U.S. patent application number 11/572150 was filed with the patent office on 2007-07-19 for package and device for simultaneously maintaining low moisture and low oxygen levels.
This patent application is currently assigned to PFIZER INC.. Invention is credited to Dwayne T. Friesen, Kenneth C. Waterman.
Application Number | 20070163917 11/572150 |
Document ID | / |
Family ID | 35219559 |
Filed Date | 2007-07-19 |
United States Patent
Application |
20070163917 |
Kind Code |
A1 |
Friesen; Dwayne T. ; et
al. |
July 19, 2007 |
Package and device for simultaneously maintaining low moisture and
low oxygen levels
Abstract
The present invention relates to a device for reducing the
oxygen content of the air surrounding pharmaceutical dosage forms
contained within an oxygen-permeable bottle, while also maintaining
a relatively low moisture level in said air during the shelf-life
of the product. Accordingly, a pharmaceutical package contains a
dessicant in a first sub-container and a self-activated
oxygen-absorber in a second sub-container.
Inventors: |
Friesen; Dwayne T.; (Bend,
OR) ; Waterman; Kenneth C.; (East Lyme, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
PFIZER INC.
|
Family ID: |
35219559 |
Appl. No.: |
11/572150 |
Filed: |
July 4, 2005 |
PCT Filed: |
July 4, 2005 |
PCT NO: |
PCT/IB05/02446 |
371 Date: |
February 21, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60588466 |
Jul 16, 2004 |
|
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|
Current U.S.
Class: |
206/528 |
Current CPC
Class: |
A61J 1/00 20130101; B65D
81/268 20130101 |
Class at
Publication: |
206/528 |
International
Class: |
B65D 85/42 20060101
B65D085/42 |
Claims
1. A pharmaceutical package comprising a bottle that maintains the
oxygen content of the air within its interior volume at a reduced
level relative to the oxygen content of the ambient air,
comprising: A) said bottle, B) a desiccant disposed within a first
sub-container disposed inside said bottle, said first sub-container
being adapted to expose said dessicant to the interior of said
bottle, C) a self-activated metal-based oxygen-absorber disposed
within a second sub-container disposed inside said bottle, said
absorber having sufficient oxygen-reducing capacity to reduce and
to maintain the interior of said container at an oxygen level less
than the oxygen level of the ambient air, said second sub-container
having an orifice that exposes said absorber to the interior of
said bottle, said orifice having dimensions that allow oxygen
scavenging while limiting the diffusion rate of water from said
second sub-container such that the interior of said container is
maintained at a relative humidity less than 50%.
2. A package as defined in claim 1, wherein the metal used in said
oxygen absorber is selected from iron, tin, nickel, copper and
zinc
3. A package as defined in claim 1 or 2, wherein the cross
sectional area of said orifice is between 0.8 and
38.times.10.sup.-4 cm.sup.2.
4. A package as defined in any one of claims 1-3, wherein said
orifice is a hole having a diameter between 100 and 700 .mu.M.
5. A package as defined in any one of claims 1-4, wherein said
bottle is fabricated from a polymeric plastic having a thickness
such that the oxygen permeability of said bottle is from 3500 cc
mil/(m.sup.2day atm) to 9500 cc mil/(m.sup.2day atm).
6. A package as defined in any one of claims 1-5, wherein said
sub-containers are physically separate.
7. A package as defined in any one of claims 1-6, wherein said
sub-containers are formed as physically separate compartments of a
unitary cartridge.
8. A package as defined in any one of claims 1-7, further
comprising, within said bottle, a third sub-container (D) adapted
to contain a quantity of self-activated metal-based oxygen absorber
separate from the absorber contained in sub-container (C).
9. A package as defined in claim 8, wherein said sub-container (D)
is physically separate from sub-containers (B) and (C).
10. A package as defined in claim 8 or 9, wherein said
sub-container (D) is engineered as a compartment in a cartridge
also containing, as individual compartments, sub-containers (B) and
(C).
11. A package as defined in any one of claims 1-10, wherein said
bottle is fabricated at least in part of a pharmaceutically
acceptable polymer.
12. A package as defined in any one of claims 1-11, wherein said
desiccant is silica gel.
13. A package as defined in any one of claims 1-12, wherein the
metal used in said oxygen absorber is iron.
14. A package as defined in any one of claims 1-13, wherein the
orifice of the second sub-container is a hole having a diameter
between 200 and 600 .mu.M.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a device for reducing the
oxygen content of the air surrounding pharmaceutical dosage forms
contained within an oxygen-permeable bottle, while also maintaining
a relatively low moisture level in said air during the shelf-life
of the product.
BACKGROUND OF THE INVENTION
[0002] Oxygen induced drug degradation is a factor that can limit
the shelf life, usually as indicated by the expiration date, of a
drug product. In the case of drugs that are highly
oxygen-sensitive, such degradation may render a drug unmarketable
or cause a candidate to be excluded from development.
[0003] In some cases, oxygen sensitivity occurs only in the
presence of certain excipients. Since oxidation is often not
accelerated by standard Arrhenius-based increased temperature
studies (known in the art as "accelerated aging studies"),
instances can occur in which the oxygen sensitivity of the drug is
not recognized until drug development has progressed into late
stages of development. At such later stages of development,
reformulation and addition of standard antioxidants can require
considerably more time and money. In addition, more clinical data
may be necessary with a new formulation. Thus, a need for reducing
or eliminating oxygen-based drug instability, without requiring a
formulation change, has existed in the art.
[0004] Often in drug development, a need may arise to reduce or
prevent oxygen-induced degradation of a drug candidate or to
provide adequate stability for initial studies without investing a
lot of resources prior to proof of concept. Once a candidate has
been selected for further development, oxygen-sensitivity can then
be addressed by more traditional strategies.
[0005] In addition to oxygen sensitivity of a pharmaceutically
active ingredient in a dosage form, the dosage form itself can be
sensitive to moisture. This sensitivity can be due to direct
reaction (e.g., hydrolysis), or to physical effects such as
plasticization of drug or excipients, sticking of dosage forms
together ("twinning"), or to deliquescence (absorption of
atmospheric moisture). For these reasons, many pharmaceutical
dosage forms are packaged with added desiccants. The most common
pharmaceutically acceptable desiccant is silica, which controls the
relative humidity (RH) to below 20%.
[0006] The use of metal-based oxygen absorbers in the food industry
for preservation of foods is well known. In such systems a metal in
a reduced oxidation state reacts with oxygen in the presence of
water to form a metal oxide. For example, Mitsubishi Gas
Corporation introduced iron-plus-carbonate salt sachets under the
trade name Ageless.TM. for use in stabilizing packaged foods by
preventing oxidation. Other iron and metal-based oxygen absorbers
combined with various salts and other incremental improvements
quickly followed suit, usually with the metal in the form of a
powder or other subdivided form, and with all components of the
absorber being contained within an oxygen permeable sachet. In a
metal oxidation reaction, water provides the activation mechanism
used in most such oxygen-scavenging applications. Oxygen-absorbing
sachets are generally stored dry where they can be handled without
consuming oxygen. In the presence of moist foods, the
oxygen-absorber is activated and begins removing oxygen.
[0007] Recently, companies in the food industry have introduced
self-activated oxygen absorbers to provide oxygen absorption with
dry food products. These have involved combining moisture-holding
additives with the metals (usually iron) in sachets (See, e.g.,
Japanese Publications SHO56-50618 and SHO57-31449; and U.S. Pat.
No. 5,725,795). European Patent Application Nos. 864630A1 and
964046A1 describe the use of iron iodide and bromide to allow
oxygen absorption in a low humidity environment without the need to
bring in water; however, commercial application of this technology
has not been realized.
[0008] In the pharmaceutical industry, there have been some limited
reports of using oxygen absorbers to stabilize drugs. For example,
in 1984, tablets of an anti-inflammatory drug were stabilized in
large glass (i.e., oxygen-impermeable) jars with oxygen absorbing
sachets for six months at 50.degree. C. (Japanese Patent No.
SHO59-176247). The source of the oxygen being removed was primarily
from the headspace and not from ingress, i.e., due to permeation of
oxygen through the walls of the jar. Similarly, Japanese Patent No.
SHO96-253638 describes cold remedy powders stabilized in
impermeable bottles by either nitrogen purging or with oxygen
absorbers in the bottle. In a 1990 publication, L-cysteine in an
ophthalmic ointment was stored with an oxygen absorber. (See, i.e.,
Kyushu Yakugakkai Kaiho, "L-Cysteine Ophthalmic Solution Stabilized
with Oxygen Absorber," 44, 37-41 (1990).) In 1995, tonic solutions
of vitamin C were stabilized using a bottle cap having an oxygen
absorber covered with a polyolefin (Japanese Patent No.
SHO94-17056). U.S. Pat. No. 5,839,593 describes the incorporation
of an oxygen-absorber into the liner of a bottle cap. More
recently, U.S. Pat. Nos. 6,093,572; 6,007,529; and 5,881,534; and
PCT publication WO 9737628 describe the use of oxygen absorbers
with parenterals and their particular benefit for sterilization.
Placement of oxygen-absorbing sachets between an intravenous (IV)
bag or blood bag and its outer packaging is commonly used in
commercial applications. Pre-filled syringes with absorbers between
the syringes and outer packaging are also known. EP 0 837 o69 A1
discloses the use of oxygen absorbers to stabilize acarbose in
gas-impermeable bottles.
[0009] U.S. Pat. No. 6,688,468B2 and EP 1 243 524 A2 disclose the
use of oxygen absorbers with pharmaceutical dosage forms in
permeable packaging. The oxygen absorbers used in these patent
applications are largely iron based with added moisture controlled
by salt slurries. Although these systems perform well for many
pharmaceutical applications, they cause the humidity in the bottle
environment to be at 55 to 75% relative humidity, since the oxygen
consumption reaction requires humidity to operate. Although it is
possible to dry the bottle environment somewhat using a desiccant,
the oxygen absorber will, in general, also be dried by the
desiccant and be less effective at removing the oxygen permeating
through the bottle walls. The result is that the oxygen level in
the bottle will not remain low enough to provide for beneficial
stabilization of the pharmaceutically active ingredient over its
entire shelf life.
[0010] In all of the aforementioned documents, there is no
disclosure or guidance relating to the issue of how to use a
self-activated oxygen absorber to absorb oxygen in an
oxygen-permeable pharmaceutical container while simultaneously
maintaining the environment in the container low in moisture, for
example through the use of a dessicant. Doing so would require the
combination of a self-activated oxygen absorber, which requires
water to function, with a dessicant which absorbs the water.
[0011] Non-iron based oxygen absorbers that do not increase the
relative humidity near the absorbing unit have been marketed for
use with pharmaceuticals under the registered trademark
PharmaKeep.RTM. by Mitsubishi Gas Corporation and Sud-Chemie
Corporation. These absorbers, however, provide only a limited
absorption capacity (typically less than about 40-cc of oxygen),
which is not adequate to provide for protection of pharmaceuticals
in permeable packages for a typical shelf life of at least two
years. Although it is possible, in theory, to use a number of such
units to provide for adequate oxygen absorption on an ongoing
basis, for common bottle sizes of 30-250 cc, the sheer number
needed to maintain a low oxygen level during the shelf life of the
pharmaceutical would generally preclude filling with dosage
forms.
[0012] For all of the reasons noted above, there remains a need for
an oxygen absorber that is capable of providing, in a convenient
and cost effective manner, adequate oxygen absorption capacity to
be usable with oxygen permeable pharmaceutical packaging for at
least two years of shelf life, but which also allows the relative
humidity inside the packaging to be maintained below 50%,
preferably less than 40%, more preferably less than 30%.
SUMMARY OF THE INVENTION
[0013] The present invention provides a pharmaceutical package
comprising an oxygen permeable bottle containing therein at least
one sub-container containing a self-activated oxygen absorber and
at least one sub-container containing a desiccant. The
sub-containers can be separate units or unitary, i.e., fabricated
together as separate compartments within a single unit, termed
herein a "cartridge", containing the self-activated oxygen absorber
in one compartment and the desiccant in a separate compartment. The
invention solves a problem, namely that the interior of the bottle
is maintained at a low oxygen level to protect oxygen-sensitive
pharmaceuticals and also at a low moisture level to protect
moisture-sensitive pharmaceuticals and/or dosage forms. This dual
protection occurs even though the self-activated oxygen absorber
requires moisture to function and the sub-container or compartment
in which it resides is exposed to the interior of the bottle.
[0014] In one aspect the invention provides a method of maintaining
the oxygen content of the air inside a pharmaceutical bottle at a
reduced level relative to the oxygen content of the air outside the
bottle, said bottle being fabricated at least in part of a
pharmaceutically acceptable oxygen-permeable material, while
simultaneously maintaining said inside air at a relative humidity
of less than 50%, comprising the steps of: [0015] disposing, within
said bottle, a first and second sub-container, [0016] said first
sub-container containing a desiccant and being adapted to expose
said desiccant to the interior of said bottle, [0017] said second
sub-container containing a self-activated metal-based
oxygen-absorber, [0018] said absorber having sufficient
oxygen-reducing capacity to reduce and to maintain the oxygen
content of said inside air at a level that is less than the oxygen
level of the ambient (i.e., outside the bottle) air, [0019] said
second sub-container having an orifice that exposes said absorber
to the interior of said bottle, said orifice having dimensions that
allow oxygen scavenging by said absorber inside said bottle while
simultaneously limiting the diffusion rate of water from said
second sub-container such that the interior of said bottle is
maintained below 50% RH, preferably below 40% RH, more preferably
below 30% RH.
[0020] In a second aspect the invention provides a pharmaceutical
package comprising a bottle that maintains the oxygen content of
the air within its interior volume at a reduced level relative to
the oxygen content of the ambient air, comprising: [0021] A) said
bottle, which is fabricated at least in part of an oxygen permeable
material, [0022] B) a desiccant disposed within a first
sub-container disposed inside said bottle, said first sub-container
being adapted to expose said dessicant to the interior of said
bottle, [0023] C) a self-activated metal-based oxygen-absorber
disposed within a second sub-container disposed inside said bottle,
[0024] said absorber having sufficient oxygen-scavenging capacity
to reduce and to maintain the interior of said bottle at an oxygen
level less than the oxygen level of the ambient air, [0025] said
second sub-container having an orifice that exposes said absorber
to the interior of said bottle, said orifice having dimensions that
allow oxygen scavenging while limiting the diffusion rate of water
from said second sub-container such that the interior of said
bottle is maintained below 50% RH, preferably below 40% RH, more
preferably below 30% RH.
[0026] In most embodiments the bottle is closed, and preferably
sealed, although it is possible to implement the invention in the
absence of a seal.
[0027] The term "bottle" is intended to be general, and to include
any type or shape of pharmaceutical container that is fabricated at
least in part from an oxygen-permeable material. A "pharmaceutical
bottle" is one wherein the oxygen-permeable material from which it
is fabricated is pharmaceutically acceptable. Thus "bottle"
includes traditional square or round plastic bottles, jars, bags,
pouches, or other pharmaceutically-acceptable containers.
[0028] "Relative humidity", sometimes abbreviated herein as "RH",
has its usual meaning, i.e., the ratio of the actual humidity over
the saturated humidity at the same temperature.
[0029] The "package" disclosed herein refers to the combination of
a pharmaceutical bottle having disposed therein a self-activated
oxygen absorber and a desiccant, each contained in its own
sub-container, the bottle being intended to be filled by a (usually
pre-determined) number of solid pharmaceutical dosage forms,
typically tablets or capsules. The "inside" or "interior" of the
bottle refers to the free, i.e., unoccupied volume of the bottle
once filled and containing the first and second sub-containers
described in (B) and (C) above, or additional sub-containers or
cartridges, as described below. The free volume, also referred to
in the art as "headspace", of such filled bottles is generally
between 10 and 100 cc. The amount of headspace is not critical
since more than one oxygen-absorbing sub-container can be added to
the bottle. Generally, given the typical size of a pharmaceutical
bottle and the rate at which oxygen permeates known
oxygen-permeable plastics used to fabricate pharmaceutical bottles,
the oxygen-absorbing sub-container is implemented to have a hole
(uncovered) that is 100-700 microns in diameter, preferably 200-600
microns. The hole will generally be round since it can be
implemented with a drill, although shape is not critical and other
shapes having an equivalent area can also be used. In an alternate
embodiment a larger hole can be implemented and covered with a
microporous material having a porosity generally between 0.05 and
0.2, and a thickness between 0.5 and 2.5 mm. Suitable membranes are
widely commercially available, for example from General Electric
Osmonics (a division of GE Water Technologies, Trevose, Pa.) and
from Millipore Corporation, (Billerica, Mass.). The total amount of
pore area, defined as the porosity times the area, should be
equivalent to the area of a hole having dimensions as described
above.
[0030] An oxygen-permeable bottle generally refers to one made of a
material that, when sealed or closed, will admit sufficient oxygen
to cause oxidative degradation of the contained active
pharmaceutical ingredient over a reasonable shelf life, a
"reasonable shelf life" usually being between six months and three
years, typically two years. Such materials include any of the
pharmaceutically acceptable available plastics commonly used in the
industry and further discussed and identified below. As stated
above, the bottle is one that, as part of the manufacturing
operation, is closed and preferably sealed once it has been filled
with pharmaceutical dosage forms and the at least two
sub-containers (B) and (C) described above. Any oxygen-permeable
bottle that allows for oxidative degradation of more than 0.2% of
the contained active pharmaceutical ingredient or compound during
its reasonable shelf life can benefit from this invention. Bottle
shape is not critical.
[0031] The term "self-activated oxygen absorber" refers to a
metal-based substance that removes oxygen by reacting with it to
chemically bind it, generally by forming a metal oxide. The term
"activated" means that the metal-based substance requires the
presence of water (i.e., as a reactant) to drive the metallic
oxide-forming reaction. The oxygen absorbers useful in the present
invention are "self-activated", meaning that they are sold as a
unit that contains the water needed to enable the oxide-formation,
the water usually being present in the form of a humidity
controlling substance, typically an aqueous slurry of a salt or a
sugar, such compositions being designed to maintain a specific
humidity in a closed environment. The preferred metal is elemental
iron, powdered to increase its surface area. Other metals that are
useful, although less preferred, include nickel, tin, copper and
zinc.
[0032] The oxygen absorber reduces the oxygen content of the air
within the bottle, once the bottle has been closed or sealed, to a
level that is below the oxygen level of the surrounding air outside
the bottle, for example the ambient air in a warehouse or shipping
hold, or other storage environment or transportation means.
Thereafter, the absorber maintains the oxygen in the headspace air
at a level preferably below 10.0% (i.e., by volume, based on the
headspace volume) preferably below 3.0%, more preferably below
1.0%, most preferably below 0.5%.
[0033] Sub-containers (B) and (C) can be implemented as physically
separate containers that are added to the bottle separately in the
manufacturing process. In a preferred embodiment, and as disclosed
further below, sub-containers (B) and (C) are formed as physically
separate compartments of a single unit, referred to herein as a
"cartridge". When discussing such a cartridge, the compartments
therein are designated as (B), (C), etc to have a meaning
corresponding to the letter designations given above for
sub-containers (B), (C), and so forth. The cartridge can
advantageously be fabricated out of a plastic (including the
oxygen-permeable ones disclosed herein) by a suitable molding
operation.
[0034] A further preferred embodiment, illustrated below, relates
to the inclusion, in said bottle, of a third sub-container or
cartridge compartment (D) adapted to contain a separate quantity of
self-activated metal-based oxygen absorber from that in
sub-container or canister compartment (C). This third sub-container
or compartment functions to rapidly reduce or remove the oxygen
initially contained in the bottle headspace once the bottle has
been closed or sealed for storage, transport, and/or sale.
Preferably, (D) is engineered as a third compartment in a cartridge
also containing, as individual compartments therein, (B) and (C).
Because this third sub-container or compartment is designed to
remove the oxygen initially present in the headspace, it preferably
contains only enough metal and water to react approximately
stoichiometrically with the oxygen initially present in the
headspace once the bottle has been closed or sealed. To facilitate
oxygen removal from the headspace, the third sub-container or
compartment has an orifice, preferably in the form of a porous
membrane having a permeability such that the flux of oxygen allows
the entire head space to be scavenged to below 3% (VN) of oxygen in
less than 3 days, preferably to below 2% in 3 days relative to the
orifice provided in the sub-container or compartment (C) that
contains the self-activated oxygen-absorber. Providing a much
larger pore area in sub-container or compartment (D) enables it to
effect oxygen removal rapidly and, therefore, to quickly implement
a relatively oxygen-free environment once the bottle has been
closed or sealed. Thereafter, sub-container or compartment (C)
maintains the oxygen at a relatively low level.
[0035] Hereinafter the invention will be described by reference to
cartridges and the compartments therein, it being understood that
this is for convenience and ease of description, and that the
cartridges and compartments described hereinafter can also be
implemented equivalently as separate sub-containers.
[0036] The access opening to compartment (B) which contains the
desiccant is also relatively much larger, hence more open to the
bottle interior, than the access to the bottle interior provided by
the orifice in compartment (C). The opening that exposes the
desiccant in compartment (B) to the headspace is preferably in the
form of a membrane, having a large pore area, to avoid spillage of
the desiccant from compartment (B). Alternatively, a plurality of
small orifices, such as drilled holes, can be separately
implemented in lieu of a membrane. By making the total orifice
surface area in compartment (B) relatively much larger than the
orifice in canister compartment (C), the interior of the bottle is
maintained relatively dry, much drier than the interior of the
(water-containing) oxygen-absorbing compartment (C). This area,
however, may be restricted to provide a relative humidity in bottle
A at a somewhat higher value than is typically maintained with
desiccants. This serves to minimize moisture loss from compartment
(C). The total area of the orifice area in sub-container (B),
whether the area is in the form of holes or a porous membrane, is
typically at least 0.3 cm.sup.2, preferably between 0.3 cm.sup.2
and 0.4 cm.sup.2.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIG. 1 is a front view of a bottle having a cartridge
disposed therein in a preferred embodiment according to the
invention.
[0038] FIG. 2 is a graph illustrating the rate of water removal by
the desiccant as a function of orifice size in compartment (B).
[0039] FIG. 3 is a graph illustrating the rate of oxygen
consumption by an iron-based self-activated oxygen absorber in
compartment (C) as a function of orifice size.
DETAILED DESCRIPTION
[0040] FIG. 1 illustrates a preferred embodiment of the present
invention designed to provide oxygen absorption with low moisture
for an extended period in a packaged product. In FIG. 1, "A"
represents a pharmaceutical bottle, which is generally fabricated,
in whole or in part, of an oxygen-permeable plastic. Bottle A is
preferably sealed, most preferably with a heat induction seal (HIS)
1 made of a metal foil and an adhesive that effects bonding of the
bottle to the foil. Disposed within pharmaceutical bottle A are
pharmaceutical dosage forms 3, preferably tablets, capsules or the
like. Also disposed within pharmaceutical bottle A is a cartridge,
designated generally as 5 and comprised, for the sake of
illustration only, of three separate compartments B, C, and D,
separated from each other by dividers 7 and 9, which are walls
preferably fabricated from the same material as the rest of
canister 5 and manufactured integrally therewith, for example as
part of a molding process. Compartment B contains a desiccant (not
shown) such as silica gel and is exposed to the bottle interior by
means of porous membrane 11, thereby allowing relatively free
exchange between compartment (B) and the bottle headspace, whereby
moist air inside bottle A enters and dry air leaves the
compartment. A second compartment D contains a self-activated
oxygen absorber present in sufficient quantity to remove the
initial head-space oxygen in bottle A. Compartment D contains
porous membrane 13 which allows for relatively free access by
compartment D to the oxygen-containing air in the headspace of
bottle A, thereby effecting oxygen scavenging. A third compartment
C contains sufficient self-activated iron absorber (i.e., metal and
moisture) to scavenge oxygen permeating through the bottle walls
during the shelf-life of the product. Compartment C contains an
orifice 15 that can be implemented in the form of a hole, tube or
microporous filter. The cross sectional area of the orifice is such
that it effects a rate of oxygen scavenging sufficient to match the
ingress rate of oxygen into bottle A, yet the area is such that the
orifice limits the rate of moisture loss from compartment C so that
there is adequate moisture in the compartment (i.e., to enable
metallic oxide formation) during the entire shelf-life of the
pharmaceutically active ingredient. Some moisture does escape from
compartment (C), but the rate is small relative to the
moisture-absorbing capacity of the desiccant in subunit "D". This
is a critical feature of the invention, i.e., the cross-sectional
area of the orifice (or orifices) in compartment (C). On one hand,
the area is large enough to effect efficient oxygen scavenging from
the interior of the bottle during the shelf life of the product,
thereby eliminating or reducing oxidative degradation of the
pharmaceutical product. On the other hand, the area is small enough
to limit the amount of moisture that escapes compartment (C) to no
more than that that can be removed by the desiccant during the
shelf life.
[0041] As stated previously, if the orifice is implemented as a
circular hole, it should have a diameter of from 100 to 700
microns, corresponding to a cross sectional area of from about
0.8.times.10.sup.-4 to about 38.times.10.sup.-4 cm.sup.2. Orifice
shape is not critical, and other shapes having equivalent
cross-sectional areas can be implemented equally effectively.
[0042] FIG. 2 shows the (experimentally-determined) variation in
the rate of moisture scavenging by the desiccant silica gel as a
function of orifice diameter (e.g., in compartment (C)) through a
barrier having a single tube therein of varying diameter. The data
points in the graph were measured while maintaining the external
environment at 40.degree. C. and 75% relative humidity (RH). The
graph demonstrates that the rate of moisture transfer out of a
cartridge with a high humidity compartment (C) can be controlled in
a predictable manner by picking a suitable size for the
orifice.
[0043] FIG. 3 shows the rate of oxygen scavenging by iron through a
barrier having a single tube implemented therein, as a function of
orifice (i.e., tube) cross sectional area. The data demonstrate
that the rate of oxygen scavenging, i.e. by compartment (C) can be
controlled in a predictable manner depending on orifice size.
[0044] In FIG. 1, pharmaceutical container A is a bottle or other
container for dispensing pharmaceutical dosage forms. The bottle is
designed to protect a dosage form from mechanical harm and to limit
exposure of the dosage forms contained therein to light and
contaminants in the environment. Glass bottles can in some cases
function effectively due to the low (essentially no) permeability
of glass to oxygen and moisture, and are within the scope of the
present invention. However, due to the risk of breakage and the
added expense of working with glass, bottles are preferably made,
usually entirely, of plastic, essentially all of such plastics
being oxygen-permeable in varying degrees. Suitable plastics for
use in fabricating pharmaceutical bottles generally involve such
plastics as low density polyethylene (LDPE), high density
polyethylene (HDPE), polypropylene (PP), polystyrene (PS) and
polycarbonate (PC). The oxygen permeability of these materials
ranges from 3500 cc mil/(m.sup.2day atm) for PS to 9500 cc
mil/(m.sup.2day atm) for LDPE. Other suitable packaging materials
include polyesters (PET, PEN), nylon, polyvinyl chloride (PVC),
poly(vinylidine chloride) (PVDC), poly(tetrafluoroethylene), etc.,
and laminates containing layers of one or more such materials. The
present invention provides, in a preferred embodiment, for a
cartridge that can be added to a pharmaceutical bottle and that
provides for a significant reduction in the oxygen and moisture
levels, including such a reduction at the permeation rates
disclosed above.
[0045] Once an oxygen permeable bottle is filled with a
pre-determined amount of dosage forms containing an
oxygen-sensitive drug and a cartridge according to the invention,
the botle is then closed, as by capping with a twist-on cap, or
stoppering, or sealing. If the bottle is sealed, a preferred seal
is a heat-induction seal (HIS). Other useful seals include
adhesives such as pressure sensitive adhesives, thermal adhesives,
photocured adhesives, and binary mixture adhesives such as epoxy
resins. Adhesion can also be effected by such techniques as
ultrasonic welding which do not require adhesives. A packing
material (e.g., cotton) may be optionally added to the bottle prior
to sealing to prevent any damage to the contents such as chipping
or cracking of the unit dosage forms. HIS is commonly used in the
pharmaceutical industry to seal plastic bottle tops, both as a
means of protecting the dosage form from the environment and as a
means of preventing (and making obvious) any tampering. The
induction seal and the bottle are preferably matched to achieve an
acceptable seal. Procedures for induction sealing are well known to
those skilled in the art. For a detailed description see "Induction
Sealing Guidelines", R. M. Cain (Kerr Group, Inc.), 1995 and W. F.
Zito "Unraveling the Myths and Mysteries of Induction Sealing", J.
Packaging Tech., 1990.
[0046] Any pharmaceutical dosage form 3 containing an
oxygen-sensitive pharmaceutical compound susceptible to degradation
as a result of exposure to oxygen may be disposed within
pharmaceutical bottle A. Examples of oxygen-sensitive materials
that are subject to degradation due to oxygen exposure include
materials such as amines either as salts or as free bases,
sulfides, allylic alcohols, phenols, alcohols, aldehydes and the
like. In addition, some basic pharmaceutically active materials or
compounds, especially amines, with pK.sub.a values in the range
from about 1 to about 10, more particularly in the range from about
5 to about 9, are often subject to oxygen degradation and may
accordingly benefit from the present invention, as well as some
pharmaceutically active materials or compounds having redox
potentials less than or equal to about 1300 mV vs. Ag/Ag.sup.+,
more preferably less than or equal to about 1000 mV vs.
Ag/Ag.sup.+. Suitable pharmaceutically active compounds include
compounds such as atorvastatin (especially when used in an
amorphous form), pseudoephedrine, tiagabine, acitretin,
rescinnamine, lovastatin, tretinoin, isotretinoin, simvastatin,
ivermectin, verapamil, oxybutynin, hydroxyurea, selegiline,
esterified estrogens, tranylcypromine, carbamazepine, ticlopidine,
methyldopahydro, chlorothiazide, methyldopa, naproxen,
acetominophen, erythromycin, bupropion, rifapentine, penicillamine,
mexiletine, verapamil, diltiazem, ibuprofen, cyclosporine,
saquinavir, morphine, sertraline, cetirizine,
N-[[2-methoxy-5-(1-methyl)phenyl]methyl]-2-(diphenylmethyl)-1-azabicyclo[-
2.2.2]octan-3-amine and the like. The invention is particularly
suitable for stabilizing high-energy drug forms to oxidation.
Examples of high-energy drug forms include amorphous forms and
small particle sized drug forms. A preferred example of a
high-energy form of a drug is prepared by spray-drying a drug as a
dispersion in combination with an enteric polymer as described in
EP 1027886A2 and EP 901786A2, each incorporated herein by
reference. Suitable enteric polymers include those described in
Patent application Nos. WO 0147495 A1, EP 1027886 A2, EP 1027885
A2, and U.S. Pub. No. 2002/0009494 A1, incorporated herein by
reference.
[0047] The present invention can additionally stabilize excipients
in the dosage form to oxidative degradation. For example,
degradation that leads to discoloration, harmful reactivity with
the active component of the drug or changes in the dosage form
performance, such as dissolution or disintegration rates.
Nonexclusive examples of excipients commonly used in pharmaceutical
formulations that could be stabilized by application of the present
invention include poly(ethylene oxides), poly(ethylene glycols) and
poly(oxyethylene) alkyl ethers.
[0048] The present invention provides a reduction in the degree of
oxidative degradation or discoloration where such degradation or
discoloration can be measured by light absorption or reflection
spectroscopy and/or chromatographic analysis, in particular, HPLC
analysis. The invention need not totally eliminate such
degradation; however, practice of the present invention preferably
reduces the degradation by at least about 20%, more preferably by
about 50% and most preferably by about 75% when compared to samples
stored in the absence of the cartridge/oxygen absorber as disclosed
herein.
[0049] Although the shape of the cartridge is not critical, the
cartridges described herein can be generally tubular in shape to
facilitate high speed bottle insertion. The cartridge can be in the
form of a canister, i.e., a tubular container with the desired
number of compartments and having either or both end compartments
openable to facilitate filling. The ends of the tube can be flat or
circular, convex or concave, as desired. The cartridge can be
fabricated as known in the art by using a suitable mold and molding
process, typically injection molding with a thermoformable
polymer.
[0050] The desiccant (sub-container or compartment B) provides for
a low relative humidity in the pharmaceutical package. The
desiccant for use in the practice of the invention can be any
available desiccant. Preferred desiccants include those commonly
used in the pharmaceutical industry that have adequate capacity to
handle the combination of moisture ingress into the bottle and
moisture given off by the self-activated oxygen absorber. Suitable
desiccants are discussed in R. L. Dobson, J. Packaging Technol., 1,
127-131 (1987). A preferred desiccant is silica gel. The desiccant
can be supplied in the form of a sachet, cartridge or canister.
[0051] It is desirable to maintain the relative humidity in the
bottle A at a level that, while still providing protection of the
dosage forms from the adverse effects of humidity, minimizes the
loss of moisture from compartment C. To this effect, the barrier 11
can be made to limit the moisture transfer rate. This rate
limitation can be effected using a membrane of somewhat limited
moisture permeation (by virtue of material or thickness) or by
suitable choice of a material having an appropriate permeability.
This material and surface area selection can be made based on
experiments and depends on the particular moisture sensitivity of
the dosage form used. In general, it is desirable that the
permeability of barrier 11 to moisture be such that the relative
humidity in the bottle A is maintained at or below 40% RH, more
preferably, below 30% RH, under, as a reference, storage conditions
of 30.degree. C., and 75% RH).
[0052] The amount of desiccant used is preferably sufficient to
handle moisture ingress through the pharmaceutical bottle walls
during the storage duration, which depends on the humidity of the
external environment. For conditions of 30.degree. C. and 60% RH,
the rate of water permeation into a 60-cc HDPE bottle with an
internal humidity kept below 40% RH can be estimated at about 0.25
mg/day (91 mg/yr). In addition, there is preferably enough
desiccant to handle moisture loss from the oxygen absorber
(estimated at about 146 mg/yr, as discussed below). Silica gel has
an approximate capacity to maintain a relative humidity below 40%
at about 0.5 mg H.sub.2O/mg silica. Thus an amount of silica gel to
place in sub-container or compartment B is between 475 and 1100 mg,
an amount that will absorb both moisture from external permeation
and moisture escaping internally from absorber compartment (C),
based on the orifice size in the compartment, during a reasonable
shelf life. It will be recognized by those skilled in the art that
similar calculations can be made for different bottle materials
having different rates of water permeation, headspace volumes, and
different conditions of temperature and relative humidity. The
cartridge compartment is constructed such that it physically
separates the desiccant from direct contact with the pharmaceutical
ingredients, yet allows the moisture from inside the pharmaceutical
package to be scavenged.
[0053] Compartment D of the cartridge contains a self-activated
oxygen absorber capable of rapidly removing oxygen from the
headspace in pharmaceutical bottle A. This absorber is preferably
an iron-based absorber and can be the same material used as the
self-activated oxygen absorber disposed within absorber compartment
(C). To enable the metal to scavenge oxygen, a moisture source must
be provided. In the present invention, and as commercially
available, this moisture source is preferably provided in the form
of a salt or sugar slurry. Because compartment D is designed to
rapidly remove the oxygen from the headspace inside bottle A, it
only needs to function for a few days, and thus requires only a
relatively small amount of absorber. The absorber in compartment
(D) can therefore be at a high relative humidity, though it will
rapidly deplete its moisture as the desiccant in compartment B
competes for the moisture. Preferably, the humidity source in
compartment B maintains a relative humidity (RH) above about 50%;
more preferably above 60%; still more preferably, above 65%.
Preferred moisture sources are salts or salt mixtures. Particularly
preferred salts are sodium chloride, potassium chloride and
potassium sulfate. Compartment D is constructed such that it
physically separates the self-activated oxygen absorber from direct
contact with the pharmaceutical dosage forms, yet allows oxygen
from inside the pharmaceutical package to be scavenged. Preferred
compartments (D) contain sachets wherein the containment sack is
fabricated of porous (e.g., woven) material. Alternatively the
cartridge compartment (D) can itself be porous, as by having an
open section covered with a porous fabric or membrane.
[0054] The amount of headspace oxygen in bottle A can be determined
by measuring the volume of the bottle, subtracting the volume of
the dosage forms and dividing the remaining volume by five (to
account for the oxygen abundance). For example, in an approximately
60-cc bottle that is half filled with dosage forms, the headspace
volume will be about 6-cc of oxygen. The amount of iron used to
remove the oxygen, and excluding any oxygen due to ingress, should
be at least stoichiometrically sufficient. Since the
oxygen-absorbing capacity of the iron is about 300-cc/g, the
minimum amount of iron needed for removal of the headspace oxygen
of a 60-cc bottle is 20 mg. Therefore, the amount of iron for this
subunit is preferably between 20 and 100 mg.
[0055] Compartment C contains sufficient oxygen absorber to enable
the oxygen level in the pharmaceutical bottle to remain low during
the product's reasonable shelf life by balancing the oxygen ingress
rate into the bottle with a comparable rate of oxygen scavenging.
At the same time, the rate of loss of moisture from compartment C
is sufficiently low that the overall moisture level in bottle A
remains low due to the desiccant and there remains enough water in
the subunit to provide for the needed relative humidity in the
subunit for iron activity during the duration of the shelf-life. It
has been determined that these contradictory and opposing goals can
be met with an oxygen absorber and a moisture controlling element
encased in a low permeability cartridge compartment in combination
with a rate-controlling port (15 in FIG. 1). Preferentially, the
cartridge is made from a plastic or metal material considered safe
for contact with pharmaceutical ingredients. Examples of preferred
materials include plastics such as polyethylene (PE), polystyrene
(PS) and polyvinylchloride (PVC). Although the cartridge can be
made out of permeable plastics, the actual amount of oxygen and
moisture that transfers through these materials (as opposed to the
holes or membranes) is a low due to the low surface area and does
not significantly impact the oxygen and moisture levels in bottle
A. The rate-controlling port has the property of restricting
moisture transfer while allowing sufficient oxygen transfer.
[0056] FIG. 2 shows the rate of moisture transfer from a test
environment controlled to be at 40.degree. C. and 75% RH into a
sub-container having a fixed amount of silica gel, the
sub-container having a single orifice, implemented therein as a
tube, as the only entrance for moisture from the environment. The
amount of water entering through the tube was monitored as a
function of time and the diameter of the tube. These data provide
the basis for calculating the moisture transfer rate from the
self-activated oxygen absorber compartment (C) to the bottle A
headspace. Once this transfer rate has been calculated, it can in
turn be used to calculate the amount of desiccant needed for
compartment (B).
[0057] As an example, to function effectively in pharmaceutical
applications, the relative humidity in bottle A is preferably
maintained at below about 50% RH, more preferably below 30% RH,
while the RH in compartment (C) is preferably 40-70%, more
preferably 50-60%. Therefore, the rate of moisture transfer from
the test system (75% RH to 10% RH) can be corrected to take into
account the relative humidities in the product as envisioned (60%
RH to 30% RH) by dividing the value by (75-15)/(60-30)=2 wherein
[0058] 75 is the RH (in %) of the test environment [0059] 15 is the
RH maintained by the desiccant [0060] 60 is the minimum desired RH
for the oxygen absorber to function [0061] 30 is the desired RH of
the headspace.
[0062] FIG. 3 shows the rate of oxygen transfer through similar
tubes into an iron oxygen absorber. In this case, the oxygen
depletion of a fixed oxygen volume was used for the measurement.
Again the oxygen transfer rate was monitored as a function of the
size of the tube. The desired rate of oxygen scavenging and,
therefore, the diameter of a hole or tube needs to take into
account the fact that the oxygen scavenger will need to handle the
oxygen permeation into the pharmaceutical package and to maintain a
low oxygen level (e.g., 1%). The tube (or other orifice) must
accordingly have a hole large enough to compensate for the
incremental difference in the rate of oxygen diffusion as the
difference in pressure is increased from that used in the test.
Since this latter rate should be proportional to the difference in
pressure, on going from 0 to 20.8% oxygen of the test to 0 to 1%
oxygen in the final product, the corresponding oxygen rate found
from the graph in FIG. 3 should be multiplied by 20.8.
[0063] To determine the amount of oxygen entering the
pharmaceutical package, a round bottle made of high-density
polyethylene (HDPE) with a labeled capacity of 60 cm.sup.3 and a
wall thickness of 37 mils (0.94 mm) can be used as a representative
sample. If the bottle is 4 cm in diameter and 7.3 cm in height (in
reality the bottle will taper to give less surface area than this
approximation), then the surface area will be approximately 100
cm.sup.2. If one uses HDPE as the bottle material and assumes the
inside of the pharmaceutical package to be maintained at 1% oxygen,
then the rate of oxygen permeation into the bottle can be
calculated as follows: 4000 cm.sup.3 mil/(m.sup.2d
atm).times.(0.18-0.009) atm.times.0.01 m.sup.2/37 mil=0.18 cm.sup.3
of O.sub.2/day Using this value and the factor of 20.8 discussed
above, it can be determined that the hole size to meet the oxygen
demand for a 60-cm.sup.3 HDPE bottle (to bring the oxygen to 1%) is
about 500 .mu.m in diameter.
[0064] At this diameter, the amount of water loss can be estimated
from the graph of FIG. 2 at 0.87 mg/day. Correcting this for the
envisioned system as described above brings this value to 0.43
mg/day.
[0065] Thus the use of data such as that exemplified in FIGS. 2 and
3 will be appreciated by those skilled in the art. Using FIG. 3,
one can calculate the size of the orifice in (oxygen absorber)
compartment (C) to effectively scavenge oxygen. FIG. 2 can be used
to determine the corresponding moisture loss from the compartment
and the amount of desiccant needed.
[0066] The orifice in compartment (C) that controls the rate of
moisture and oxygen transfer ("I5" in FIG. 1) can be produced in
the following manners: [0067] (1) A single hole can be used as the
orifice. The hole preferably has a diameter of between 100 and 700
.mu.m; more preferably, between 200 and 600 .mu.m. The hole can be
cylindrical (round with parallel sides), conical (round with
sloping sides) or rectangular. The hole can be made by any
technique known in the art. Particularly preferred methods of
forming the hole include drilling through the cartridge wall using
a mechanical, ultrasonic or laser drill, or forming the compartment
hole in place by, for example, injection molding. A high porosity
material or mesh can be used in conjunction with this hole to
prevent powder from escaping from the cartridge of canister. The
diameter of a mesh should be smaller than the fine particles in the
subunit, preferably smaller than about 15 .mu.m. [0068] (2) A tube
is placed through the port area. The tube preferably has an
internal diameter of between 100 and 700 .mu.m; more preferably,
between 200 and 600 .mu.m. The tube is preferably sealed into the
cartridge in the port area using an adhesive or by melting the
adjacent wall. The tube length can range from 1 to 25 mm. A high
porosity material or mesh can be used in conjunction with this tube
to prevent powder from escaping from the cartridge of canister. The
diameter of a mesh should be smaller than the fine particles in the
subunit, preferably smaller than about 15 .mu.m. [0069] (3) A
microporous membrane is placed in the port area. This filter
restricts the moisture and oxygen diffusion. Preferably, the
microporous membrane has a porosity of between 0.05 and 0.20 and a
thickness of 0.5 to 2.5 mm. The preferred diameter of the membrane
is between 100 and 1000 .mu.m.
[0070] The active oxygen absorber in compartment (C) is preferably
iron. The iron is preferably in its reduced form (that is,
Fe.sup.0). The iron can be atomized, milled, pulverized,
electrolyzed or otherwise treated to form a fine powder as is known
in the art. The amount of iron used in the present invention can be
optimized based on the permeability of the pharmaceutical packaging
"A" and the storage duration. Using the round HDPE bottle described
above as a representative example, the amount of oxygen that needs
to be scavenged is about 66 cm.sup.3/yr. Based on an
oxygen-absorption capacity for iron of about 300 cm.sup.3/g, the
amount of iron needed in compartment (C) (FIG. 1) is about 220 mg.
To build in for losses, the subunit therefore preferably contains
between about 225 and 500 mg of iron.
[0071] To enable the iron to scavenge oxygen, a moisture source
must be provided. In the present invention, this moisture source is
preferably provided in the form of a salt or sugar slurry. The
moisture controlling material should be able to control the
moisture in the compartment of the oxygen absorber. Since the rate
of loss of moisture from compartment (C) is proportional to the
difference in relative humidity between that in compartment (C) and
in the pharmaceutical bottle headspace itself, it is desirable to
make the relative humidity in compartment (C) as low as possible
while still providing adequate moisture to enable oxygen-scavenging
activity. It is therefore preferred to control the humidity in
compartment (C) to between 40 and 70% RH; more preferably, between
50 and 60% RH. The humidity-controlling salt or sugar slurry can be
an inorganic or organic salt or salt mixture, a sugar or sugar
mixture, or a mixture of salts and sugars, provided such materials
can control the relative humidity to the desired range.
Particularly preferred materials for controlling said relative
humidity include sodium chloride, calcium nitrate, sodium
bisulfate, sodium chlorate, potassium iodide, sodium bromide,
magnesium acetate, sodium nitrate, ammonium chloride, potassium
nitrate, potassium bromide and magnesium nitrate. The amount of
salt or sugar used needs to be sufficient to provide for the
desired control of the relative humidity even as some of the water
is removed in the use of the present invention.
[0072] For the slurry to control the relative humidity in
compartment (C) during the shelf life of the product, there must be
sufficient water to handle the anticipated water loss. Based on the
size of the rate-controlling port "I" (FIG. 1), this rate can be
kept to about 157 mg per year. In the practice of the present
invention, the amount of water in the cartridge is therefore
preferably between 150 and 400 mg; more preferably, between 180 and
360 mg.
[0073] To control the relative humidity with this much water, the
amount of the salt or sugar used must be sufficient that at least
some of the solid remains undissolved. As such, one can determine
the amount of salt or sugar by multiplying the amount of water
added by the water solubility of the salt or sugar. As an example,
for the humidity controlling additive magnesium nitrate, this leads
to a preferred amount of this additive of between 225 and 450 mg,
based on a solubility of 1250 mg/mL.
[0074] The present invention provides for the removal of oxygen not
only from the entrapped air within the pharmaceutical bottle (FIG.
1) but also oxygen that enters the bottle via ingress. It will be
appreciated that in the use of the oxygen-absorbing cartridge, one
can engineer a unit having the appropriate absorption capacity for
the given bottle and desired shelf-life. It is also possible to
engineer an oxygen-absorbing unit that is standard, but for which
the number of such units actually applied will depend on the bottle
design and shelf-life.
[0075] The oxygen-absorber need not remove 100% of the oxygen from
the interior air in the bottle; however, it is preferred that the
absorber be present in an amount such that it is capable of
maintaining a level of oxygen less than or equal to about 10.0%
preferably less than or equal to about 3.0%, more preferably less
than or equal to about 1.0%, most preferably less than or equal to
about 0.5%, for about 2 years inside the oxygen permeable
bottle.
EXAMPLES
Example 1
[0076] A 20 mm Flurotec.RTM. Teflon stopper (West Pharmaceutical
Services, Jersey Shore, Pa.) was drilled through the center with a
1.0 mm drill bit. HPLC tubing (Upchurch Scientific, Oak Harbor,
Wash.) was cut to 2 cm in length and forced through the drilled
hole in the stopper. The tubing used included model 1520 (762 .mu.m
inner diameter), model 1532 (508 .mu.m inner diameter), model 1531B
(254 .mu.m inner diameter), model 1535 (127 .mu.m inner diameter)
and model 1560 (64 .mu.m inner diameter), all from Upchurch
Scientific (a division of Scivex Inc., Oak Harbor, Wash.).
[0077] For the measurement of water vapor uptake, a 1 gram
Sorb-It.RTM. canister (Sud-Chemie, Belen, N. Mex.) was cut open and
the silica gel contents poured into a 10-cc tubular flint Type I
glass vial (Wheaton Science Products, Syracuse, Nebr.). The stopper
with tubing was crimp-sealed to the vial and the initial weight
recorded. The test units were then placed in a 40.degree. C./75% RH
stability chamber and periodically weighed over two weeks.
[0078] For the measurement of oxygen consumption, the contents of
an oxygen scavenger (DSR#4062B, 200-cc oxygen absorber from
Multisorb Corp., Buffalo, N.Y.) was cut open and the contents
poured into a vial (same as above), and the stopper with tubing was
crimp-sealed to the vial within 3 minutes. Each test unit was
placed in a 250-cc HDPE bottle, which was then heat induction
sealed under ambient air conditions. Thus each system initially
contained approximately 21% oxygen. The bottles were stored at
ambient temperature and RH (approximately 20.degree. C. and 30%
RH). At the end of two weeks, the oxygen level inside the HDPE
bottle was measured using a Mocon PAC Check 450 (Mocon Inc.,
Minneapolis, Minn.), which was standardized with ambient air (21%
oxygen) and a 0.5% oxygen standard from Mocon Inc.
Example 2
[0079] A cartridge is made by injection molding polyethylene into
two compartments with cylindrical shape of diameter 0.5 inches (1.3
cm) and wall diameters of approximately 1 mm. The top compartment
has a single 600 .mu.m diameter hole with a lattice (diameter of
openings of 25 .mu.m) on the side as part of the mold. The bottom
compartment is 0.25 inches in height (0.63 cm). The top compartment
is 0.5 inches in height (1.3 cm). Into the bottom compartment is
filled 0.5 g of silica gel. A cap of sintered polyethylene
(porosity of 0.1) is adhered to the bottom compartment to seal in
the powder. Magnesium nitrate (1.0 kg) is slurried with 800 g of
water to give a 44% (w:w) slurry. The top compartment is filled
with a combination of 300 mg of fine iron powder (as described in
U.S. Pat. No. 5,725,795) and 450 mg of the magnesium nitrate
slurry. A cap is formed by injection molding polyethylene into a
cylinder with a wall and a top having a high porosity (0.4). The
cap is 0.55 inches in diameter (1.4 cm) and 0.2 inches in height
(0.5 cm). The cap compartment is filled with 50 mg of
self-activated iron oxygen absorber (available from Multisorb
Corp., Buffalo, N.Y.), then the porous top is adhered to it. This
entire cap is then adhered to the top compartment of the above
cylinder. A 60 cm.sup.3 polyethylene bottle is loaded with
pharmaceutically active tablets and one of the above cartridges.
The bottle is sealed using a heat induction seal.
* * * * *