Patent Application
20050268573
The present invention relates generally to sterilized medical devices and packaging for sterilized medical devices. In particular, the present invention relates to the packaging of sterilized environmentally sensitive medical devices, such as drug-coated stents.
Most, if not all, disposable medical devices require sterilization prior to or concurrent with packaging. The packaging, which may be in the form of a pouch, bag, tube, box, or other sealed container, will maintain the sterility of the product until it is withdrawn from the packaging for use. A particularly successful system and method for sterile packaging of medical devices relies on use of high-density polyethylene (HDPE) pouches which are used to contain the medical device or other product. The device may be placed in the package prior to sterilization. Sterilization is then effected by placing the package in an environment including a sterilant gas, such as ethylene oxide (EtO), ethylene oxide with nitrogen, various blends of ethylene oxide and carbon dioxide, ethylene oxide with chlorofluorocarbon diluent(s), Oxyfume 2000 series of sterilant, ozone, hydrogen peroxide, chlorine dioxide, or others. The spun HDPE material, such as Tyvek® which is available from Medical Packaging Division of E. I. DuPont de Nemours and Company (DuPont), permits passage of the small molecule sterilant gas while remaining a barrier to bacteria, viruses, and other larger substances which might compromise sterility. It also acts as a barrier to water and other fluids which might detrimentally affect the sterilized contents.
While this packaging system has been highly successful for conventional medical devices, such as catheters, stents, surgical instruments, probes, and the like, it is frequently not suitable for “hybrid” devices which contain coatings or components which are subject to oxygen degradation. For example, the use of drug-eluting stents is promising to revolutionize interventional cardiology. The stents are coated with drug at a central fabrication facility and must be distributed to the end user in sterile packaging. While at least some drugs presently contemplated for use will remain stable during ethylene oxide sterilization, exposure to oxygen during lengthy distribution and storage periods can adversely affect the drug.
For these reasons, it would be desirable to provide improved methods and systems for sterilizing and packaging medical devices.
The present invention is directed to packages of articles such as medical devices, methods of packaging such articles and is particularly directed to packaging articles which are labile when exposed to ambient oxygen concentrations or oxygen containing materials over prolonged periods of time. The present invention provides convenient, effective, and economical approaches for such packaging. The method of packaging, the packages and the packaging systems are particularly suitable for drug-device combinations, such as drug-eluting stents and other drug-coated medical articles. The packaging, the system and method may be utilized for sterilizing articles such as medical devices which are reactive to an ambient environment.
The sterilized packaging embodying features of the invention generally includes a container which has a wall defining at least part of an interior configured to receive one or more articles or products for sterilization. The container has a portion, such as part of a wall forming the container, which is permeable to sterilizing gas, e.g. EtO, ethylene oxide with nitrogen, various blends of ethylene oxide and carbon dioxide, ethylene oxide with chlorofluorocarbon diluent(s), Oxyfume 2000 series of sterilant (from Honeywell Chemicals, Morristown, N.J.), ozone, hydrogen peroxide, chlorine dioxide, or others. The permeable portion allows the article or articles to be placed in the interior, the container sealed, a vacuum applied to the container interior and an environment of sterilizing gas in contact with the permeable portion of the container under conditions which drives the sterilizing gas through the gas permeable portion into the inner chamber to sterilize the one or more products disposed within the chamber.
The container interior is evacuated to about 15 psia to about 0.1 psia preferably 7 psia to about 0.5 psia for the purpose of aspirating the sterilizing gas through the permeable portion of the container. During this time, the container interior can be partially or totally evacuated of oxygen and replaced totally or partially with a non-reactive gas such as nitrogen. This is followed by a steam injection slightly increasing the vacuum to about 0.1 psia to about 5 psia higher than the container interior, preferably to about 1 psia to about 3 psia higher than the container interior. Sterilizing gas maintained about the exterior of the permeable portion of the container is drawn into the container interior through the permeable portion thereof. The pressure of the sterilizing gas within the container interior for effective sterilization is about 20 psia to about 2 psia, preferably about 15 psia to about 5 psia. The dwell time of the sterilizing gas within the container interior at that pressure is about 1 to about 24 hours preferably about 6 to about 18 hours.
After the sterilization, essentially all of the sterilizing gas is removed from the container interior, either by exposing the interior to a vacuum, by flushing or purging the container interior with air or a non reactive gas such as nitrogen, or some combination thereof or both. Usually, after the sterilizing gas is removed from the container interior, the sterilized package is left at room temperature for several days to ensure that the interior is essentially free of sterilizing gas, i.e. less than about 150 ppm, preferably about 10 to about 50 ppm, and typically about 25 ppm.
At this point, at least the permeable portion of the container is sealed to prevent permeation of undesirable gas into the container interior while the one or more articles remain within the interior. The sealing of the container may comprise, for example, sealing the permeable portion of the container with a impermeable patch or partitioning the container to isolate or seal off the portion of the container interior which contains the article(s) from the portion of the container interior in fluid communication with the gas permeable portion of the container. Optionally, the gas permeable portion of the container may be separated, e.g. severed, from the non-gas permeable portion. Another approach is to place the sterilized container inside a impermeable enclosure in order to prevent subsequent gas permeation into the container interior containing the sterilized article(s) through the permeable portion of the container. In the latter instance, any atmosphere within the impermeable enclosure would have to be non-detrimental to the articles disposed in the interior of the container within the enclosure. It would of course also be possible to combine two or more of these approaches, although that will usually not be necessary.
The gas permeable portion of the container will typically be composed of a material which is permeable to the sterilizing gas and impermeable to liquids. Suitable gas permeable materials include high-density polyethylene (HDPE), typically a spun HDPE or other spun olefin. Commercially available materials such as Tyvek® (2FS, 1059B, 1073B or others) are specifically designed for packaging medical devices. Typically, the available materials are coated partially or totally with an adhesive for the purpose of sealing the material to itself or to adjacent materials.
The permeability required for the sterilizing gas to permeate into the interior of the container and contact the one or more articles therein, can vary depending upon the pressure differential, the temperature and the time available for permeation of the sterilizing gas into the interior.
In one embodiment, the container has both a gas permeable portion, as described above, and a gas impermeable portion, typically formed from a metal or polymer film or a metal-polymer composite which is impermeable to gases. By “impermeable to gases,” it is meant that the permeation of oxygen is below about 30 cm3/100 in2/day-atm, preferably below about 2 cm3/100 in2/day-atm. Exemplary suitable material for the gas impermeable portion include metal foils such as aluminum; polymer films such as polyethylene, polyester, polyester (PET)/modified low density polyethylene (LDPE) laminated film; or any combination thereof (e.g., metalized PET).
In one embodiment, the impermeable portions of the container may be incorporated with suitable oxygen scavenger materials or have adjacent thereto a partial or complete film of suitable oxygen absorbers or scavengers, such as ethylene-cyclohexenylmethyl acrylate copolymer (ECHA) and ethylene-methylacrylate-cyclohexeneylmethyl acrylate terpolymer (EMCM) described in Ching et al. (2001), referenced above. Other oxygen scavengers include ethylenically unsaturated polymer, ferrous oxide (partially oxygenated iron), titanium oxide, activated carbon with sodium ascorbate, diethylhydroxylamine (DEHA), carbohydrazide, combination of above, or other chemicals which are readily reactive or combine with oxygen gas. When suitable oxygen scavenger materials are incorporated or lie adjacent to the impermeable portion, oxygen within the interior of the container can be removed to very low levels. Suitable oxygen levels in the container interior in most instances will be below 5% oxygen, preferably below 1%, more preferably below 0.1%.
The permeable portion or portions of the container may be incorporated with suitable oxygen scavenger materials or may be positioned adjacent to a partial or complete film of suitable oxygen scavengers. Not only oxygen is removed from the package, oxygen gas trying to permeate through the permeable portion will be limited from entering the package.
Oxygen scavengers can be placed inside the package, such as inside a permeable packet that is placed within the interior of the container or within the interior of an enclosure surrounding the container. Oxygen scavengers can be embedded in a protective sheath over or adjacent to the article within the inner chamber. The sheath can be a polymer incorporated with suitable oxygen scavenger, or it can be formed of a polymer fully or partially coated with a suitable oxygen scavenger, or it can be made from suitable oxygen scavenger.
Another approach for sealing the gas permeable enclosure is to place a patch, cover, or other gas impermeable barrier over that portion of the enclosure which is initially gas permeable. For example, a window or other area of the enclosure, typically a portion of a pouch, may be formed from gas permeable Tyvek or other material, while the remaining portion of the pouch or other enclosure is formed from a gas impermeable foil, polymer, or other material. A patch sized to cover the gas permeable window may be provided to be sealed over the window after the initial sterilization has been completed.
Another approach for sealing the gas permeable enclosure is to place the enclosure inside of a separate gas impermeable enclosure after the initial sterilization has been performed.
Preferred gas impermeable materials will also be non-transmissive for light, UV radiation, heat, and the like. The gas impermeable materials will also be impermeable to moisture.
In some cases, it will be further desirable to provide desiccant materials in or over a portion of the impermeable enclosure in order to sequester any moisture which may remain within the pouch after final sealing. The desiccant may be coated over or laminated within the polymer or metal film which comprises the gas impermeable enclosure. Alternatively, a small inserter canister of the desiccant material may be provided within the enclosure, similar to the desiccant placed in conventional pharmaceutical packaging.
These and other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying exemplary drawings.
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The present invention relies upon gas sterilization where the articles to be sterilized are first placed and sealed within a container. At least a portion of the container is gas permeable so that one or more articles within the interior of the container may be sterilized by placing the container in an environment of the sterilizing gas, typically an environment of essentially all ethylene oxide. Once the one or more articles are placed in the interior of the container, the interior may be evacuated to remove ambient gases which may be present. Sterilizing gas is introduced into the container interior through the permeable portion of the container and maintained within the container interior at sufficient levels to sterilize the articles therein. After sterilization is complete, the interior is preferably evacuated to remove the sterilizing gas, and the container is modified, partitioned, replaced into a secondary enclosure, or otherwise placed in a condition so that further gas exchange between the exterior and interior of the container is inhibited or prevented. The method and system of the present invention provide for convenient and effective sterilization of articles using a conventional gas sterilant, and prevent the degradation of the sterilized articles or portions thereof by subsequent exposure to oxygen, water, or other ambient gases.
EtO sterilization and packaging according to the present invention usually employs five major steps, including: pre-sterilization conditioning, sterilization, evacuation, air wash, and aeration. The conditioning step includes placing the one or more articles to be sterilized into the interior of the container, sealing the container and evacuating the gas from the container interior. The sterilization step includes introducing the sterilant into the interior of the container by passing a sterilizing gas through the permeable portion of the container, establishing the appropriate operating parameters, such as temperature, pressure, and relative humidity, within the inner chamber and keeping these conditions in the chamber for a pre-determined period of time for effective sterilization of the articles. The container may be placed in a sterilization vessel with the atmosphere surrounding the container within the vessel being adjusted to control the procedure. The evacuation step after sterilization includes the removal of EtO from the container interior by one or more vacuum washes and/or one or more purges with air or nitrogen, or combinations thereof. In order to further remove residual EtO from the inner chamber, the container package then undergoes aeration which can be performed in either the sterilization vessel or in a separate aeration chamber.
The EtO sterilization process embodying features of the present invention is performed at process parameters which are particularly useful and effective in the sterilization of an article which is at least in part formed of a reactive or labile material, such as a therapeutic agent coated on the device, while minimizing adverse effects on the integrity of the reactive or labile material during and post sterilization process. The packaged device sterilized according to the present invention enables enhanced product shelf-life and greater confidence in the integrity and suitability of the sterilized aged device.
The sterilization step is preferably carried out at a temperature below 30° C. with a dwell time of about 6 to 18 hours or greater. While ethylene oxide is reactive in both liquid and gaseous phase, it is preferred to employ EtO in gaseous phase to increase penetration of the gas into the device/package and its reactivity. Either or both, higher temperature and lower pressure as well as relative humidity can increase gas penetration and/or reactivity.
The boiling point for ethylene oxide at atmospheric pressure is about 10° C. (51° F.) where EtO is in gaseous state. Therefore, this temperature of 1° C. is the preferred lowest temperature at which to perform the sterilization step at atmospheric pressure. Alternatively, the temperature of the container interior can further be reduced below 10° C. by further reducing the pressure to below atmospheric pressure. By way of example, the sterilization step can effectively be performed at a temperature of 0° C. by reducing the pressure within the container interior to about 4 psi (pounds per square inch).
The following examples are offered by way of illustration, not by way of limitation.
A drug eluting stent mounted onto the balloon of a stent delivery catheter (a drug eluting stent system) is packaged in a foil pouch that has a permeable portion or patch formed of Tyvek®. The pouch is subjected to a vacuum within the inner chamber with a surrounding atmosphere of EtO gas at temperatures of 60° C. to sterilize the drug eluting stent and delivery catheter. After sterilization, the pouch is resealed with the stent and delivery system within the post seal area and the Tyvek patch outside the post-seal area. The foil pouch minimizes the light exposure as well the oxygen and moisture exposure to the sterilized contents of the container.
A drug eluting stent mounted onto the balloon of a stent delivery catheter is packaged in a Tyvek pouch along with ferrous oxide as an oxygen absorber and desiccant. The pouch is closed, subjected to ethylene oxide gas which permeates the pouch. After sterilization, the Tyvek pouch is evacuated and purged with nitrogen and air to remove essentially all EtO and then placed inside a gas impermeable foil pouch. The foil pouch is evacuated by vacuum to remove the remaining air and nitrogen gas, and then finally sealed. The foil pouch minimizes the exposure of the sterilized product within the Tyvek pouch to light and to oxygen and moisture, thus providing a long shelf life.
A drug eluting stent crimped onto a PTCA catheter or a drug eluting stent system is packaged on Tyvek pouch along with ferrous oxide oxygen absorbers and desiccant. The pouch is sterilized by ethylene oxide gas with sterilization temperatures of about 55° C. After sterilization, the sterilized Tyvek pouch with the stent system sealed inside is inserted inside a foil pouch. The foil pouch is sealed using a vacuum sealer that first purge the bag with nitrogen gas which replaces the air inside the foil pouch and that finally seal the foil pouch. This minimizes the light exposure as well as limit oxygen and moisture exposure.
A drug eluting stent mounted onto the balloon of a stent delivery catheter is packaged in an essentially gas impermeable foil container that has a Tyvek patch which allows for gas permeability through the gas permeable patch. The pouch is exposed to ethylene oxide gas using the following cycle:
A drug eluting stent mounted onto the balloon of a stent delivery catheter is packaged on foil pouch that has a Tyvek patch (i.e., breathable). The pouch is exposed to ethylene oxide gas using the following cycle:
A drug eluting stent is crimped onto the balloon of a stent delivery catheter. A protective sheath made from ethylene-cyclohexenylmethyl acrylate copolymer (an oxygen absorber) is inserted over the drug eluting device. The drug eluting stent and delivery catheter is packaged in a Tyvek pouch, the pouch is sealed and then sterilized by ethylene oxide gas at normal sterilization parameters. The protective sheath formed of oxygen absorbing polymer material minimizes the oxidative degradation of the drug eluting stent by limiting exposure to oxygen gas.
While the invention has been described herein primarily in terms of packaging medical devices, and in particular to drug eluting stents, it is also suitable for sterilization and packaging of other articles, including foods, pharmaceuticals, diagnostic and assay systems, sensitive electrical components, chemical system components, and the like, where the ability to sterilize articles after initial packaging has been completed is desirable. The methods and systems of the present invention are simple to perform, require minimum changes from existing packaging practices, and provide a package to the end user which is as convenient and easy to use as prior packaging systems.
Many other alterations and modifications may be made by those of ordinary skill in this art, without departing from the spirit and scope of this invention. For example, the method and packaging may be utilized for packaging articles treated by gases other than sterilizing gases The illustrated embodiments have been shown only for purposes of clarity and the examples should not be taken as limiting the invention as defined in the following claims. The claims are intended to include all equivalents, whether now or later devised.
Moreover, individual features of embodiments of the invention may be shown in some drawings and not in others, but those skilled in the art will recognize that individual features of one embodiment of the invention can be combined with one or more features of another embodiment. Accordingly, it is not intended that the invention be limited to the specific embodiments illustrated or described. It is therefore intended that this invention to be defined by the scope of the appended claims as broadly as the prior art will permit.
Terms such a “element,” “member,” “component,” “device,” “section,” “portion,” “means,” “steps” and words of similar import when used herein shall not be construed as invoking the provisions of 35 U.S.C. §112(6) unless the following claims expressly use the term “means” followed by a particular function without specific structure or expressly use the term “step” followed by a particular function without specific action. All patents and patent applications referred to above are hereby incorporated by reference in their entirety.
This application is based upon and claims priority to Provisional Application Ser. No. 60/537,972, filed on Jan. 20, 2004 and Provisional Application Ser. No. 60/540,828, filed on Jan. 29, 2004. Both applications are incorporated herein by reference in their entireties.
| Number | Date | Country | |
|---|---|---|---|
| 60540828 | Jan 2004 | US | |
| 60537972 | Jan 2004 | US |
