PACKAGING FOR OXYGEN-SENSITIVE PHARMACEUTICAL PRODUCTS
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.
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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 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.
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 INVENTIONThe 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.
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:
Exemplary embodiments of the invention will now be described in more detail with reference to the figures.
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
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 Süd-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
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
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 K(D) desiccants jointly distributed by Süd-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 Sep. 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.
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
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.
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.
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
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° 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° 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° 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° 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.
Type: Application
Filed: Dec 2, 2009
Publication Date: Oct 6, 2011
Applicant: Merck Sharp & Dohme Corp. (Rahway, NJ)
Inventors: Matthew P. Bolton (Harleysville, PA), Rey T. Chern (Lansdale, PA), Arthur L. Jaeger (Pennsburg, PA), Matthew Moyer (Douglassville, PA), Anthony P. Panarello (Ewing, NJ)
Application Number: 13/139,020
International Classification: B65D 83/04 (20060101);