WO2010068527A1

WO2010068527A1 - Package for oxygen-sensitive pharmaceutical products

Info

Publication number: WO2010068527A1
Application number: PCT/US2009/066310
Authority: WO
Inventors: Matthew P. Bolton; Rey T. Chern; Arthur L. Jaeger; Matthew Moyer; Anthony P. Panarello
Original assignee: Merck Sharp & Dohme Corp.
Priority date: 2008-12-10
Filing date: 2009-12-02
Publication date: 2010-06-17
Also published as: US20110240511A1; EP2376348A1; EP2376348A4

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.

Description

TITLE OF THE INVENTION

PACKAGE FOR OXYGEN-SENSITIVE PHARMACEUTICAL PRODUCTS

BACKGROUND OF THE INVENTION 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.

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.

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 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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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° C. to about 40° 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. 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).

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

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:

FIGs. IA_j IB 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.

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. IA and 1C.

FIGs. 3 A, 3B and 3 C 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.

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.

FIGs. 5A_> SB, 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.

FIGs. 5E, 5F and 5G show alternative "child resistant" configurations for 10- cavity blister packs according to alternative embodiments of the invention. 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

Exemplary embodiments of the invention will now be described in more detail with reference to the figures, FIGs. IA, IB 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. IA, 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 1 10, 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®, 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.

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.

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 Sϋd-Chemie Performance Packaging and Mitsubishi Gas Chemical Company, Inc. under the brand name PharmaKeep® (Types CH, KH and KD).

Blister pack 110, best shown in the schematic diagrams of FIGs. IB 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-senstive 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. 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 40⁰C. The inventors of the present invention have found through testing, for example, that sealing a 7-cavity blister pack and 1 canister of PharmaKeep® 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. 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® brand (Type KD) desiccants jointly distributed by Sϋd-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. 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 September 21 , 2009).

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. IA 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.

FIGs. 3 A, 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. 3 A, 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. 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. 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. 3 A - 3C). Multiple airflow channels 320 and 350, as well as multiple large diameter outlets 36Oa, 36Qb, 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. 3 A 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.

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. 4 A, 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.

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. 5 A 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. 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.

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 PartNos. 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.

FIG. 5 G 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 plasic 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

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. 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.

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 Alcan (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® 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.

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.

Claims

WHAT IS CLAIMED IS:

1. A package for an oxygen-sensitive pharmaceutical product, comprising:

(a) a sealed outer container having oxygen-barrier properties;

5 (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

10 (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

] 5 (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;

20 (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.

2. The package of claim 1 , wherein said oxygen scavenger removes a sufficient amount of oxygen from the interior of the sealed outer container to maintain an oxygen

25 concentration level of less than 1 % by volume for a period of at least 2 years.

3. The package of claim 1, wherein said oxygen scavenger removes a sufficient amount of oxygen from the interior of the sealed outer container to maintain an oxygen concentration level of less than 1% by volume for a period of at least 3 years.

4. The package of claim 1 , wherein the oxygen scavenger 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.

5. The package of claim 1, wherein the oxygen concentration level inside the sealed outer 5 container is reduced to less than 1% by volume within 14 days after the sealed outer container is sealed.

6. The package of claim 1, wherein 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.

10 7. The package of claim 1 , wherein the oxygen absorption capacity of the oxygen scavenger is not greater than 150 cc at 40⁰C.

8. The package of claim 1 , wherein the oxygen absorption capacity of the oxygen scavenger is not greater than 100 cc at 40°C.

9. The package of claim 1 , wherein the oxygen absorption capacity of the oxygen scavenger ] 5 is not greater than 50 cc at 4O⁰C.

10. The package of claim 1, further comprising a desiccant disposed on the inside of the sealed outer container and the outside of the blister pack.

1 1. The package of claim 10, wherein:

(a) the sealed outer container has moisture barrier properties;

20 (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.

25 12. The package of claim 1 1 , wherein the 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 2 years.

13. The package of claim 11, wherein the relative humidity inside the sealed outer container is reduced to less than 25% approximately 14 days after the sealed outer container is sealed.

14. The package of claim 11, wherein the relative humidity inside the sealed outer container is reduced to less than 25% approximately 8 days after the sealed outer container is sealed.

15. The package of claim 1, wherein the outlet is located at the end of the airflow channel that is opposite from the end of the airflow channel connected to the cavity.

16. The package of claim 1 , wherein the outlet is located on the surface of the airflow channel opposite from the frangible lidding.

17. The package of claim I₅ wherein the outlet is located on the frangible lidding.

18. The package of claim 1, wherein the sealed outer container comprises aluminum, nylon, polyvinyl chloride, polyethylene terephthalate, linear low density polyethylene, polypropylene, or a combination thereof.

19. The package of claim 1 , wherein the oxygen transmission rate of the sealed outer container is less than about 0.0017 ccs per package per day at 25° C₅ 60% relative humidity, and a driving force of 100% oxygen.

20. The package of claim 1, wherein the sealed outer container is resealable.

21. The package of claim 1 , wherein the shaped film comprises polyvinyl chloride, polyvinylidene chloride, polycarbonate, polyester, copolyester, acrylonitrile, low density polyethylene, polypropylene, or a combination thereof.

22. The package of claim 1 , wherein said frangible lidding comprises aluminum.

23. The package of claim 1₅ 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.

24. The package of claim 23, wherein the shaped film comprises:

(a) a plurality of cavities configured to hold a respective plurality of single unit doses of the pharmaceutical product; and

(b) a plurality of airflow channels, connecting the plurality of cavities to the plurality of outlets, respectively, which permit oxygen located in the plurality of cavities to pass out of the plurality of cavities, into the plurality of airflow channels and through the plurality of outlets.

25, The package of claim 1, wherein an active pharmaceutical ingredient in the pharmaceutical product comprises amorphous atorvastatin.

26. The package of claim 1, wherein an active pharmaceutical ingredient in the pharmaceutical product comprises simvastatin.

27. 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.

28. The package of claim 27, wherein said oxygen scavenger removes a sufficient amount of oxygen from the interior of the sealed outer container to maintain an oxygen concentration level of less than 1 % by volume for a period of at least 2 years.

29. The package of claim 27, wherein said oxygen scavenger removes a sufficient amount of oxygen from the interior of the sealed outer container to maintain an oxygen concentration level of less than 1% by volume for a period of at least 3 years.

30. The package of claim 1, wherein the oxygen scavenger 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.

31. The package of claim 27, 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.

32. The package of claim 27, wherein 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.

33. The package of claim 27 , wherein the oxygen absorption capacity of the oxygen scavenger is not greater than 150 cc at 40⁰C.

34. The package of claim 27, wherein the oxygen absorption capacity of the oxygen scavenger is not greater than 100 cc at 40⁰C.

35. The package of claim 27, wherein the oxygen absorption capacity of the oxygen scavenger is not greater than 50 cc at 4O⁰C.

36. The package of claim 27, further comprising a desiccant disposed on the inside of the sealed outer container and the outside of the blister pack.

37. The package of claim 36, 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

38. The package of claim 37, wherein the 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 2 years.

39. The package of claim 37, wherein the relative humidity inside the sealed outer container is reduced to less than 25% approximately 14 days after the sealed outer container is sealed.

40. The package of claim 37, wherein the relative humidity inside the sealed outer container is reduced to less than 25% approximately 8 days after the sealed outer container is sealed.

41. The package of claim 27, wherein the outlet is located at the end of the airflow channel that is opposite from the end of the airflow channel connected to the cavity.

42. The package of claim 27, wherein the outlet is located on the surface of the airflow channel opposite from the frangible liddiag.

43. The package of claim 27, further comprising a second outlet located on the frangible lidding opposite said at least one cavity.

44. The package of claim 27, wherein the sealed outer container comprises aluminum, nylon, polyvinyl chloride, polyethylene terephthalate, linear low density polyethylene, polypropylene, or a combination thereof.

45. The package of claim 27, wherein the oxygen transmission rate of the sealed outer container is less than about 0.0017 ccs per package per day at 25° C, 60% relative humidity, and a driving force of 100% oxygen.

46. The package of claim 27, wherein the sealed outer container is resealable.

47. The package of claim 27, wherein the shaped film comprises polyvinyl chloride, polyvinylidene chloride, polycarbonate, polyester, copolyester, acrylonitrile, low density polyethylene, polypropylene, or a combination thereof.

48. The package of claim 27, wherein said frangible lidding comprises aluminum.

49. The package of claim 27, wherein the shaped film comprises a plurality of cavities configured to hold a respective plurality of single unit doses of the pharmaceutical product; each cavity having an outlet that permits oxygen to pass out of said cavity and into the sealed outer container.

50. The package of claim 27, wherein an active pharmaceutical ingredient in the pharmaceutical product comprises amorphous atorvastatin.

1. The package of claim 27, wherein an active pharmaceutical ingredient in the pharmaceutical product comprises simvastatin.