U.S. patent application number 13/139020 was filed with the patent office on 2011-10-06 for packaging for oxygen-sensitive pharmaceutical products.
This patent application is currently assigned to Merck Sharp & Dohme Corp.. Invention is credited to Matthew P. Bolton, Rey T. Chern, Arthur L. Jaeger, Matthew Moyer, Anthony P. Panarello.
Application Number | 20110240511 13/139020 |
Document ID | / |
Family ID | 42243037 |
Filed Date | 2011-10-06 |
United States Patent
Application |
20110240511 |
Kind Code |
A1 |
Bolton; Matthew P. ; et
al. |
October 6, 2011 |
PACKAGING FOR OXYGEN-SENSITIVE PHARMACEUTICAL PRODUCTS
Abstract
The present invention relates to packaging and containers for
oxygen-sensitive pharmaceutical products, or oxygen- and
moisture-sensitive pharmaceutical products. More particularly, the
invention relates to pharmaceutical packages comprising a blister
pack with airflow channels and outlets, an oxygen scavenger, and,
optionally, a desiccant, all of which are sealed inside an outer
container having oxygen and moisture barrier properties.
Inventors: |
Bolton; Matthew P.;
(Harleysville, PA) ; Chern; Rey T.; (Lansdale,
PA) ; Jaeger; Arthur L.; (Pennsburg, PA) ;
Moyer; Matthew; (Douglassville, PA) ; Panarello;
Anthony P.; (Ewing, NJ) |
Assignee: |
Merck Sharp & Dohme
Corp.
Rahway
NJ
|
Family ID: |
42243037 |
Appl. No.: |
13/139020 |
Filed: |
December 2, 2009 |
PCT Filed: |
December 2, 2009 |
PCT NO: |
PCT/US09/66310 |
371 Date: |
June 10, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61201401 |
Dec 10, 2008 |
|
|
|
Current U.S.
Class: |
206/532 |
Current CPC
Class: |
A61J 1/035 20130101;
B65D 75/328 20130101; B65D 2205/00 20130101; B65D 2205/02 20130101;
B65D 77/003 20130101; B65D 81/266 20130101; B65D 81/268
20130101 |
Class at
Publication: |
206/532 |
International
Class: |
B65D 83/04 20060101
B65D083/04 |
Claims
1-51. (canceled)
52. A package for an oxygen-sensitive pharmaceutical product,
comprising: (a) a sealed outer container having oxygen-barrier
properties; (b) a blister pack, disposed inside of the sealed outer
container, the blister pack comprising (i) at least one outlet that
permits gases to pass out of the blister pack and into the sealed
outer container, (ii) a shaped film comprising (A) at least one
cavity configured to hold a single unit dose of the pharmaceutical
product, and (B) at least one airflow channel, coupling the cavity
to the outlet, that permits oxygen located in the cavity to pass
out of the cavity, into the airflow channel and through the outlet,
and (iii) a frangible lidding sealed to the shaped film so that the
single unit dose is substantially confined between said frangible
lidding and said at least one cavity; and (c) an oxygen scavenger
disposed on the inside of the sealed outer container and the
outside of the blister pack; (d) whereby said oxygen scavenger
removes a sufficient amount of oxygen from inside the sealed outer
container to maintain an oxygen concentration level of less than 1%
by volume for a period of at least 1 year.
53. The package of claim 52, wherein the oxygen concentration level
inside the sealed outer container is reduced to less than 1% by
volume within 14 days after the sealed outer container is
sealed.
54. The package of claim 52, wherein the oxygen absorption capacity
of the oxygen scavenger is not greater than 150 cc at 40.degree.
C.
55. The package of claim 52, further comprising a desiccant
disposed on the inside of the sealed outer container and the
outside of the blister pack.
56. The package of claim 55, wherein: (a) the sealed outer
container has moisture barrier properties; (b) the airflow channel
further permits moisture located in the cavity to pass out of the
cavity, into the airflow channel and through the outlet, and (c)
said desiccant removes a sufficient amount of moisture from inside
the sealed outer container to maintain a relative humidity of less
than 25% for a period of at least 1 year.
57. The package of claim 52, wherein the sealed outer container
comprises aluminum, nylon, polyvinyl chloride, polyethylene
terephthalate, linear low density polyethylene, polypropylene, or a
combination thereof.
58. The package of claim 52, wherein the oxygen transmission rate
of the sealed outer container is less than about 0.0017 ccs per
package per day at 25.degree. C., 60% relative humidity, and a
driving force of 100% oxygen.
59. The package of claim 52, wherein the blister pack comprises a
plurality of outlets that permit gases to pass out of the blister
pack and into the sealed outer container.
60. The package of claim 52, wherein an active pharmaceutical
ingredient in the pharmaceutical product comprises amorphous
atorvastatin.
61. The package of claim 52, wherein an active pharmaceutical
ingredient in the pharmaceutical product comprises simvastatin.
62. A package for an oxygen-sensitive pharmaceutical product,
comprising: (a) a sealed outer container having oxygen-barrier
properties; (b) a blister pack, disposed inside of the sealed outer
container, the blister pack comprising (i) a shaped film comprising
at least one cavity configured to hold a single unit dose of the
pharmaceutical product, said at least one cavity having at least
one outlet that permits oxygen to pass out of said at least one
cavity and into the sealed outer container, and (ii) a frangible
lidding sealed to the shaped film so that the single unit dose is
substantially confined between said frangible lidding and said at
least one cavity; and (c) an oxygen scavenger disposed on the
inside of the sealed outer container and the outside of the blister
pack; (d) whereby said oxygen scavenger removes a sufficient amount
of oxygen from inside the sealed outer container to maintain an
oxygen concentration level of less than 1% by volume for a period
of at least 1 year.
63. The package of claim 62, wherein the oxygen concentration level
inside the sealed outer container is reduced to less than 1% by
volume within 14 days after the sealed outer container is
sealed.
64. The package of claim 62, wherein the oxygen absorption capacity
of the oxygen scavenger is not greater than 150 cc at 40.degree.
C.
65. The package of claim 62, further comprising a desiccant
disposed on the inside of the sealed outer container and the
outside of the blister pack.
66. The package of claim 65, wherein: (a) the sealed outer
container has moisture barrier properties; (b) said at least one
outlet permits moisture located in the cavity to pass out of the
cavity and into the sealed outer container; and (c) said desiccant
removes a sufficient amount of moisture from inside the sealed
outer container to maintain a relative humidity of less than 25%
for a period of at least 1 year.
67. The package of claim 62, wherein the sealed outer container
comprises aluminum, nylon, polyvinyl chloride, polyethylene
terephthalate, linear low density polyethylene, polypropylene, or a
combination thereof.
68. The package of claim 62, wherein the oxygen transmission rate
of the sealed outer container is less than about 0.0017 ccs per
package per day at 25.degree. C., 60% relative humidity, and a
driving force of 100% oxygen.
69. The package of claim 62, wherein the shaped film comprises
polyvinyl chloride, polyvinylidene chloride, polycarbonate,
polyester, copolyester, acrylonitrile, low density polyethylene,
polypropylene, or a combination thereof.
70. The package of claim 62, wherein an active pharmaceutical
ingredient in the pharmaceutical product comprises amorphous
atorvastatin.
71. The package of claim 62, wherein an active pharmaceutical
ingredient in the pharmaceutical product comprises simvastatin.
Description
BACKGROUND OF THE INVENTION
[0001] Certain pharmaceutical products include active
pharmaceutical ingredients that undergo chemical degradation and
can become physically unstable in the presence of even very small
amounts of oxygen or moisture. For these products, it is critical
that they be shipped and stored in containers capable of achieving
and maintaining extremely low oxygen and moisture levels. It has
been found, however, that developing and producing a packaging
solution that provides strong and reliable protection against the
effects of unwanted oxygen, and moisture, while simultaneously
addressing a host of manufacturing, marketing, child safety,
usability and regulatory concerns, is an enormous challenge for
pharmaceutical product manufacturers and distributors.
[0002] There are primarily two sources for the oxygen, or moisture,
found in pharmaceutical product packages. Some of the unwanted
oxygen and moisture is trapped in the headspace of the packaging
when the pharmaceutical product is assembled and sealed.
Additionally, during the 1 to 3 year period of time that the
pharmaceutical package may sit in storage or on a pharmacy shelf
before use, a certain quantity of oxygen or moisture will pass into
the package through small holes or gaps in the package seals, or
otherwise pass directly through the walls of the package by a
process known as molecular diffusion.
[0003] One known technique for reducing a pharmaceutical product's
exposure to oxygen during its shelf life is to enclose the
pharmaceutical product inside an oxygen-permeable inner container,
such as a plastic bottle, or an aluminum or plastic blister pack,
and then seal the oxygen-permeable inner container, along with an
oxygen scavenger, inside a substantially oxygen-impermeable outer
container. Pharmaceutical packages using this technique operate by
the process of molecular diffusion. That is, oxygen molecules
trapped inside the sealed oxygen-permeable inner container slowly
pass through the walls of the inner container to the interior of
the outer container, where those molecules are consumed by the
oxygen scavenger. U.S. patent application Ser. No. 11/217,579,
filed by Barshied (and published in 2006 as U.S. Pub. No.
20060076536), hereby incorporated herein in its entirety by this
reference, describes just such a pharmaceutical packaging
solution.
[0004] But the double-container molecular diffusion technique has
significant limitations and disadvantages. First, it is the
accepted view in the pharmaceutical container field that this
technique alone can only reduce the concentration of oxygen inside
the container down to the level of about 3% to 6% by volume within
the short time frames required by most oxygen-sensitive products.
While concentrations of about 3% to 6% by volume may be adequate
for some pharmaceutical products, they are still too high for
pharmaceutical products containing active pharmaceutical
ingredients that are extremely sensitive to oxygen or moisture.
Indeed, some pharmaceutical product formulations experience
degradation and physical instability when they are exposed to
environments containing as little as 1% oxygen by volume.
[0005] Second, molecular diffusion is a slow process--sometimes
requiring several weeks or even months for the oxygen molecules
trapped inside the inner container during the manufacturing process
to pass through the walls of the inner container and into the outer
container where they are consumed by the oxygen scavenger. Under
these circumstances, a relatively large quantity of oxygen may
remain in direct contact with the oxygen-sensitive pharmaceutical
product for an extended period of time, thereby causing
irreversible damage to the oxygen-sensitive pharmaceutical product
before the oxygen concentration can be reduced to an acceptable
level.
[0006] Accordingly, there is a considerable need in the
pharmaceutical and packaging fields for a packaging solution for
pharmaceutical products that are extremely sensitive to oxygen and
moisture. More particularly, there is a significant need for a
packaging solution that reduces the oxygen trapped in the headspace
of the package during the packaging process to a concentration of
less than 1%. There is also considerable need for a packaging
solution that reduces the moisture level inside the package to less
than 25% relative humidity at 40 degrees C. Moreover, the solution
should achieve these low oxygen and low moisture conditions
relatively quickly and maintain these conditions, despite oxygen or
moisture ingress into the package, for a period of at least one
year, more preferably for a period of at least two years, and even
more preferably, for a period of at least three years after the
package has been sealed.
SUMMARY OF THE INVENTION
[0007] The instant invention is directed to a package for an
oxygen-sensitive pharmaceutical product comprising a blister pack
and an oxygen scavenger, which are both sealed inside a sealed
outer container (such as a foil pouch) having oxygen barrier
properties. Where the pharmaceutical product is also
moisture-sensitive, a desiccant is also included within the sealed
outer container, which is preferably made of a material that also
acts as a barrier to moisture. The blister pack has a plurality of
cavities configured to hold a plurality of single unit doses of the
pharmaceutical product, a plurality of outlets that permit oxygen
and moisture molecules to pass out of the blister pack and into the
interior of the outer container, and a plurality of air flow
channels that carry the oxygen and moisture molecules from the
cavities to the outlets. When the oxygen and moisture molecules
pass out of the blister pack and into the sealed outer container,
they are consumed by the oxygen scavenger and the desiccant (if a
desiccant is included) in sufficient quantities to protect the
pharmaceutical product from chemical degradation and physical
instability for at least 1 year, and most preferably, at least 3
years. As a result, a low oxygen and low moisture environment is
created and maintained, which: (1) rapidly removes oxygen and
moisture trapped in the packaging headspace during the
manufacturing process, (2) provides an outer container having
oxygen and moisture barrier properties that substantially reduce
the amount of oxygen and moisture permitted to pass into the
package during the pharmaceutical product's shelf life, and (3)
continuously removes relatively small amounts of oxygen and
moisture that do pass into the package despite the oxygen and
moisture barrier properties of the sealed outer container.
[0008] The blister pack comprises at least one outlet that permits
gases to pass out of the blister pack and into the interior of the
sealed outer container, and a shaped film comprising at least one
cavity configured to hold a single unit dose of the pharmaceutical
product, and at least one airflow channel, coupling the cavity to
the outlet, which permits oxygen located in the cavity to pass
rapidly out of the cavity, into the airflow channel and through the
outlet. The blister pack also includes a frangible lidding, affixed
to the shaped film, so that the single unit dose of the
pharmaceutical product is substantially confined between the
frangible lidding and the cavity. The frangible lidding is
preferably made from aluminum foil sufficiently thin so as to
enable a consumer to push the single unit dose through it by
pressing on the underside of the cavity, or it may be made from an
aluminum foil laminate (i.e., layers of aluminum, polyethylene
terepthalate (PET) and/or paper) that is attached to the shaped
film in a manner that permits the consumer to easily tear it away
from each cavity, thereby gaining access to the single unit
doses.
[0009] Before the outer container of the package is sealed, it is
loaded with a sufficient amount of the oxygen scavenger to reduce
the oxygen concentration in the package to a level of less than 1%
by volume, and further, to maintain this level for a period of at
least 1 year from the time the package is sealed. In preferred
embodiments, a sufficient amount of the oxygen scavenger is
included to keep the oxygen concentration below 1% by volume for a
period of at least 2 years. In a most preferred embodiment, the
sealed outer container is loaded with enough oxygen scavenger to
maintain the oxygen concentration level of less than 1% by volume
for a period of at least 3 years. In preferred embodiments, the
oxygen concentration level inside the sealed outer container is
reduced to less than 1% by volume within 14 days after the outer
container is sealed. More preferably, the oxygen concentration
level inside the sealed outer container is reduced to less than 1%
by volume within 8 days after the sealed outer container is
sealed.
[0010] A desiccant may also be disposed on the inside of the sealed
outer container and the outside of the blister pack in order to
remove moisture from the package. In this case, the airflow channel
also permits moisture, as well as oxygen, located in the cavity to
pass out of the cavity, into the airflow channel and through the
outlet into the interior of the sealed outer container.
[0011] For most situations, but not all, the blister pack will
include a plurality of cavities, a plurality of outlets and a
plurality of airflow channels (at least one outlet and at least one
airflow channel per cavity), which together permit oxygen and
moisture trapped in the plurality of cavities to easily pass out of
the cavities, into the plurality of airflow channels and out of the
blister pack through the plurality of outlets. In some embodiments,
however, there may even exist a plurality of airflow channels and
outlets for every cavity in the blister. The outlets on the blister
pack are typically located at the end of the airflow channel that
is opposite from the end of the airflow channel connected to the
cavity. However, the outlet may also be located on the bottom
surface of the airflow channel, opposite from the frangible
lidding. The outlet may also be located on the frangible lidding
itself.
[0012] In an alternative embodiment, the outlets may comprise one
or more "pinholes" located directly on the wells of each cavity in
the blister pack, thereby eliminating the need for airflow
channels. With pinhole outlets on the cavity wells, the oxygen and
moister molecules may pass directly from each cavity into the
interior of the sealed outer container through the pinhole
outlets.
[0013] Where there is a concern that the single unit doses of drugs
inside the cavities in the blister pack may be too easily accessed
by a child, embodiments of the invention may also include a hard
plastic "shell pack" container, configured to receive, cover and
protect the blister pack, the outlets and airflow channels from
direct access until the blister pack is extracted from inside the
shell pack. In this alternative configuration, the blister pack may
be inserted into the shell pack, and the shell pack sealed inside
the sealed outer container, along with the oxygen scavenger (and a
desiccant, if moisture-reduction is required) during the package
manufacturing stage.
[0014] The term "oxygen-sensitive pharmaceutical product" refers to
any pharmaceutical product containing a substance that is prone to
react with oxygen under normal ambient conditions (about 5.degree.
C. to about 40.degree. C.). The reaction may involve the addition
of oxygen to the substance, removal of hydrogen from the substance,
or the loss or removal of one or more electrons from a molecular
entity in the substance, with or without concomitant loss or
removal of protons. It can also involve indirect processes where,
for example, an oxidizing agent (e.g., peroxide, superoxide) is
generated which oxidizes a substance in the pharmaceutical
product.
[0015] The term "moisture-sensitive pharmaceutical product" refers
to any pharmaceutical product containing a substance that is prone
to degradation, crystal form conversion, physical instability
and/or structural alteration under normal ambient conditions when
water, water vapor and/or humidity are present. Thus, any
pharmaceutical product containing a substance having a propensity
for uptake of moisture, and the uptake unacceptably affects the
physical properties or stability (dissolution, disintegration,
hardness, friability) of the finished form of the product, is an
example of a moisture-sensitive pharmaceutical product. The term
also refers to any pharmaceutical product containing a substance
affected by hydrolysis, whereby a bond in the substance is cleaved
by addition of hydrogen and hydroxide ions (ions resulting from the
split of a water molecule).
[0016] It is expected that the present invention will provide
reliable protection for a variety of oxygen-sensitive
pharmaceutical products or oxygen- and moisture-sensitive
pharmaceutical products. Examples of such products include, but are
not limited to, products containing certain HMG CoA reductase
inhibitors, such as simvastatin and atorvastatin. In an embodiment
of the instant invention, the pharmaceutical product comprises
amorphous atorvastatin.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The present invention and various aspects, features and
advantages thereof are explained in detail below with reference to
exemplary and therefore non-limiting embodiments and with the aid
of the drawings, which constitute a part of this specification and
include depictions of the exemplary embodiments. In these
drawings:
[0018] FIGS. 1A, 1B and 1C show, respectively, an orthogonal
cut-away view of a package according to an embodiment of the
invention, an orthogonal cut-away view of the blister pack
component of the package, and a schematic diagram of the
package.
[0019] FIG. 2 shows for purposes of illustration a perspective view
of an opened and unsealed package 200, that may be sealed according
to the principles of the present invention to produce the
embodiment of the invention shown in the diagrams of FIGS. 1A and
1C.
[0020] FIGS. 3A, 3B and 3C show, respectively, a front side
orthogonal view, a right side orthogonal view, and a bottom side
orthogonal view of a 7-cavity blister pack, according to one
embodiment of the present invention.
[0021] FIGS. 4A, 4B and 4C show, respectively, a front side view, a
bottom side view and a left side view of an 8-cavity blister pack
according to another embodiment of the invention.
[0022] FIGS. 5A, 5B, 5C and 5D show, respectively, a front side
view, a right side view, a bottom side view, and a detail view of a
blister pack according to other embodiments of the present
invention.
[0023] FIGS. 5E, 5F and 5G show alternative "child resistant"
configurations for 10-cavity blister packs according to alternative
embodiments of the invention.
[0024] FIG. 6 depicts a graph containing two plotted curves fitted
to the data obtained from measuring the oxygen concentration inside
two packages configured according to the present invention over an
8-day period.
DETAILED DESCRIPTION OF THE INVENTION
[0025] Exemplary embodiments of the invention will now be described
in more detail with reference to the figures. FIGS. 1A, 1B and 1C
show, respectively, an orthogonal cut-away view of a package
according to an embodiment of the invention, an orthogonal cut-away
view of the blister pack component of the package, and a schematic
diagram of the package. Referring to FIG. 1A, package 100 includes
a multilayered outer container 101 that is sealed shut in the
manufacturing process so that it surrounds and encloses a blister
pack 110, an oxygen scavenger 140, and an optional desiccant 145.
In preferred embodiments, sealed outer container 101 comprises a
foil pouch having an innermost layer 103 made of linear low density
polyethylene (LLD PE), a middle layer 105 made of aluminum (Al)
foil, and an outermost layer 107 made of polyethylene terephthalate
(PET). The layers are typically glued or heat sealed together with
a suitable adhesive, laminate or extrusion coating process to form
a composite foil laminate having a thickness of between about 66
and about 77 microns. However, it should be understood that pouches
having more or fewer layers, and pouches having one or more other
materials besides or instead of LLD PE, aluminum and PET (such as
Surlyn.RTM., nylon, polyvinyl chloride, polypropylene, or any
combination thereof), as well as pouches using the same materials
in a different order, may be used without departing from the scope
of the invention.
[0026] Preferably, the oxygen transmission rate of the pouch is
about 0.0017 cubic centimeters per package per day at 25 degrees C.
and 60% relative humidity, the measurement being taken with a
concentration gradient of 100% outside of the package and 0% inside
the package. Suitable foil pouches that meet these criteria may be
made, for example, from foil laminate material that can be obtained
from Alcan Packaging Pharma Center (Product Code Nos. 90038, 92025
and 92037) of Shelbyville, Kentucky, USA. These foil pouches are
known to have excellent resistance to moisture, oxygen and other
gases, can be configured to be resealable after opening, and
provide surface areas that are good receptors for ink, printed
instructions and labels. A heat seal (designated with reference
number 109 in FIG. 1C) may be formed at one end of foil pouch 101
using methods well-known in the art.
[0027] In preferred embodiments, the oxygen scavenger 140 is of the
organic type, which does not rely on a chemical reaction between a
metal-based substance and water to remove oxygen from the interior
of the sealed outer container and the blister pack. The organic
type of oxygen scavenger is preferred because it performs well
independent of the relative humidity in the package, which makes it
extremely well-suited for environments that require no or very low
levels of moisture. Suitable organic oxygen scavengers are jointly
distributed in canister and packet forms by Sud-Chemie Performance
Packaging and Mitsubishi Gas Chemical Company, Inc. under the brand
name PharmaKeep.RTM. (Types CH, KH and KD).
[0028] Blister pack 110, best shown in the schematic diagrams of
FIGS. 1B and 1C, comprises a plurality of outlets 115a -115f (i.e.,
holes, gaps or spaces) and a shaped film 120 having a plurality of
cavities 125a -125f that are configured to hold single unit doses
of the oxygen-sensitive pharmaceutical product or the oxygen- and
moisture-sensitive pharmaceutical product (not shown). An example
of an oxygen-sensitive pharmaceutical product includes, but is not
limited to, a pharmaceutical product containing certain HMG CoA
Reductase inhibitors, such as simvastatin or atorvastatin, as an
active pharmaceutical ingredient. In one embodiment of the instant
invention, the oxygen-sensitive pharmaceutical product comprises
amorphous atorvastatin. Blister pack 110 also comprises a frangible
lidding 135, which is sealed or affixed to the shaped film 120,
such as by heat induction, for instance, so that the single unit
doses of pharmaceutical product are substantially confined between
the wells of the cavities 125a -125f and the frangible lidding
135.
[0029] The cavities 125a -125f in the shaped film 120 are coupled
to the plurality of outlets 115a -115f, respectively, via a
plurality of airflow channels 130a -130c, which permit oxygen and
moisture molecules trapped in the cavities 125a -125f during the
manufacturing process to flow rapidly out of the cavities, into the
airflow channels 130a -130c, through the plurality of outlets 115a
-115f, and into the interior of sealed outer container 101, where
those molecules are consumed by the operation of oxygen scavenger
140 and desiccant 145. This flow of oxygen and moisture molecules
out of the cavities 125a -125f, through the airflow channels 130a
-130c and outlets 115a -115f (indicated in FIG. 1C with flow
direction arrows F) removes oxygen and moisture from direct contact
with the pharmaceutical product significantly faster than the
process of molecular diffusion through the walls of a closed and
sealed blister pack. An advantage of the present invention is that
it does not require an oxygen scavenging element having a large
oxygen absorption capacity. Thus, it is possible to achieve the
required low oxygen conditions inside the sealed outer container
101 using oxygen scavengers having oxygen absorption capacities of
150 ccs, 100 ccs, and even as low as 50 ccs, at 40.degree. C. The
inventors of the present invention have found through testing, for
example, that sealing a 7-cavity blister pack and 1 canister of
PharmaKeep.RTM. Type CH oxygen scavenger (approx. 1 gram) inside a
pouch made from foil laminate material obtained from Alcan (Product
No. 92037), the pouch measuring approximately 4.875 inches in width
and 8 inches in length, causes the oxygen concentration level
inside the pouch to be reduced to less than 1% within 8 days, as
shown graphically in FIG. 6.
[0030] Embodiments of the present invention may include a
sufficient amount of desiccant 145 to achieve a relative humidity
of less than 25% in 14 days or less and maintain that low humidity
level for a period of at least 1 year. Suitable desiccation
material include silica gel, as well as PharmaKeep.RTM. brand (Type
K(D) desiccants jointly distributed by Sud-Chemie Performance
Packaging and Mitsubishi Gas Chemical Company, Inc. , which absorb
both oxygen and moisture, thereby eliminating the need for separate
components for the oxygen absorber and desiccant elements.
[0031] The amount of desiccant required to achieve a relative
humidity of less than 25% within 14 days will depend primarily on
four factors: (a) the moisture capacity of the desiccant, (b) the
volume of gas initially trapped in the headspace of the outer
container when the outer container is sealed, (c) the relative
humidity of the volume of gas trapped in the headspace, and (d) the
initial moisture level (relative humidity) of the pharmaceutical
products stored inside the cavities of the blister pack. Based on
these four factors, those of ordinary skill in the art will be able
to determine the amount of desiccant to use for a particular
desiccant, a particular package and a particular pharmaceutical
product. It is anticipated, for instance, that about 0.5 grams of
silica gel desiccant is sufficient achieve a relative humidity of
less than 25% within 14 days when: the volume of gas initially
sealed in the headspace of the outer container is about 150-300
cubic centimeters (e.g., a foil pouch measuring 4.875 inches wide
and 8 inches long); the initial relative humidity of the trapped
gas is about 35%; and the blister pack sealed inside the outer
container contains 7 single unit doses of a pharmaceutical product
having an initial relative humidity in the range of 25-35% (e.g., a
pharmaceutical product containing an amorphous atorvastatin
formulation as disclosed and claimed in international patent
application No. PCT/US09/57647, filed on Sep. 21, 2009).
[0032] The shaped film 120 may be made from a polymer, such as
polyvinyl chloride, polyvinylidene chloride, polycarbonate,
polyester, copolyester, acrylonitrile, low density polyethylene,
polypropylene, or a combination thereof. The polymer may be
amorphous or crystalline in form. It may be transparent,
translucent or opaque. The shaped film 120 can also be made from
aluminum. It can be manufactured by any one of a variety of
techniques known in the art for shaping and molding polymer films
and aluminum sheets, including without limitation, film or sheet
extrusion, thermoforming, and/ or cold-forming. The frangible
lidding 135 is typically formed from aluminum, but may also be
formed from other materials. FIG. 2 shows for purposes of
illustration a perspective view of an opened and unsealed package
200, that may be sealed according to the principles of the present
invention to produce the embodiment of the invention shown in the
diagrams of FIGS. 1A and 1C. As shown in FIG. 2, blister pack 210,
comprises a shaped film 220 having a plurality of cavities 225a
-225e, which are coupled to a plurality of outlets 215a -215d by
airflow channels 230a -230c. The airflow channels intersect and
join cavities 225a -225e. Blister pack 210 also includes a
frangible lidding 240 (shown in an atypical peeled back position),
which is affixed to the shaped film 220 in such a way as to
substantially confine single unit doses (not shown) of an oxygen-
and moisture-sensitive pharmaceutical product in each one of the
cavities 225a -225e. When the package is assembled, the entire
frangible lidding 240 is affixed to the surface of shaped film 210
so that a single unit dose of the pharmaceutical product, such as a
tablet or pill, located in one of the cavities 225a -225c can be
removed from blister pack 210 by applying sufficient force to the
bottom side of a cavity to force the pharmaceutical product through
the frangible lidding 240. The portions of the frangible lidding
240 that are directly adjacent to the cavities are designed to
rupture when such force is applied without causing ruptures in
other portions of the frangible lidding 240. During assembly, the
blister pack 210 (in its unopened form) is inserted, along with an
oxygen scavenger 250 and a desiccant 260, into the outer container
201 (such as a foil pouch), which is then sealed tight using known
sealing techniques to produce a package 200 according to an
embodiment of the present invention.
[0033] FIGS. 3A, 3B and 3C show, respectively, a front side
orthogonal view, a right side orthogonal view, and a bottom side
orthogonal view of a 7-cavity blister pack, according to one
embodiment of the present invention. As shown best in FIG. 3A,
blister pack 300 comprises two columns of cavities, formed in
shaped film 305, which are adapted to hold single unit doses of a
pharmaceutical product containing an active pharmaceutical product
that is sensitive to oxygen. The first column contains 2 single
unit dose cavities 310 and 315, while the second column contains 5
single unit dose cavities 325, 330, 335, 340 and 345. A section of
the shaped film 305 has been cut away to show a portion of the
frangible lidding 365, which is glued or heat sealed-to the
opposite side of the shaped film 305.
[0034] Cavities 310 and 315 are fluidly coupled to each other by a
vertical airflow channel 320, which intersects cavities 310 and 315
through their centers in a direction that is parallel to the minor
axes of the cavities (i.e., perpendicular to their major axes).
Cavities 325, 330, 335, 340 and 345 are fluidly coupled to each
other by another vertical airflow channel 350, which intersects all
five of the cavities 325, 330, 335, 340 and 345 through their
centers in a direction parallel to their minor axes. Airflow
channel 320 also couples cavities 310 and 315 to outlets 360a and
360b, which permits oxygen and/or moisture molecules that may have
been trapped inside cavities 310 and 315 during the manufacturing
process to pass out of the cavities 310 and 315, into and through
the airflow channel 320, and then out of the blister pack 300
through outlets 360a and 360b. Similarly, airflow channel 350
couples cavities 325, 330, 335, 340 and 345 to each other and to
outlets 370a and 370b on blister pack 300, so that oxygen molecules
can pass freely from the inside of cavities 325, 330, 335, 340 and
345, into and through airflow channel 350, and then out of the
blister pack 300 through outlets 370a and 370b.
[0035] Once the oxygen and moisture molecules pass out of the
blister pack 300 and into the interior of the sealed outer
container, they are removed from the package by the operation of
the oxygen scavenger and desiccant elements (not shown in FIGS.
3A-3C). Multiple airflow channels 320 and 350, as well as multiple
large diameter outlets 360a, 360b, 370a and 379b are provided in
blister pack 300 in order to reduce any diffusion resistance in the
blister pack and to facilitate a maximum flow of oxygen and
moisture molecules from the interior areas of the blister pack 300
to the interior of the sealed outer container (not shown in FIGS.
3A through 3C). Multiple airflow channels and outlets also provide
multiple paths for the oxygen molecules to pass out of the blister
pack, thereby reducing the possibility that oxygen molecules will
be permanently trapped inside any one cavity due to damage or
obstruction in one of the channels or outlets.
[0036] It will be appreciated that a variety of alternative
configurations for the blister pack, in terms of the number and
orientation of cavities and airflow channels, may be selected
without departing from the scope of the present invention. For
example, it may be desirable for aesthetic, marketing,
manufacturing or usability reasons to place more or fewer cavities
and airflow channels on a blister pack, or to use a substantially
different orientation of the cavities and airflow channels. FIGS.
4A, 4B and 4C show, respectively, a front side view, a bottom side
view and a left side view of an 8-cavity blister pack that may be
used with the present invention. As shown best in FIG. 4A, blister
pack 400 has 8 cavities 410, 415, 420, 425, 430, 435, 440 and 445,
arranged in a 2-by-4 matrix configuration, and 4 horizontal airflow
channels 450, 460, 470 and 480, each of these 4 airflow channels
intersecting two of the cavities at their centers and in a
direction that is parallel to their major axes (perpendicular to
their minor axes). Horizontal airflow channel 450 provides a
passageway between cavities 410 and 415 and outlets 452 and 454, so
that oxygen and moisture molecules trapped inside cavities 410 and
415 during the manufacturing process can pass out of the blister
pack 400 through outlets 452 and 454, where those molecules will be
consumed by the oxygen scavenger. Likewise, horizontal airflow
channel 460 is fluidly coupled to cavities 420 and 425, as well as
outlets 462 and 464, to provide a passageway for oxygen and
moisture molecules trapped in cavities 420 and 425 to pass out of
the blister pack 400. Horizontal airflow channels 470 and 480 are
similarly fluidly coupled to cavities 430, 435, 440 and 445, and
outlets 472, 474, 482 and 484, to provide a means of escape for
oxygen and moisture molecules trapped inside those cavities during
the manufacturing process.
[0037] FIGS. 5A, 5B, 5C and 5D show, respectively, a front side
view, a right side view, a bottom side view, and a detail view of a
blister pack according to another embodiment of the present
invention, wherein the blister back 500 contains 10 cavities
arranged in a 2-by-5 matrix configuration. Notably, blister pack
500 has 2 diagonal airflow channels for every cavity, for a total
of 20 different airflow channels; As best shown in the front side
view of FIG. 5A and the detail view of FIG. 5D, cavity 510 is
intersected at one end by 2 diagonal airflow channels 520 and 530,
which provide two separate and independent passageways for oxygen
molecules trapped in cavity 510 to flow toward and through outlets
540 and 550 in order to pass out of the blister pack 500. It will
be appreciated, however, that having two airflow channels 520 and
530 and two outlets 540 and 550 also permits air, oxygen and
moisture to flow into one of the outlets and out of the other. Each
one of the rest of the cavities on blister pack 500 are similarly
connected to 2 diagonal airflow channels and 2 outlets. Blister
pack 500 also contains horizontal and vertical perforations 560 and
570, which are designed to permit consumers to easily tear the
blister pack along the perforations and detach and remove
individual cavities from the blister pack.
[0038] FIG. 5E shows an alternative "child resistant" configuration
for a 10-cavity blister pack 580, which shows diamond-shaped spaces
582 on the shaped film where there is no frangible lidding
attached. In the child resistant configuration, the cavities
containing the single unit doses are opened by peeling portions of
the frangible lidding away from each cavity, not by pushing single
unit dose through the lidding. Thus, the diamond-shaped spaces 582
where the perforations 560 and 570 intersect provide easy access to
the edges of the frangible lidding in order to facilitate the
process of peeling the frangible lidding off the top of each
cavity.
[0039] FIG. 5F shows yet another embodiment of the invention
comprising child resistance features. In this embodiment, the
blister pack 584 is inserted into a plastic shell 586, and both the
plastic shell 586 and the blister pack 584 are then sealed inside
an oxygen- and moisture-resistant foil pouch 588, along with an
oxygen scavenger (not shown in FIG. 5F) and, optionally, a
desiccant (also not shown in FIG. 5F). Plastic shell 586, which may
be manufactured, for instance, from impact modified polystyrene, is
designed to receive and hold the blister pack 584, and to protect
the cavities 590, the airflow channels 591a, 591b and 591c, and
outlets 592a and 592b from the prying fingers of children, without
impeding the flow of oxygen and moisture molecules from the
cavities to the inside of the foil pouch 588. Preferably plastic
shell 586 includes an internal retention dagger or locking
mechanism (not shown) to engage and hold the blister pack 584
securely and firmly in place when the blister pack 584 is
fully-inserted into the plastic shell 586 and not in use by an
adult patient. The retention dagger and/or locking mechanism may be
mechanically coupled to a child-proof push tab or lever 587, that
can be operated by an adult patient to disengage the blister pack
584 from the plastic shell 586, thereby permitting the blister pack
584 to slide sufficiently out of the plastic shell 586 to access
and remove from the cavities one or more units of the
pharmaceutical product. Plastic shells suitable for this purpose
may be obtained, for example, from Mead West Vaco Corporation, of
Raleigh, North Carolina, USA (www.meadwestvaco.com), as Part Nos.
P50605 and P50610. Although the illustration of FIG. 5F shows only
one blister pack inserted into the plastic shell, it is understood
that the plastic shell may be adapted to receive and secure
multiple blister packs, if so desired, without departing from the
scope of the invention.
[0040] FIG. 5G shows an alternative configuration for the blister
pack, wherein the blister pack comprises cavities having pinhole
outlets 596a and 596b located directly on the wells of each cavity.
Thus, there are no airflow channels in this configuration. Rather,
oxygen and moisture molecules pass directly from the interior of
each cavity to the interior of the sealed outer container (pouch)
or plastic shell via the pinhole outlets 596a and 596b. Pinhole
outlets with a diameter of approximately 2 millimeters have been
found to produce the desired effect of permitting a sufficient
amount of oxygen and moisture to escape the cavities, although
other sizes may be used, depending on the size, shape and contents
of the cavities, and/or the particular pharmaceutical product
formulation.
Manufacturing the Package
[0041] The blister packs of the present invention may be
manufacture using an automatic blister thermoformer known in the
art. The blister thermoformer forms the cavities and the airflow
channels, fills the cavities with tablets/caplets, covers and seals
the blister pack and cavities with the frangible lidding, and then
die-cuts the sealed blister packs into their desired final
marketing configuration. In some embodiments, die-cutting the
blister packs may also serve to create the outlets by slicing open
one or both ends of the airflow channels, although other methods of
creating the outlets may also be used. The sealed blister packs are
then transported to either an automatic or manual pouch
machine.
[0042] An automatic or manual pouch machine may be employed to
insert each sealed blister pack into a foil pouch. In some
embodiments two or more blister packs are inserted in each foil
pouch. One or more oxygen scavenger canisters are then inserted
into each foil pouch either by an automated process or by a manual
operation. Next, a desiccant canister is inserted into each foil
pouch either by an automated process or by a manual operation. The
packaged foil pouch is then hermetically sealed. Typically, the
hermetically sealed foil pouch is then transported to a secondary
packaging operation, where one or multiple foil pouches are
inserted into a folding carton.
[0043] FIG. 6 depicts a graph containing two plotted curves fitted
to the data obtained from measuring the oxygen concentration inside
two packages configured according to the present invention. In both
packages, a 7-cavity blister pack was sealed inside a foil pouch
made from foil laminate material obtained from Akan (Product No.
90237), the pouch measuring approximately 4.875 inches wide by 8
inches long and capable of holding between 150 and 300 cubic
centimeters of air. However, the first package contained one
canister (approx. 1 gram) of PharmaKeep.RTM. Type CH oxygen
scavenger, while the second package contained 2 canisters (approx.
2 grams). The first curve in the graph, which is fitted to the
measurements represented by the solid circle markers, shows the
rate of oxygen depletion in the pouch with 1 canister of oxygen
scavenger. The second curve, which is fitted to the measurements
represented by the solid diamond markers, shows the rate of oxygen
depletion in the foil pouch having two canisters of oxygen
scavenger. The x-axis of the graph shows the number of days elapsed
after the pouches were sealed, while the y-axis shows the oxygen
concentration inside the pouches as a percentage of the air by
volume. As illustrated by the circles and diamonds in FIG. 6, five
separate oxygen concentration measurements were taken for each
package over an eight day period. Although the rate of reduction
was somewhat faster in the package containing two canisters of
oxygen scavenger, the oxygen concentration in both packages went
from approximately 20.5% by volume to less than 1% by volume by the
end of the 8-day period.
[0044] Although the exemplary embodiments, uses and advantages of
the invention have been disclosed above with a certain degree of
particularity, it will be apparent to those skilled in the art upon
consideration of this specification and practice of the invention
as disclosed herein that alterations and modifications can be made
without departing from the spirit or the scope of the invention,
which are intended to be limited only by the following claims and
equivalents thereof.
* * * * *