises a thinned elastomeric
region which is capable of resiliently sealing around a hypodermic
needle when said needle is inserted therethrough.
4. The closure of claim 1 wherein the desiccant is located on only
part of the closure wall, and the puncturable region is situated
between areas of the closure wall on which the desiccant is present.
5. The closure of claim 1 wherein the desiccant material is distributed
in the form of a ring shape on the closure wall, with the puncturable
region within the ring.
6. The closure of claim 5 wherein the ring-shaped distribution
of desiccant is located in a holder defining a ring-shaped cavity
which extends inwardly from the closure wall, the cavity opening
into the interior of the vessel when the closure is in place.
7. The closure of claim 6 wherein the holder is in the form of
two generally concentric walls comprising an inner wall and an outer
wall extending inwardly from the closure wall, the space between
the walls defining the ring-shaped cavity, and the central space
within the inner wall defining a central passage in direct communication
with the puncturable region.
8. The closure of claim 7 wherein the holder is formed integrally
with the closure wall.
9. The closure of claim 6 wherein the cavity is a ring-shaped cavity
between generally concentric cavity-defining walls, and the membrane
covers the opening of the cavity into the interior of the vessel.
10. The closure of claim 9 wherein in addition to covering the
opening of the cavity into the interior of the vessel, the membrane
also covers the central space within the ring.
11. The closure of claim 9 wherein the membrane is integral with
the closure.
12. The closure of claim 1 wherein the semi-permeable membrane
is a thin film of a plastic material.
13. The closure of claim 12 wherein the plastic material is selected
from the group consisting of polyolefins, polystyrene, polyamides,
polyesters and halogenated polyvinyls.
14. The closure of claim 11 wherein the membrane is provided as
a coating over the desiccant or over areas on the closure face on
which the desiccant is located or over part of the cavity which
opens out into the interior of the vessel when the closure is in
place.
Description This invention relates to containers, particularly to containers
for moisture sensitive materials particularly pharmaceutical substances.
BACKGROUND OF THE INVENTION
It is frequently necessary to store moisture sensitive materials
for relatively long periods in containers. In a particular example,
certain pharmaceutical substances are supplied and/or stored in
small vials containing one or more unit doses of the dry substance,
and having a puncturable seal through which a hypodermic needle
may be inserted. By means of such a needle water may be injected
into the vial, the substance dissolved in situ, and the solution
then withdrawn via the needle into a syringe for short-term use
before hydrolysis of the moisture sensitive material. Such puncturable
seals enable this operation to be sterile. During storage the presence
of atmospheric moisture within the container, or the ingress of
atmospheric moisture, can cause decomposition of such materials
Often moisture sensitive pharmaceutical substances are provided
in containers together with an internal desiccant in the container,
for example a small sachet of molecular sieve or silica gel. Clearly
this is not practical when the substance has to be made up in situ
within the container as described above, as contamination by desiccant
on dissolution of the substance is likely.
An example of a moisture sensitive pharmaceutical substance is
clavulanic acid and its salts, such as potassium clavulanate. Potassium
clavulanate is both hygroscopic and readily hydrolysed by water,
so for handling and long term storage of potassium clavulanate it
is necessary for the immediate environment to be kept extremely
dry, e.g. 30% Relative Humidity ("RH") or less.
Potassium clavulanate is a .beta.-lactamase inhibitor, and is often
provided in a formulation in combination with a partner .beta. lactam
antibiotic. A partner which is often used in such formulations is
amoxycillin. For injectable formulations, which may be dry reconstitutable
powders or oily suspensions for i.m. injection amoxycillin is used
in the form of sodium amoxycillin. In some forms sodium amoxycillin
is a powerful desiccant, and when contained together with potassium
clavulanate in a sealed vial such forms of sodium amoxycillin can
exert a dehydrating effect which helps to preserve the potassium
clavulanate. Other forms of sodium amoxycillin, such as the anhydrous
crystalline form disclosed in EP 0131147 B are less desiccating,
and although it would be desirable to use such forms in formulations
together with potassium clavulanate, the problem arises that these
forms can be insufficiently desicatting to protect the potassium
clavulanate.
BRIEF SUMMARY OF THE INVENTION
It is an object of this invention to provide a container having
an internal desiccant which inter alia is suitable for use with
moisture sensitive pharmaceutical substances and allows sterile
dissolution without the problem of contamination by desiccant. Other
objects and advantages of the invention will be apparent from the
following description.
According to this invention, a container comprises a vessel having
a mouth opening and a closure capable of sealing engagement with
the mouth opening. the closure comprising a closure wall having
a puncturable region therein in communication with the interior
of the vessel, and having on an inwardly facing region of the closure
wall a desiccant material separated from the interior of the vessel
by a semi-permeable membrane which permits transmission of water
vapour therethrough but is substantially impermeable to liquid water.
The term "inwardly" used herein refers to directions
toward the interior of the vessel unless otherwise defined.
By means of the invention, moisture-sensitive substances within
the vessel may be protected by the desiccant material, and water
may be introduced into the vessel by means of a hypodermic needle
puncturing the puncturable region of the closure face. The substance
within the vial may then be dispersed or dissolved, whilst the membrane
prevents the desiccant from contacting the introduced water, so
as to dissolve the substance without any contamination by the desiccant.
The vessel may suitable comprise a vial of generally conventional
construction, with a neck and a mouth opening being defined by the
rim of the neck of the vial. Such a vial may be made of conventional
materials such as glass, rigid plastics materials etc. The vial
should be made of materials which are substantially impermeable
to atmospheric water vapour, or at most allow only slow ingress
of water vapour in quantities which can be absorbed by the desiccant
without an undesirable degree of hydrolysis of the moisture-sensitive
contents. Glass is particularly suitable as a vial material.
The closure may be made of generally conventional materials, preferably
pharmaceutically acceptable materials, such as plastics materials,
elastomeric materials etc., or composite materials such as metal
and plastics or elastomeric materials. Preferably the closure is
made of plastics or elastomeric materials which are of low moisture
content, of low moisture permeability and low moisture affinity.
Preferably the closure is at least partly, more preferably wholly
more of an elastomeric material such as a natural or synthetic rubber,
thereby allowing a tight compression fit with the mouth of the vessel.
The sealing engagement of the closure with the mouth opening may
be by a generally conventional construction e.g. similar to a conventional
stopper. For example the closure may be engaged with the rim of
the neck of a vial by a screw thread, a friction/compression fitting,
or a circlip-type clamp around the neck of the vial. Such constructions
are known in the art. The closure may seal the mouth in a generally
conventional manner, e.g. by a compression fitting of the closure
wall against the rim of the mouth, or by a sealing ring compressed
between the closure face and the rim of the mouth etc.
The puncturable region of the closure wall may suitably comprise
a thinned region of the closure wall, and is preferably provided
in a region of elastomeric material which can resiliently seal around
a hypodermic needle which is inserted therethrough, so as to facilitate
sterile insertion and withdrawal. The region of elastomeric material
may be of integral construction with the remainder to the closure.
The desiccant may be essentially conventional, and should be a
material which does not normally give off fumes or readily form
fine powdery particles either inherently, or as a result of absorbing
water. Conventional materials may be used, for example molecular
sieves or silica gel.
To allow the puncturable region of the closure face to be in direct
communication with the interior of the vessel, the distribution
of the desiccant material may be such that the desiccant is located
on only part of the closure wall, so that the puncturable region
is situated between areas of the closure wall on which is the desiccant
material, or beside of such an area. By such a construction a hypodermic
needle may be inserted through the puncturable region of the closure
wall without coming into contact with the desiccating material,
whilst the desiccating material itself is in desiccating communication
with the interior of the vessel through the membrane.
In one embodiment of the invention, the desiccating material may
be distributed in the form of, or about, a ring shape on the closure
wall, with the puncturable region within, e.g. near or at the centre
of, the ring. Such a ring shape may for example be circular, polygonal,
or oval etc., suitable conforming to the general internal section
of the closure. Such a ring-shaped distribution of desiccant may
be located in a corresponding ring-shaped holder or cavity in the
closure wall, or alternatively a ring-shaped distribution of desiccant
may be located in a holder defining a ring-shaped cavity which extends
inwardly from the closure wall, the cavity opening into the interior
of the container when the closure is in place on the vessel. Such
a holder may suitably be in the form of two generally concentric
walls extending inwardly from the closure wall, the space between
the walls defining the ring-shaped cavity, and the central space
within the inner wall defining a central passage in direct communication
with the puncturable region, down which a hypodermic needle may
be inserted. Such a holder may be formed integrally with the closure
wall, or may be separate part of the closure.
Closures for pharmaceutical vials are commonly in the form of a
closure wall across the mouth of the vial, from which integrally
extends a shirt which sealingly engages the internal surface of
the neck of the vial. In the closure of this invention the skirt
of such a conventional closure may suitable be made in the form
of the above described two generally concentric walls to form a
holder.
Suitably the outer surface of the outer wall may be constructed
so as to engage the rim of the neck and/or mouth, suitably contributing
to the sealing engagement of the closure and the vessel. Suitably
both the said generally concentric walls may be integral with the
closure wall, so that the closure wall forms the base of the cavity
and of the central passage. Suitable in such a construction the
base wall of the central passage includes the puncturable region.
The nature and quantity of desiccant material used in the container
of the invention will vary with the nature of the moisture sensitive
contents, and can easily be determined by straightforward experimentation
or calculation, e.g. from the moisture content of the contents of
the vessel. In the case of potassium clavulanate and its mixtures
with amoxycillin, e.g. crystalline anhydrous sodium amoxycillin,
molecular sieve is a suitable desiccant. Suitably the desiccant
material may be compacted into a ring shape, for example by compression,
sintering, binders etc., either by forming a hard compact prior
to insertion into the cavity, or by forming such a compact in situ
within the cavity in the closure face by in situ compression. Methods
of forming such compacts comprising desiccant materials are known.
The desiccant may for example be introduced into the mould, and
the closure made by moulding around it.
The membrane is preferably substantially permeable to water vapour,
such that the RH within the vessel is kept at a level at which a
moisture sensitive material, such as a moisture sensitive pharmaceutical
substance is protected from hydrolysis in the extent that long term
storage with an acceptably small level of hydrolysis can be achieved.
The membrane may allow permeation of moisture vapour from the interior
of the vessel to the desiccant material at a rate which desiccates
the contents before significant degradation occurs.
By "substantially impermeable to liquid water" in the
context of this invention is meant membranes which are water insoluble
and completely and permanently impenetrable by liquid water. The
term also includes membranes which, whilst in a long term would
dissolve or allow liquid water through, in practice during the few
seconds or minutes whilst liquid water is in contact with the membrane
during the action of dissolving a moisture sensitive pharmaceutical
substance contained in the vessel, as described herein, do not permit
any liquid water through, or permit so little that no significant
contact of water with the desiccant occurs which might cause contamination
of the solution of the pharmaceutical substance. The term also includes
membranes with permeability characteristics between these two extremes.
Suitably the membrane material should be pharmaceutically acceptable.
The semi-permeable membrane may be a continuous film of material
or a microporous material. The semi-permeable membrane may for example
be a thin film of a plastics material. Suitable plastics material,
which when thin enough are semi-permeable, allowing water vapour
to pass through at a rate which permits suitable desiccation whilst
being substantially impermeable to liquid water to penetrate, are
known. Suitable plastics materials include for example polyolefins,
such as polyethylene or polypropylene, polystyrene, polyamides,
polyesters and halogenated polyvinyls such as polyvinyl chloride.
Such a membrane may be provided as a coating over the desiccant,
or over areas on the closure face on which the desiccant is located,
or over part of the cavity which opens out into the interior of
the vessel when the closure is in place. When the cavity is a ring-shaped
cavity, for example a cavity defined in a holder as described above,
the membrane may cover the opening of the cavity into the interior
of the vessel.
In addition to covering the opening of a ring-shaped cavity into
the interior of the vessel, the membrane may also cover the central
space within the ring shape, e.g. within the inner wall of a ring
shaped holder as described above, i.e. the central passage down
which a hypodermic needle may pass. This may advantageously enable
the membrane to be made more conveniently in the form of a disc
generally corresponding to the circular shape of the closure, rather
than a ring shape, and consequently the disc shaped membrane may
lie between the puncturable region and the interior of the vessel.
Such a membrane should therefore be easily puncturable by the hypodermic
needle. The presence of such a membrane across the central passage
may assist in reducing withdrawal losses.
The membrane may be attached to the closure material by conventional
methods such as welding, adhesives etc., or alternately physically
attached by for example pinching into slots etc. in the closure
material, or pinching between parts of the closure, or between the
closure and the vessel, or physical cohesion between the membrane
material and the closure material.
It may also be possible for the membrane to be integral with the
closure, i.e. made of the same plastics or elastomeric material
as the closure. In such an embodiment the material of the closure
may be such that when in the form of a thin film it is semi-permeable
as described above, but when in bulk or in a thicker form it is
substantially impermeable as described above. In such an embodiment
the desiccant may be present in the mould as the closure and integral
membrane are formed, or the membrane may be integrally moulded on
after the closure is moulded with the desiccant material in situ.
It is usually a requirement of containers such as vials for use
with injectible pharmaceutical substances that all parts of the
vial and their closure are washable to remove particulates, and
sterilisable. The container of the present invention provides for
this in that a rapid wash may be used followed by rapid drying.
This can remove particulates but maintains the semi permeable membrane
in contact with liquid water for only a short time, as discussed
above, so that liquid water does not permeate through the membrane.
Sterillisation of the containers and their closures is possible
using gamma radiation. When this method of sterilisation is used,
it should be ensured that the materials of which the container and
closure, including the membrane and the desiccant, are stable to
the amounts of gamma radiation used.
The container of the invention is particularly suitable for the
containment of moisture-sensitive pharmaceutical substances such
as a formulation of potassium clavulanate and sodium amoxycillin,
particularly anhydrous crystalline sodium amoxycillin e.g. as disclosed
in EP 0131147. Such a formulation may be dry solids for reconstitution
with water, or any oily non-aqueous suspension for i.m. injection.
The invention therefore further provides a container as described
above, containing a mixture which comprises potassium clavulanate
and sodium amoxycillin.
The closure of the invention, independent of the vessel, is also
believed to be novel, and therefore the invention further provides
a closure capable of sealing engagement with the mouth opening of
a vessel, the closure comprising a closure wall having a puncturable
region therein arranged so as to be in communication with the interior
of a vessel on which the closure is in place, and having on an inwardly
facing region of the closure wall a desiccant material covered with
a semi-permeable membrane which permits transmission of water vapour
therethrough but is substantially impermeable to liquid water.
Suitable and preferred forms of the closure are as described above.
BRIEF DESCRIPTION OF THE INVENTION
The invention will now be described by way of example only with
reference to the accompanying drawings, which show:
FIG. 1 a longitudinal section through a vial and closure of the
invention.
FIG. 2 a sectional view through the closure of FIG. 1 about the
line A--A of FIG. 1 looking in the direction of the arrows.
FIG. 3 a longitudinal section through an alternative construction
of the closure of the invention.
FIG. 4 a longitudinal section through another alternative construction
of the closure of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Referring to FIGS. 1 and 2 a glass vial (1) has a mouth opening
(2) defined by the rim of a neck (3). In the neck (3) of the vial
(1) is a closure (4 generally) integrally made of a synthetic rubber
material which comprises a closure wall (5) which sealingly engages
the rim of the mouth opening (2). Centrally located in the closure
wall (5) is a thinned puncturable region (6).
Extending inwardly into the vial (1) from the closure wall (5)
is an integral holder (7) in the form of two concentric walls (7A,
7B) the outer of which (7A) at its periphery sealingly engages the
neck (3) with a compression fit. The holder (7) is generally in
the shape of the conventional skirt of a conventional elastomeric
closure for a vial (1) made in the form of the two concentric walls
(7A, 7B). The inner wall (7B) surrounds a central space (8) with
the puncturable region (6) at its top. A hypodermic needle (9) may
be inserted through the puncturable region (6) and passed along
the passage into the vial defined by the space (8).
Between the inner and outer walls (7A, 7B) is a ring-shaped cavity
(10) which contains a compacted desiccant (11). the opening of the
cavity (10) into the interior of the vial (1) is closed by a thin,
semi-permeable membrane (12) being a film of a plastics material
which allows water vapours to pass through, thereby allowing the
desiccant (11) to exert its desiccating effect on the interior of
the vial (1) and to keep it at a low relative humidity. The membrane
(12) is compression and heat welded to the walls (7A, 7B). Alternatively
the membrane (12) may be mechanically pinched into slits (not shown)
in the walls (7A, 7B), or fastened thereto by a pharmaceutically
acceptable adhesive (now shown). The thickness of the membrane (12)
is shown exaggerated.
Referring to FIG. 3 the upper part of a combination of a vial (1)
and closure (4) are shown. Parts corresponding to FIGS. 1 and 2
are numbered correspondingly. The membrane (12A) is in the form
of a thin disc shaped film of a plastics material which allows water
vapour to pass through, thereby allowing the desiccant (11) to exert
its desiccating effect on the interior of the vial (1) and to keep
it at a low relative humidity. The membrane (12A) covers the central
passage (8) within walls (7B) and is thin enough to be punctured
by the hypodermic needle (9) when this is inserted into the vial
through puncturable region (6). The membrane (12A) is compression
and heat welded to the walls (7A, 7B), although alternative methods
of attachment as described above could be used.
Referring to FIG. 4 the upper part of a combination of a vial (1)
and closure (4) are shown. Parts corresponding to FIGS. 1 and 2
are numbered correspondingly. The membrane (12B) is integrally moulded
with the closure (4), and is hence made of the same polymeric material,
which in bulk form, i.e. as in the closure wall (5) and walls (7)
is substantially impermeable to water vapour, but when in the form
of a thin film such as the membrane (12B) is semi-permeable as described
above.
In cross section the closures (4) of FIGS. 3 and 4 are identical
to FIG. 2 and the thickness of the membrane (12A, 12B) is again
shown exaggerated.
The closure wall (5) may be fastened tightly against the rim of
the neck (3) by means of a surrounding thin metal circlip (not shown)
of conventional construction as used with known vials.
Cavity (10) may be strengthened by integral radial braces (not
shown) bridging the walls (7A, 7B). In another embodiment (not shown)
a holder for the desiccant (11) may be made as a separate part in
the form of two walls analogous in shape to walls (7A, 7B) with
a cavity (10) and desiccant (11) between them closed by a membrane
(12), and by a base wall.
In use, the hypodermic needle (9) is inserted through the puncturable
region (6), and along the passage (8), also puncturing the membrane
(12A) of the embodiment of FIG. 3 into the vicinity of the contents
(13) of the vial (1), a dry mixture of potassium clavulanate and
anhydrous crystalline sodium amoxycillin. Sterile water is injected
down the needle (9) to dissolve the contents (13), and as the membrane
(12 12A, 12B) is impermeable to liquid water the vial may be shaken
to encourage dissolution without causing the solution to be contaminated
by contact with the desiccant (11). The solution may then be withdrawn
through the needle (9) into a syringe (not shown) for subsequent
use.
The closure (4) of FIGS. 1 to 4 may be made by injection moulding
techniques which will be apparent to those skilled in the art, and
the desiccant (11) may be introduced into the cavity (10) mechanically,
followed by formation or attachment of the membrane (12). |