U.S. patent application number 10/170755 was filed with the patent office on 2003-01-16 for desiccating container for moisture-sensitive material.
This patent application is currently assigned to West Pharmaceutical Services, Inc.. Invention is credited to Holland, Simon Joseph, Taskis, Charles Bernard.
Application Number | 20030010668 10/170755 |
Document ID | / |
Family ID | 26305410 |
Filed Date | 2003-01-16 |
United States Patent
Application |
20030010668 |
Kind Code |
A1 |
Taskis, Charles Bernard ; et
al. |
January 16, 2003 |
Desiccating container for moisture-sensitive material
Abstract
The present invention is to a container, particularly for
moisture sensitive materials, having a container body of a
substantially atmospheric moisture-impermeable material and
incorporating a solid element which is made at least in part of a
desiccating polymer and which is in contact with the atmosphere
inside the container.
Inventors: |
Taskis, Charles Bernard;
(Worthing, GB) ; Holland, Simon Joseph; (Hove,
GB) |
Correspondence
Address: |
AKIN, GUMP, STRAUSS, HAUER & FELD, L.L.P.
ONE COMMERCE SQUARE, SUITE 2200
2005 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Assignee: |
West Pharmaceutical Services,
Inc.
Lionville
PA
|
Family ID: |
26305410 |
Appl. No.: |
10/170755 |
Filed: |
June 13, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10170755 |
Jun 13, 2002 |
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09245684 |
Feb 8, 1999 |
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09245684 |
Feb 8, 1999 |
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08776807 |
Feb 20, 1997 |
|
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5947274 |
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Current U.S.
Class: |
206/528 ;
215/294 |
Current CPC
Class: |
B65D 51/30 20130101;
B65D 81/266 20130101; B65D 51/002 20130101 |
Class at
Publication: |
206/528 ;
215/294 |
International
Class: |
B65D 083/04; B65D
085/42 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 5, 1994 |
GB |
9415864.9 |
Jun 16, 1995 |
GB |
9512243.8 |
Claims
We claim:
1. A container for a moisture-sensitive material comprising (a) a
container body comprising a substantially atmospheric
moisture-impermeable material and (b) a closure comprising at least
one part that is a desiccant polymer, wherein the at least one part
of the closure is in contact with an atmosphere in an interior of
the container and the desiccant polymer is a water-absorbent
hydrophilic polymer.
2. The container of claim 1, wherein the closure comprises a
closure wall having a puncturable region therein in direct
communication with the interior of the container.
3. The container of claim 2, wherein the closure wall comprises at
least one part that is a desiccating polymer.
4. The container according to claim 1, wherein the container body
comprises at least one part that is a desiccant polymer and the at
least one part is exposed to the interior of the container.
5. The container according to claim 3, wherein the puncturable
region is located in a part of the closure wall that is not a
desiccating polymer.
6. The container of claim 1, wherein the closure wall contains a
first part that is a desiccant polymer, wherein the first part is
in the form of a ring shape encircling the puncturable region
within.
7. The container of claim 6, wherein the first part of the closure
wall is encircled by a second part that is ring shaped, wherein the
second part is not made of a desiccant polymer.
8. The container of claim 7, wherein the second part comprises two
generally concentric walls extending inwardly from the closure wall
and the space between the walls defines a ring-shaped cavity, the
cavity having a central space, wherein the central space defines a
central passage in direct communication with the puncturable
region.
9. The container of claim 1, wherein the closure of the container
relies on a compression fit on a lip of a mouth of the container
and the closure comprises an insert that is capable of forming a
compression seal between the lip and the mouth of the container
when the closure is tightened, wherein the insert consists of the
desiccant polymer, and is selected from the group consisting a
disc, a ring washer, and an inward facing coating layer.
10. The container of claim 1, wherein the water-absorbent
hydrophilic polymer is selected from the group consisting of a
hydrogel polymer, a homologous ester of the glycol monomethacrylate
series, a homologous ester of the glycol monomethacrylate series
that is slightly cross-linked, a copolymer of the higher glycol
monomethacrylates and 2-hydroxyethyl methacrylate, an acrylamide
hydrogel, a 2-hydroxyethyl methacrylate-vinylpyrrolidinone
copolymer, and a water-insoluble methacrylate copolymerised with
2-hydroxyethyl methacrylate.
11. The container of claim 1, wherein the container is a vial
suitable for a moisture-sensitive pharmaceutical material.
12. The container of claim 1, comprising at least on part of
desiccant polymer in an amount capable of taking up atmospheric
moisture at 30% RH or less, wherein the vial contains potassium
clavulanate or its mixture with sodium amoxycillin.
13. The container of claim 12, wherein the desiccant polymer is
capable of taking up atmospheric moisture at 10% RH or less.
14. The container of claim 12, wherein the sodium amoxycillin is
crystalline sodium amoxycillin.
15. A closure capable of sealing engagement with a mouth of a
container, the closure comprising a closure wall having an inwardly
facing region wherein the wall comprises or has thereon a desiccant
polymer.
16. A method of desiccating a moisture sensitive material, the
method comprising enclosing the material in a container and
maintaining a desiccant polymer in contact with the atmosphere
inside the container.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/245,684, filed Feb. 8, 1999, which is in
turn a continuation of U.S. patent application Ser. No. 08/776,807,
filed Feb. 20, 1997, now U.S. Pat. No. 5,947,274, issued Sep. 7,
1999, the contents of each of which are incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] 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. Such vials are normally sealed with an
elastomeric closure including a closure wall across the mouth, and
having a puncturable region such as a thin part of the closure wall
through which a hypodermic needle may be inserted. By means of such
a needle water or other suitable aqueous medium may be injected
into the vial, the substance dissolved in situ, and the solution
then withdrawn via the needle into a syringe for use in the short
term before significant hydrolysis of the moisture sensitive
material occurs. Such an elastomeric closure is often retained on
the mouth opening of the vial by a thin metal circlip. 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.
[0003] 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.
[0004] It is known to compound polymeric materials with desiccants
for various applications, but mostly as moisture absorbing spacers
for multiple glazing panels. For example U.S. Pat. No. 4,485,204
and U.S. Pat. No. 4,547,536 disclose blends of polyester or
polyester plus a butadiene polymer, plus a desiccant such as
calcium oxide. European Patent 0599690 discloses a blend of a
polymer such as styrene butadiene rubber, plus molecular sieve,
plus also a fibrous material. European Patent 0599690 suggests the
general possibility of use of such a polymer for drying of moisture
sensitive pharmaceuticals, giving results for moisture absorption
at 80% relative humidity ("RH").
[0005] 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 hydrolyzed 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% RH or less, preferably 10% RH or
less, ideally as low as possible. To obtain and maintain such
conditions in a container such as a vial of the type mentioned
above requires quite a powerful desiccant ability.
[0006] 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,
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 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 desiccating to protect the potassium clavulanate
from hydrolysis, resulting from traces of moisture in the vial.
BRIEF SUMMARY OF THE INVENTION
[0007] 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, particularly
potassium clavulanate and formulations containing potassium
clavulanate, 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.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0008] The foregoing summary, as well as the following detailed
description of preferred embodiments of the invention, will be
better understood when read in conjunction with the appended
drawings. For the purpose of illustrating the invention, there is
shown in the drawings embodiments which are presently preferred. It
should be understood, however, that the invention is not limited to
the precise arrangements and instrumentalities shown.
[0009] In the drawings:
[0010] FIGS. 1, 2, and 3 show longitudinal sections through
alternative multi-part construction vials and closures of the
invention.
[0011] FIG. 4 shows a sectional view through the closure of FIG. 1
about the line A-A of FIG. 1 looking in the direction of the
arrows.
[0012] FIGS. 5 to 7 demonstrate in graphical format moisture uptake
for rubbers compounded with various listed desiccants.
[0013] FIG. 8 demonstrates a graph of normalized moisture uptake
for dried hydrogels (a) to (f) as tested in Example 4.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides a container for a moisture
sensitive material, having a container body of a substantially
atmospheric moisture-impermeable material, and incorporating a
solid element which is made at least in part of a desiccant polymer
and which is in contact with the atmosphere inside the
container.
[0015] The term "inwardly" used herein refers to directions toward
the interior of the vessel unless otherwise defined.
[0016] The term "desiccant polymer" means a polymer which absorbs
water from the surrounding atmosphere to the extent that it can
exercise a desiccating effect upon the interior of a space within
which it is contained or to the atmosphere within which it is
exposed.
[0017] The desiccating polymer is suitably a polymer from which no
or minimal material can be extracted by liquid water, at least
during the time period the desiccant polymer is expected to be in
contact with liquid water during the making up and subsequent
storage of a solution in the container, e.g., during injection of
water into a vial and make-up of a medicament for administration by
injection.
[0018] Suitably the desiccant polymer is a biocompatible desiccant
polymer.
[0019] The desiccant polymer may be an inherently desiccant
polymeric material, such as a hydrophilic polymer.
[0020] Suitable biocompatible inherently desiccant polymers are the
known water-absorbent hydrophilic polymers used for the manufacture
of contact lenses, artificial cartilages and other bodily implants
etc. Suitable such materials include hydrogel polymers, such as
polymers which comprise hydroxy alkyl methacrylates, for example
2-hydroxyethyl methacrylate. Other suitable desiccant polymer
include the homologous esters of the glycol monomethacrylate
series, such as diethylene glycol monomethacrylate, and
tetraethylene glycol monomethacrylate; slightly cross-linked, for
example with a dimethacrylate of a glycol; copolymers of the higher
glycol monomethacrylates and 2-hydroxyethyl methacrylate;
acrylamide hydrogels and 2-hydroxyethyl
methacrylate-vinylpyrrolidinone copolymers. Such polymers may be
cross-linked for example with ethylene dimethacrylate and/or
1,1,1-trimethylpropane trimethacrylate. Other suitable polymers
include water-insoluble methacrylates copolymerised with
2-hydroxyethyl methacrylate. Poly (2-hydroxyethyl methacrylate)
polymers can for example absorb up to 40% w:w of water. Copolymers
of 2-hydroxyethyl methacrylate with a small amount of a
dimethacrylate, some methyl or other alkyl methacrylate and some
methacrylic acid, which can be converted to their alkali salts, can
absorb at least 45% w:w of water. Copolymers of 2-hydroxyethyl
methacrylate may for example also be copolymerised with n-pentyl
methacrylate, vinyl propionate, vinyl acetate, isobutyl and
cyclohexyl methacrylate, to produce a suitable desiccant polymer.
Copolymers of 2-hyroxyethyl methacrylate with vinylpyrrolidinones,
such as 1-vinyl-2-pyrrolidinone, and which may be cross linked with
ethylene glycol dimethacrylate, can produce hydrogels with a higher
degree of hydration, suitable as desiccant polymers. Other suitable
hydrogel polymers include hydroxyethyl methacrylate
N,N-dimethylacrylamide copolymers, hydroxyethyl
methacrylate-N-vinyl pyrrolidone copolymers, hydroxyethyl
methacrylate-acryloyl morpholine copolymers, N-vinyl
pyrrolidone-methyl methacrylate copolymers, methyl
methacrylate-acryloyl morpholine copolymers, hydroxyethyl
methacrylate-acryloyl morpholine copolymers, methoxyethyl
methacrylate-ethoxyethyl methacrylate copolymers, and methoxy
methacrylate-acryloyl morpholine copolymers.
[0021] Alternatively the desiccant polymer may be a polymer
material that includes a desiccant filler, for example as particles
thereof dispersed in its bulk. An example of such a desiccant
polymer is an elastomeric material, such as a rubber, compounded
with a desiccant material.
[0022] The compounding of the elastomeric material with a desiccant
material causes the compounded material to exercise a desiccant
effect upon the interior of the container. The quantity of the
elastomeric material compounded with a desiccant material should be
sufficient to ensure absorption of sufficient of the water vapor in
the container, or water in the moisture sensitive material contents
to prevent or reduce to an acceptable degree any degradation of the
material by the water or water vapor.
[0023] The elastomeric material may be a rubber. Such a rubber may
be a natural rubber, or a synthetic rubber such as a
butadiene-based rubber, e.g., based on styrene-butadiene or
cis-1,4-polybutadiene, butyl rubber, halobutyl rubber,
ethylene-propylene rubber, neoprene, nitrile rubber, polyisoprene,
silicone rubber, chlorosulphonated polyethylene or epichlorhydrin
elastomer, or a mixture, blend or copolymer thereof. Halobutyl,
e.g., chlorobutyl, rubbers and silicone rubbers are
pharmaceutically acceptable rubbers known for use as materials for
stoppers etc. to be maintained in contact with pharmaceutical
products. Such elastomeric materials are sufficiently permeable to
atmospheric water vapor that the desiccant material compounded with
the rubber can exert its desiccant effect through a thin layer of
the material.
[0024] Such rubbers may be compounded in the manner with which they
are conventionally compounded for manufacture of a stopper as known
in the art of manufacture of rubber stoppers. For example they may
be compounded with reinforcing fillers, coloring agents,
preservatives, antioxidants, additives to modify their stiffness,
chemical resistance, etc., such as curing/vulcanizing agents.
Conventional reinforcing fillers include inorganic reinforcing
fillers, such as zinc oxide, and silicas, such as china clay and
other clays. Suitable compounding processes and compositions will
be apparent to those skilled in the art of compounding of
rubbers.
[0025] The reinforcing filler, such as china clay, normally used in
the rubber may be totally or preferably partly replaced with a
powdered solid desiccating material. Total replacement may lead to
a loss of mechanical strength as compared to a rubber using
entirely china clay as its filler, although desiccants may be found
which can be used as the entire filler without loss of strength.
Such a powdered desiccating material may have a particle size the
same as or similar to that of the conventional inorganic fillers
referred to above, so that the desiccant can serve as the filler as
well. The quantity of the powdered desiccating material used may be
up to the quantity in which conventional inorganic fillers are
used, that is, they may completely replace the usual inorganic
filler. For example the powdered desiccant may replace up to 50% of
the weight of the normal weight of filler used in the rubber, e.g.,
10-50%, such as 20-40%. The quantities of filler normally used in a
rubber for a particular application such as a vial closure will be
known to those skilled in the art.
[0026] The compounded rubber may also additionally include a
conventional filler as mentioned above, for example in a quantity
which together with the powdered desiccant comprises up to the
weight % of filler normally included in such a rubber.
[0027] The quantity of desiccant necessary for a particular product
contained in the container will depend upon the application but can
easily be determined by experiment.
[0028] The desiccating material should be one which is inert
relative to the elastomeric material, and vice versa. In the case
of containers such as vials in which a solution is made up in situ
by introduction of water or aqueous medium, the desiccating
material is suitably an inorganic desiccating material which is
wholly or substantially insoluble in water so that none or only a
pharmaceutically insignificant amount of the desiccant material or
its hydration product, or undesirable ions, is likely to enter
solution during the period when the desiccating polymer is in
contact with water or aqueous medium. Preferred desiccants are
those which can chemically or pysicochemically absorb or fix
absorbed water, e.g., by formation of a hydration product, so that
there is a reduced possibility of subsequent reversible release of
the absorbed water, which might for example occur if the
temperature of the polymer should rise, e.g., to around 40.degree.
C. after earlier desiccation at a lower temperature.
[0029] Suitable inorganic desiccants are the known materials sold
in the UK under the names Grace A3.TM., Siliporite.TM., and Ferben
200.TM.. Particularly preferred desiccant materials are dried
molecular sieves and calcium oxide, or mixtures thereof. Calcium
oxide chemically fixes water by formation of calcium hydroxide,
from which water can only be released at extreme temperatures, and
absorbed water can generally only be released from molecular sieves
at several hundred .degree.C.; that is, well above the temperatures
containers of pharmaceutical substances would be expected to
experience under normal storage.
[0030] A preferred desiccating polymer is therefore a halobutyl,
e.g., chlorobutyl, rubber compounded with an inorganic desiccant
such as a molecular sieve or calcium oxide.
[0031] The compounded elastomeric material may be made and formed
into a solid element by processes analogous to those by which solid
products are made from conventional compounded elastomeric
materials which include the above-mentioned inorganic fillers are
made.
[0032] In one embodiment of this invention, the solid element
comprises a closure for the container, made wholly or partly of the
said desiccating polymer. Parts of such a closure other than the
parts made of desiccant polymer which are to come into contact with
the atmosphere within the container 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 such parts are made of plastics or
elastomeric materials which are of low moisture content, of low
moisture permeability and low moisture affinity.
[0033] Preferably parts of the closure which engage the mouth
opening are at least partly, more preferably wholly made of an
elastomeric material comprising a natural or synthetic rubber
(which may be the above-described desiccating 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, and/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.
[0034] In one embodiment the present invention provides a container
for a moisture sensitive material, having a container body of a
substantially atmospheric moisture-impermeable material and having
an opening sealed by a closure, characterized in that at least part
of the closure which is exposed to the interior of the container
body is made of a desiccant polymer, which is suitably an
elastomeric material compounded with a desiccant material or a
hydrophilic polymer.
[0035] In another embodiment the present invention provides a
container for a moisture sensitive material, having a container
body of a substantially atmospheric moisture-impermeable material
and having an opening sealed by a closure, characterized in that at
least part of the closure which is exposed to the interior of the
container body is made of a desiccant polymer, which is suitably an
elastomeric material compounded with a desiccant material or a
hydrophilic polymer, the closure comprising a closure wall having a
puncturable region therein in direct communication with the
interior of the vessel.
[0036] Such a last-mentioned container may be a vial as mentioned
above suitable for a moisture-sensitive pharmaceutical material, of
generally conventional construction, the 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., but particularly glass. By means of the invention,
moisture-sensitive substances within the vessel may be protected by
the desiccant material, and, in this last-mentioned embodiment,
water may be introduced into the vessel by means of a hypodermic
needle puncturing the closure face through the puncturable region,
so as to dissolve the substance, and the so-formed solution of the
substance may be withdrawn via the needle.
[0037] 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 may comprise
the desiccating polymer) which can resiliently seal around a
hypodermic needle which is inserted therethrough, so as to
facilitate sterile insertion and withdrawal.
[0038] Conveniently all the polymeric parts of the closure, e.g.,
of a vial closure and including the puncturable region, may be made
of the desiccant polymer, particularly an elastomeric material
compounded with a desiccant material. Such a vial closure may
correspond in shape and size to conventional vial closures made of
elastomeric material, and may be retained on the mouth of the vial
by a conventional metal circlip. Elastomeric materials compounded
with a desiccant material may be molded into such shapes and sizes
by a molding process entirely analogous to that used to mould
closures out of conventional elastomeric materials such as
rubbers.
[0039] Alternatively the closure may be of multi-part construction
having only parts, including those parts which are exposed to the
interior of the container body, made of the desiccant polymer.
[0040] The distribution of the desiccant polymer may be such that
the desiccant polymer is located on only part of the closure wall,
so that for example the puncturable region may be situated between
areas of the closure wall on which is the desiccant polymer, or to
one side of such an area, thereby facilitating the construction of
the puncturable region as a thinned region of the closure face.
[0041] Such a multi-part construction includes the possibility that
the closure may be integrally made of a co-molded, or fused
together, desiccating polymer and an elastomeric or plastics
material making up parts of the structure of the closure.
Alternatively the desiccating polymer may be provided as a separate
part, retained by the closure on a suitable inward surface, e.g.,
in an inwardly facing holder or cavity.
[0042] In one embodiment a multi-part construction of closure of
the invention, the desiccant polymer may be in the form of a ring
shape on the closure wall of a closure, with the puncturable region
within, e.g., near or at the center of, the ring. Such a ring shape
may for example be circular, polygonal, or oval etc.
[0043] Such a ring-shape of desiccant polymer may be located in a
corresponding ring-shaped or cylindrical holder in the closure
wall. 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. Suitably both the walls may be integral with the closure
wall, so that the closure wall forms the base of the cavity and of
the central passage. Suitably, in such a construction, the base
wall of the central passage includes the puncturable region.
[0044] Alternatively such a ring-shape of desiccant polymer may be
located in a ring-shaped or cylindrical cavity in the closure wall,
suitably in its inward face, the cavity opening into the interior
of the container when the closure is in place on the vessel, and
the central opening in the ring shape of desiccating polymer may
define a central passage in direct communication with the
puncturable region, down which a hypodermic needle may be
inserted.
[0045] Alternatively the ring shape of desiccant polymer may be
located adjacent to the inner face of the closure wall.
[0046] The desiccant polymer may be simply physically attached to
the closure, e.g., by cooperating parts such as projections and
sockets, or simply be held in place by the inherent resilience of
other parts of the closure, particularly when this is made of an
elastomeric or other resilient material such as a plastics
material, alternatively the desiccant polymer may be bonded to the
closure e.g., by adhesives or fusion together etc.
[0047] Alternatively a closure for the container, e.g., a bottle or
jar of glass or plastics material, or a metal canister or keg, may
be in the form of a conventional screw cap (optionally provided
with tamper evident or child resistant features) or other form of
closure (e.g., cam action closure, snap-fit closure) which relies
on a compression fit on the lip of the mouth of the container, and
having an insert made of the said desiccant polymer, e.g., an
elastomeric material compounded with a desiccant material, in the
form of a disc or ring washer or inward facing coating layer which
forms a compression seal between the lip of the mouth of the
container and the closure as the container closure is tightened
down, e.g., by a screw action.
[0048] Alternatively a closure for the container, e.g., a bottle or
jar of glass or plastics material, or a metal canister or keg, may
be a screw/interference/friction/compression fit insertable bung or
other insertable stopper of its surface exposed to the interior of
the container made of the said desiccant polymer, e.g., an
elastomeric material compounded with a desiccant material.
[0049] Alternatively the container may comprise a syringe barrel,
with a plunger having at least part of its surface exposed to the
interior of the container made of the said desiccant polymer, e.g.,
an elastomeric material compounded with a desiccant material.
Suitably the entire plunger may be made of the said desiccant
polymer, e.g., an elastomeric material compounded with a desiccant
material.
[0050] Alternatively the said desiccant polymer, e.g., an
elastomeric material compounded with a desiccant material may be
included in other forms into the container of the invention, for
example as a removable resilient element such as a pad, wad, leaf,
helix, coil or spiral spring which may be included in the headspace
above the contents of a container and which exerts a restraining
action on the contents, such a tablets, pills, capsules, etc. to
prevent the contents rattling about in the container. Such an
element may be made as part of the container closure.
[0051] Alternatively the said desiccant polymer, e.g., an
elastomeric material compounded with a desiccant material may be
made in the form of a pad, e.g., a flat disc to be retained at the
bottom of a container, e.g., beneath tablet, pill or capsule
contents.
[0052] The nature and quantity of desiccant polymer 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. Suitably in the
case of the moisture sensitive material potassium clavulanate, at
the usual quantities in which it is supplied mixed with sodium
amoxycillin in vials, typically of a capacity 10-20 ml, for
reconstitution for an injectable formulation, e.g., 100-200 mg
potassium clavulanate mixed respectively with 500-1000 mg sodium
amoxycillin (expressed as the parent free acid equivalent weight)
the desiccant polymer should scavenge 5-8 milligrams of water with
a residual RH of less than 10% throughout a two year storage
period.
[0053] Preferred desiccating polymers for use with formulations
containing potassium clavulanate, e.g., its coformulation with
sodium amoxycillin, are able to take up atmospheric moisture at 30%
RH or less, preferably at 10% RH or less. Preferred desiccating
polymers exercise such a desiccant function for a long period,
ideally throughout the shelf life, typically two years, of such a
formulation.
[0054] Preferred desiccant polymers should also be capable of being
sterilized without loss of their desiccant ability at these low RH
values. For example desiccant polymer vial closures are ideally
sterilized by washing prior to use, without loss of their desiccant
ability. It is found that desiccant rubbers such as halobutyl,
e.g., chlorobutyl, rubber compounded with calcium oxide or
molecular sieves are capable of being washed without deleterious
effect on their desiccant ability.
[0055] 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 crystalline sodium amoxycillin e.g., as
disclosed in EP 0131147. The invention therefore further provides a
container as described above, containing a mixture which comprises
potassium clavulanate and sodium amoxycillin.
[0056] Other pharmaceutical substances which may usefully be
contained in the container of the invention include lyophilized
substances, for example those often employed in diagnostic assay
kits.
[0057] 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 container, the closure comprising a closure wall, the
inwardly facing region of the closure wall comprising or having
thereon a desiccant polymer.
[0058] For example such a closure may be a closure capable of
sealing engagement with the mouth opening of a container, the
closure comprising a closure wall having a puncturable region
therein in direct communication with the interior of the vessel,
and having on an inwardly facing region of the closure wall a
desiccant polymer.
[0059] Suitable and preferred forms of the closure are as described
above.
[0060] The present invention also provides a method of desiccating
a moisture sensitive material, which comprises enclosing the said
material in a container and maintaining a desiccant polymer in
contact with the atmosphere inside the container. This method may
be a method of long-term storage and/or protection against
hydrolysis during storage. The moisture sensitive material may be
potassium clavulanate or its coformulations with sodium
amoxycillin. This method is suitable for use with lyophilized,
freeze dried, materials. Normally lyophilized materials are
desiccated by an intense drying process before vials containing
them are sealed, and this method of the invention provides the
advantage that less intense drying processes may be used, and the
desiccant polymer can thereafter complete the dehydration process
whilst in the sealed vial.
[0061] Suitable and preferred forms of the process are as described
above.
[0062] The invention will now be described by way of example only
with reference to the accompanying drawings, which show:
[0063] FIGS. 1, 2 and 3: longitudinal sections through alternative
multi-part construction vials and closures of the invention.
[0064] FIG. 4: a sectional view through the closure of FIG. 1 about
the line A-A of FIG. 1 looking in the direction of the arrows.
[0065] FIGS. 5-7: graphs showing moisture uptake for rubbers
compounded with various listed desiccants.
[0066] FIG. 8: a graph of normalized moisture uptake for dried
hydrogels (a) to (f) tested in example 4.
[0067] Referring to FIGS. 1 to 4, a glass vial (1) has a mouth
opening (2) defined by the rim of an inwardly extending neck (3).
In the neck (3) of the vial (1) is a closure (4 generally)
integrally made of a synthetic rubber material, and 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).
[0068] Referring specifically to FIG. 1, 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)
forms a neck plug which sealingly engages the neck (3) with a
compression fit. The inner wall (7B) defines a central space (8)
with the puncturable region (6) at its outer end. 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).
[0069] Between the inner and outer walls (7A, 7B) is a ring-shaped
cavity (10) which contains a desiccant polymer (11) in the form of
a ring with a central opening. The ring (11) is retained in place
in the cavity (10) by the inherent resilience of the closure
material.
[0070] Referring specifically to FIG. 2 an alternative construction
of vial is shown. Parts having a common identity with FIG. 1 are
correspondingly numbered. In the vial of FIG. 2 the desiccant
polymer is in the form of a ring (12) which is bonded to the inner
face (13) of the closure wall (5) where this extends inwardly into
the interior of the vial (1) in the form of a neck plug (14), with
its central opening in communication with the central space (8) of
the closure. The neck plug (14) sealingly engages the neck (3) with
a compression fit
[0071] Referring to FIG. 3 an alternative construction of vial is
shown. Parts having a common identity with FIG. 1 are
correspondingly numbered. In the vial of FIG. 2 the desiccant
polymer is in the form of a ring (15) with a central opening (16).
The ring (15) fits into a central cavity (17) in the closure wall
(5) where this extends inwardly into the interior of the vial (1)
to form a neck plug (18) and is held there in place by the
resilience of the material of the closure (4). The central opening
(16) in the ring (15) defines a passage having the puncturable
region (6) at its outer end. The neck plug (18) sealingly engages
the neck (3) with a compression fit.
[0072] The closure wall (5) may be fastened tightly against the rim
of the neck (3) by means of a circlip (not shown). In another
embodiment (not shown) a holder for the desiccant polymer (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 polymer
(11) between them, and with a base wall.
[0073] It should be noted that if the desiccant polymer is a
hydrogel polymer shrinkage may occur on drying which may affect the
retention of the polymer on a rubber closure, and steps, e.g., a
suitable construction of holder, which will be apparent to those
skilled in the art, might be necessary to overcome this.
[0074] In use, the hypodermic needle (9) is inserted through the
puncturable region (6), and along the passage (8), 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 the vial may be shaken to encourage dissolution.
The solution may then be withdrawn through the needle (9) into a
syringe (not shown) for subsequent use.
EXAMPLE 1
Rubbers Compounded with Desiccants
[0075] A closure for a glass vial of the type conventionally used
for the containment made, using a standard known compounded
halobutyl rubber formulation, but in which 50% by weight of the
conventional china clay filler was replaced with calcium oxide
ground to a particle size distribution similar to that of the
filler. The shape and size of the closure corresponded to those of
a conventional vial closure. The volume of the vial was ca. 10 ml.
The molecular sieve was dried using a standard process for drying
the molecular sieve.
[0076] A moisture sensitive pharmaceutical formulation, being 500
mg crystalline sodium amoxycillin prepared as described in EP
0131147 coformulated with 100 mg of potassium clavulanate was
filled into the vial under conditions of less than 30% RH and the
vial was sealed with the stopper as conventional, with the stopper
being retained on the vial using a conventional thin metal
cover.
[0077] The vial containing the formulation was stored under ambient
and accelerated storage conditions. Color measurements (a known
sensitive method of assessing the degree of decomposition of
potassium clavulanate) showed a degree of protection of the
potassium clavulanate effectively equivalent to that shown using
spray-dried sodium amoxycillin having desiccant properties, in a
conventionally stoppered vial.
[0078] A similar result was achieved when calcium oxide instead of
molecular sieve was compounded with the rubber, and when all of the
filler was replaced by these desiccants.
EXAMPLE 2
Rubbers Compounded with Desiccants
[0079] In a further experiment potassium clavulanate was enclosed
within an airtight glass vessel, and a piece of halobutyl rubber
compounded with calcium oxide as mentioned above in Example 1 was
suspended inside the vial on a piece of wire. A control experiment
was set up consisting of an identical vessel enclosing the same
weight of potassium clavulanate but without the compounded rubber.
The decomposition of the potassium clavulanate under the action of
traces of moisture in the atmosphere of the vial and in the
potassium clavulanate itself, or adsorbed on the inner surface of
the vial was monitored. Color measurements showed that
decomposition of the potassium clavulanate was significantly
retarded in the vessel containing the rubber compounded with the
desiccant.
EXAMPLE 3
Rubbers Compounded with Desiccants
[0080] FIG. 5 shows the moisture uptake (normalized data) in terms
of weight % at ca. 10% RH by desiccant polymers which are halobutyl
rubbers of standard formulation except that 20-40% of the china
clay filler normally used has been replaced by the desiccant
indicated. Grace A3.TM., Siliporite.TM., and Ferben 200.TM. are
commercially available powdered desiccants, sold under these trade
names, and were pre-dried according to the standard procedures for
these desiccants. Grace A3.TM. and Siliporite.TM. are types of
molecular sieve powder obtainable from W R Grace Ltd. Northdale
House, North Circular Road, London NW10 7UH, GB. The graph relates
to the desiccant fillers:
[0081] (a) Siliporite.TM.
[0082] (b) molecular sieve
[0083] (c) Grace A3.TM.
[0084] (d) Ferben 200.TM.
[0085] FIG. 6 shows the moisture uptake (normalized data) in terms
of weight % at ca. 10% RH by desiccant polymers which are halobutyl
rubbers of standard formulation except that 20-40% of the china
clay filler normally used has been replaced by the desiccant, after
the rubber has been tote washed. The graph relates to the desiccant
fillers:
[0086] (a) calcium oxide
[0087] (b) molecular sieve
[0088] (c) Grace A3.TM.
[0089] (d) Siliporite.TM.
[0090] FIG. 7 shows the moisture uptake (normalized data) in terms
of weight % at ca. 10% RH by desiccant polymers which are halobutyl
rubbers of standard formulation that 20-40% of the china clay
filler normally used has been replaced by the desiccant indicated,
before and after the rubber has been tote washed. The graph relates
to the desiccant fillers:
[0091] (a) molecular sieve--washed
[0092] (b) molecular sieve--unwashed
[0093] (c) Grace A3.TM.--washed
[0094] (d) Grace A3.TM.--unwashed
[0095] The data presented in these graphs show that rubber
compounded with these desiccants has a desiccant ability even at RH
as low as 10% RH, and this desiccant ability is relatively
unaffected by washing.
EXAMPLE 4
Hydrophilic Hydrogels
[0096] Samples (a)-(f) of known hydrogels as tabulated below were
obtained in a hydrated state and were activated by heating to ca.
120.degree. C. under vacuum for a minimum of 3 hours.
[0097] (a) 90:10 hydroxyethyl methacrylate:N,N-dimethylacrylamide
copolymer
[0098] (b) 90:10 hydroxyethyl methacrylate:N-vinyl pyrrolidone
copolymer
[0099] (c) 90:10 hydroxyethyl methacrylate:acryloyl morpholine
copolymer
[0100] (d) 70:30 N-vinyl pyrrolidone:methyl methacrylate
copolymer
[0101] (e) 30:70 methyl methacrylate:acryloyl morpholine
copolymer
[0102] (f) 50:50 hydroxy methacrylate:acryloyl morpholine
copolymer
[0103] The moisture uptake of all six samples was evaluated in a
standardized 24 hour cycle on the Dynamic Vapor Sorption apparatus.
The samples were prepared and placed at a nominal 0% RH (actual 2%)
for 4 hours to complete activation. The RH was then raised to a
nominal 10% (actual 12%) for 1000 minutes and then returned to 0%
for a further 200 minutes completing the 24 hour cycle. Data was
normalized to allow for any weight loss during the 4 hour
activation stage, and is illustrated in FIG. 8.
[0104] In order to evaluate whether the samples had reached a
stable equilibrium at the end of the holding time at 10% RH two
samples (c) and (d) with different profiles in the screening test
above were selected and held for 24 hours at 0% RH followed by ca.
45 hours at 10% RH. This confirmed that maximum moisture uptake was
achieved within 1000 minutes.
[0105] It was clear from these results that all hydrogels tested
had highly significant water uptake at low RH, i.e. 10%. The
majority of the water uptake occurred extremely rapidly and final
equilibrium was attained within 17 hours or less. The maximum
uptake using hydrogel polymers was for sample (d) which was able to
absorb approximately 1.7% of its own weight of water at 10% RH when
fully dried.
[0106] The hydrogel samples showed the physical changes listed
below during the test:
[0107] (a) very brittle when dried
[0108] (b) least brittle when dried
[0109] (c) very brittle when dried
[0110] (d) considerable shrinkage on drying
[0111] (e) opaque when dried.
[0112] It will be appreciated by those skilled in the art that
changes could be made to the embodiments described above without
departing from the broad inventive concept thereof. It is
understood, therefore, that this invention is not limited to the
particular embodiments disclosed, but it is intended to cover
modifications within the spirit and scope of the present invention
as defined by the appended claims.
* * * * *